Skip to main content
Download PDF

Progress and application of adipose-derived stem cells in the treatment of diabetes and its complications

Stem Cell Research & Therapy volume 15, Article number: 3 (2024) Cite this article

Abstract

Diabetes mellitus (DM) is a serious chronic metabolic disease that can lead to many serious complications, such as cardiovascular disease, retinopathy, neuropathy, and kidney disease. Once diagnosed with diabetes, patients need to take oral hypoglycemic drugs or use insulin to control blood sugar and slow down the progression of the disease. This has a significant impact on the daily life of patients, requiring constant monitoring of the side effects of medication. It also imposes a heavy financial burden on individuals, their families, and even society as a whole. Adipose-derived stem cells (ADSCs) have recently become an emerging therapeutic modality for DM and its complications. ADSCs can improve insulin sensitivity and enhance insulin secretion through various pathways, thereby alleviating diabetes and its complications. Additionally, ADSCs can promote tissue regeneration, inhibit inflammatory reactions, and reduce tissue damage and cell apoptosis. The potential mechanisms of ADSC therapy for DM and its complications are numerous, and its extensive regenerative and differentiation ability, as well as its role in regulating the immune system and metabolic function, make it a powerful tool in the treatment of DM. Although this technology is still in the early stages, many studies have already proven its safety and effectiveness, providing new treatment options for patients with DM or its complications. Although based on current research, ADSCs have achieved some results in animal experiments and clinical trials for the treatment of DM, further clinical trials are still needed before they can be applied in a clinical setting.

Background

Diabetes mellitus (DM) is an endocrine disease that is prevalent worldwide, and its incidence has been rapidly increasing in recent years. According to the World Health Organization, DM is expected to affect over 693 million people by 2045 [1]. DM is a metabolic disorder that is marked by either absolute or relative insulin deficiency or insulin resistance, resulting in a clinical syndrome that manifests as a range of symptoms [2]. In addition, DM is a systemic vascular disorder that occurs when metabolic irregularities in the body cause glucose buildup, leading to a range of diabetic vascular complications, including chronic microvascular disease and macrovascular atherosclerosis [3, 4]. The disease can affect multiple organs and systems in the body and it is a leading cause of premature death [5]. The occurrence of DM is caused by the combined effects of genetic and environmental factors [6, 7]. DM is a complex condition that can be broadly categorized into four types based on its etiology: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes, and other types of diabetes [8]. Currently, the treatment of DM primarily relies on administration of exogenous insulin or oral intake of hypoglycemic drugs. However, these methods can only alleviate the symptoms of patients and cannot cure DM completely [9]. Therefore, once diagnosed with DM, patients need to continuously take medication or use insulin to control blood sugar, alleviate symptoms, and prevent disease progression [10]. This has a multifaceted impact on the daily life of patients, not only requiring them to constantly monitor the side effects and risks of hypoglycemic drugs but also inflicting a heavy economic burden to their families and society [11]. Therefore, exploring alternative treatments for DM and maintaining their therapeutic effects is necessary.

Various diseases can be treated with stem cells because of their ability to self-renew, differentiate into other cell types, and regulate immunity. There is an ongoing ethical debate surrounding the procurement and utilization of embryonic stem cells [12]. Compared with other stem cells, the adipose-derived stem cells (ADSCs) have wider and more convenient sources, such as adipose tissue in the abdomen, limbs, and face areas and obtaining ADSCs only causes minor damage [13, 14]. Animal models of DM have been treated with ADSCs, and some human clinical trials (phase I/II) have also utilized these cells [15], with a few even progressing to phase III trials [16]. This article focuses on the research progress of ADSCs in the treatment of DM and its complications and explores its underlying mechanisms of action.

ADSCs

In recent years, there have been experiments using mesenchymal stem cells (MSCs) from different sources to treat diabetes. The early focus was on bone marrow-derived MSCs (BM-MSCs), which contain various types of stem cells including hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells. After the application of BM-MSCs, the patient’s insulin requirement decreased, insulin sensitivity increased, and β-cell function improved [17,18,19]. However, BM-MSCs are obtained invasively through the femur or iliac bone, which is not only painful but also yields a small quantity of cells and carries the risk of infection after extraction [20]. Umbilical cord-derived MSCs have a higher similarity to embryonic stem cells and possess greater differentiation potential compared to other common types of MSCs. After the infusion of Umbilical cord-derived MSCs, there was an increasing trend in the number of regulatory T (Treg) cells and a slight decrease in insulin requirements [21]. Jiang et al. [22] studied the use of placenta-derived MSCs in treating type 2 diabetes mellitus (T2DM), which resulted in a decrease of ≥ 50% in insulin requirements and improvement in kidney and heart function to some extent. However, MSCs derived from fetal appendages are obtained after birth, which poses potential risks of allogeneic stem cells and corresponding ethical issues [23]. Following BM-MSCs and fetal appendage-derived MSCs, ADSCs have become an alternative choice for clinical cell therapy due to their easy accessibility, abundant source, subcutaneous location, and longer culture time [24, 25]. Compared with other types of MSCs, such as BM-MSCs, ADSCs have similar proliferation and differentiation abilities and can be obtained with less pain [26, 27]. The cell surface molecules of ADSCs have been found to include differentiation clusters such as CD9, CD29, CD36, CD44, CD49d, CD49e, CD51, CD55, CD73, CD82, CD105, CD106, CD271, and von Willebrand factor (vWF), among which CD36 and CD49d are unique to ADSCs, whereas CD3, CD11a, CD11c, CD31, CD33, CD45, CD133, c-Kit, Lin, major histocompatibility complex II, and human leukocyte antigen (HLA)-DR surface proteins are lacking [28].

In some experiments, ADSCs showed genetic and epigenetic stability [29] and did not show significant immune response [30] and tumorigenicity [31]. Additionally, there have been no significant safety issues observed when ADSCs are transplanted into animal models [16, 29] or when used in human clinical trials [32]. According to existing research, ADSCs have not shown apparent safety issues and have a low potential for stimulating anti-HLA immune responses. There have been few reports of adverse reactions to ADSC-based treatments, but the long-term immunogenicity effects still need to be considered [33]. At the same time, in some studies, researchers have observed pulmonary embolism and infarction after injecting ADSCs into mice or patients [34, 35]. Other literatures have also reported an increase in levels of thrombin-antithrombin and D-dimer after intravenous infusion of allogeneic ADSCs, both of which are markers of coagulation activation [36].

Several experiments have explored the functions of ADSCs in different cell lineages [37, 38]. The advantages of ADSCs in cell replacement therapy and cell repair functions have been validated using animal models [39]. Some studies have demonstrated that direct intravenous or in situ injection of ADSCs restores the vitality of transplanted cells, which then differentiate and integrate ADSC functions in the body [40]. Transplanted ADSCs secrete several repair molecules such as neurotrophic factors [41], chemokines [42], immune regulatory factors [43], and inflammation regulatory factors [44]. To date, the therapeutic ability of ADSCs for diseases has been verified in several clinical trials [16, 38, 45,46,47]. These findings provide evidence of the safety of ADSCs and their potential in regenerative medicine, suggesting that ADSCs hold promise for use in human clinical trials.

Application of ADSCs in type 1 diabetes mellitus

In T1DM, due to autoimmune reactions, T helper 1 (Th1) cells attack pancreatic β cells, leading to the loss of insulin-producing cells (IPCs) [48]. The presence of macrophages, dendritic cells, natural killer cells, and lymphocytes also accelerates the progression of T1DM [49]. CD4+ T cells and inflammatory factors, including interferon-gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-α), play important roles in the process of β cell damage [50]. As pancreatic β cells are the sole producers of insulin in the body, their death leads to a complete absence of insulin secretion, ultimately resulting in the development of diabetes [51].

Long-term complications, such as vascular degeneration, renal failure, and blindness, cannot be prevented with the current interventions. The methods that have been applied in clinical practice to replace β cells mainly include whole pancreas and islet cell transplantation [52]. However, there are still many obstacles to the development of these methods, such as a lack of suitable islet donors, the need for lifelong immunosuppressive therapy after transplantation, and the exhaustion of transplanted organs and cells in diabetic patients, all of which restrict the development of this technology [53]. In recent years, ADSCs have gradually gained the attention of researchers owing to their ability to self-renew, differentiate into other cell lineages, and regulate the immune system. It is hoped that the characteristics of ADSCs can be utilized to achieve the goal of curing T1DM.

Animal models and human clinical trials

In the application of ADSCs to animal models, undifferentiated ADSCs or differentiated IPCs from ADSCs can be transplanted via intravenous, intraperitoneal, or renal capsule injection [44, 50, 54,55,56,57,58,59,60,61], as shown in Table 1. According to research, the mortality rate of mice within 24 h is close to 85% when a large number of ADSCs are administered through the tail vein. Reducing the injection quantity can avoid similar occurrences [35]. Some studies use intraperitoneal or renal capsule injection to attempt to avoid this problem [50, 55, 57, 58]. Currently, the use of ADSCs for treating T1DM patients is still in the preliminary research stage. There are not many studies related to this direction, and there are differences in administration routes. Currently, the administration routes that have been used include differentiating ADSCs into IPCs and then injecting them into the portal vein, thymus, or subcutaneous tissue [62]. Alternatively, ADSCs can be induced to become insulin-secreting ADSCs and co-transplanted with unfractionated cultured bone marrow cells into the portal vein of diabetic patients [15, 63]. It is administered through portal vein infusion because it allows the cells to stay in the liver microcirculation, and the liver, being a tolerant organ, would not reject cell engraftment. However, there is currently no consensus on the specific administration method that can achieve better therapeutic effects. In addition, regarding the number of transplanted ADSCs, there are also variations in current studies. Some studies used a level of 106 cells, while others used a level of 108 cells, as shown in Table 2 [15, 62, 63]. However, the specific number of cells required to achieve therapeutic effects while minimizing the potential risks of ADSCs still needs further investigation.

Table 1 Animal experiments of application of ADSCs in T1DM
Full size table
Table 2 Clinical trials using ADSCs in T1DM
Full size table

Mechanism of ADSCs in T1DM

ADSCs differentiation to IPCs

According to current research, one of the mechanisms for using ADSCs to treat T1DM is to transplant differentiated IPCs or ADSCs into animals or humans and utilize their ability to secrete insulin. Timper et al. [68] conducted the first experiment to differentiate human ADSCs into IPCs. The glucagon-like peptide-1 (GLP-1) was used in another study to induce differentiation of human ADSCs into IPCs. Insulin and C-peptide were released by IPCs in a glucose concentration-dependent manner [61]. Additionally, the injection of differentiated IPCs or undifferentiated ADSCs into diabetic animals resulted in a rise in insulin levels in diabetic animal serum and a return to normal blood glucose levels, as shown in Table 1.

The differentiation of ADSCs into IPCs is influenced by many factors, including the Wnt signaling pathway. Pancreatic development, islet function, and insulin production and secretion depend on this pathway [69]. Some studies have found that activating the Wnt signal can induce ADSCs of rats to differentiate into IPCs, which can be identified by detecting the expression levels of genes such as INS (insulin), pancreatic and duodenal homeobox 1 (PDX1), and GLP-1, as well as the protein expression levels of PDX1, cytokeratin 19, nestin, insulin, and C-peptide [70]. Additionally, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is also crucial in the differentiation of IPCs. The PI3K/Akt signaling pathway is significantly activated during the differentiation process of ADSCs into IPCs, mediated by the stromal cell-derived factor 1α and basic fibroblast growth factor [71]. According to a recent study, the upregulation of miR-375 is a crucial aspect of ADSC differentiation into IPCs [72]. A further aspect of its expression is that it is related to the secretion of insulin as well as cell proliferation [73]. Finally, IPCs are also developed through the Sonic hedgehog signaling pathway. To promote the development of IPCs, it is necessary to remove the inhibition of the Sonic hedgehog signaling pathway on them [74].

Restore the function of residual pancreatic islets in the body

ADSCs can not only serve as a source of IPCs, but also support the function of residual pancreatic islets in patients with diabetes [75]. In these experiments, it was observed that the function of residual pancreatic was restored after injection of ADSCs or IPCs differentiated from ADSCs [50, 54, 59, 64, 66, 67, 76]. These transplanted ADSCs release a variety of cytokines, including interferon-induced protein 10, eosinophil chemotactic factor (eotaxin), vascular endothelial growth factor (VEGF), and tissue inhibitor of metalloproteinase 1 (TIMP-1), all of which can prevent apoptosis of β cells and promote β cell proliferation [54]. In addition, transplantation of ADSCs effectively improved the autoimmune mechanism of diabetes in non-obese diabetic mice by reducing the Th1 immune response and inducing the proliferation of Tregs to improve the high blood glucose levels of early-onset autoimmune diabetes [50]. Compared to the untreated diabetes group, the IPCs transplantation group showed increased pancreatic regeneration, as well as a significant increase in the number of islet cells, islet area and density, and C-peptide immunoreactive area. The percentage of collagen fiber area in the islets of the IPCs transplantation group also decreased [67].

Maintain the function of pancreatic islet grafts in vivo or in vitro

ADSCs can also be used for preconditioning of pancreatic islet grafts in vitro to enhance the viability of the transplanted islets. Existing studies have shown that co-culturing ADSCs with syngeneic islets in vitro can significantly increase the level of insulin release compared to islets cultured alone. These pre-cultured pancreatic islet transplants have a higher success rate during transplantation and significantly improve the hyperglycemic condition in diabetic mice [54, 55, 76,77,78,79]. Eotaxin [54], VEGF [54, 77], TIPP-1 [54], extracellular matrix (ECM) components, annexinA1 [78] and fibroblast growth factor 2 expression [77] in ADSCs seem to be upregulated as a result of paracrine communication between pancreatic islets and ADSCs.

In addition to pre-treating pancreatic islet grafts, studies have attempted co-transplantation of ADSCs and islets to explore the effectiveness of this approach [55, 76, 80,81,82]. Adipose-derived stem cells (ADSCs) can promote the generation of a new vascular network within the co-transplanted islets by secreting various angiogenic factors, including VEGF [77, 83], hepatocyte growth factor [83], kinase insert domain receptor [83], transforming growth factor-beta (TGF-β) [78], and IL-8 [84]. ADSCs can also significantly inhibit the production of pro-inflammatory cytokines such as IFN-γ [78], TNF-α [76, 85], IL-6β [76], and IL-17 [78]. ADSCs can suppress the infiltration of CD4+ and CD8+ T cells [80] and macrophages [85], thereby reducing the inflammatory response within the co-transplanted islets. Co-transplantation of ADSCs and islets into STZ-induced diabetic mice significantly increased vascularization of the transplanted islets and significantly suppressed infiltration of inflammatory cells, resulting in increased survival time of the co-transplanted islets [80].

Successfully differentiating ADSCs into IPCs requires a specific combination of culture media, including insulin, transferrin supplement, and nicotinamide. This means that in clinical applications, a feasible method needs to be found to provide these media components. Although ADSCs can differentiate into IPCs, their insulin secretion capacity is still relatively low. Therefore, further optimization of the differentiation process is needed to improve the efficiency and functionality of ADSCs differentiating into IPCs. Further research is also needed to determine the transplantation method and the number of transplanted cells, which will contribute to the translation of ADSCs into a clinical therapeutic approach.

Application of ADSCs in type 2 diabetes mellitus

T2DM is distinguished by insulin resistance in insulin-responsive tissues and impaired insulin secretion by pancreatic β cells. This type of diabetes accounts for 85–95% of all DM cases [86]. Additionally, excessive nutrition can lead to inflammation in adipose tissue, affecting multiple tissues and worsening insulin sensitivity and β cell function [86, 87].

Currently, there are few clinical trials on the treatment of T2DM with ADSCs. Most applications are still being tested in animal experiments, which indicate that injecting ADSCs through the tail vein, peritoneum, and renal capsule of mouse can improve hyperglycemia by restoring pancreatic β cells, reducing inflammation, and increasing insulin sensitivity [88, 89]. The exploration of some of these mechanisms has provided new directions for the clinical application of ADSCs [90,91,92,93]. See Table 3 for details.

Table 3 Animal experiments of application of ADSCs in T2DM
Full size table

Mechanism of action of ADSCs in T2DM

Improvement of insulin resistance

Transplantation of ADSCs in vivo was discovered to restore the count of glucose transporter 4 and insulin receptors on the cell membranes of skeletal muscle, liver, and adipose tissue, and increase the phosphorylation of insulin receptor substrate 1 in a high-fat diet/STZ-induced T2DM rat model. Consequently, this alleviated the state of hyperglycemia and insulin resistance [89]. Insulin resistance may be linked to systemic chronic inflammation related to obesity, where inflammatory factors can impede the phosphorylation of the insulin receptor substrate and PI3K in the insulin signaling pathway, resulting in obstructed signal transduction and insulin resistance [96]. Studies have shown that after ADSCs are injected, TNF-α, IL-6, and IL-1β in T2DM rats are significantly reduced [89]. Injection of ADSCs reduces liver weight and fat degeneration by inhibiting the expression of pro-inflammatory genes and reduces the level of insulin resistance by increasing the expression of insulin receptor substrate [88], indicating that injection of ADSCs has a favorable effect on liver fat degeneration.

Promotion of insulin production

In addition to insulin resistance, the dysfunction of pancreatic β cell also plays a crucial role in the development of T2DM. Animal experiments have shown that after different sources of ADSCs are transformed into IPCs in vitro and transplanted into mice, they can effectively reduce the blood glucose levels compared with injecting undifferentiated ADSCs and blank groups [91, 94]. ADSCs can facilitate the restoration of remaining pancreatic islet function and enhance the quantity of pancreatic islet β cells. They repair pancreatic islet cells by decreasing caspase-3 activity and promote pancreatic islet vascularization by secreting angiogenic factors such as VEGF, insulin-like growth factor 1, hepatocyte growth factor (HGF), and vWF, thus contributing to the regeneration of pancreatic islet β cells [89].

Regulating liver glucose metabolism

Within 24 h after infusion of ADSCs, the hyperglycemic state of a T2DM rat model can be quickly relieved. This rapid action cannot be fully explained by improving β cell function and insulin resistance. The liver maintains normal blood glucose levels by regulating glycogen metabolism and gluconeogenesis. A 24-h period after ADSC infusion, T2DM rat models’ liver enzyme levels increased related to glucose metabolism, suggesting that ADSCs have a rapid effect on glucose homeostasis [93]. However, only this one research has reported similar phenomena, and the specific mechanism has not been clearly expounded.

However, it is worth noting that the clinical application of ADSCs in T2DM treatment is still in its early stages and requires further research to fully understand their safety and efficacy. Many technical and regulatory issues still need to be addressed. Despite these challenges, the potential benefits of ADSCs in T2DM treatment are significant, and their use represents a promising direction for future research and development in the field of regenerative medicine.

The potential mechanisms of ADSCs application in DM are summarized in Fig. 1.

Fig. 1
figure 1

The application and mechanism of ADSCs in Diabetes Mellitus. ADSCs adipose-derived stem cells, IPCs insulin-producing cells. All of the elements in the diagram were provided by Figdraw (http://www.fgdraw.com)

Full size image

Application of ADSCs in DM complications

Diabetic wounds

Diabetic wounds are a chronic complication of DM, which severely affect the quality of life of patients with diabetes. Diabetic foot ulcer is the most serious form of diabetic wounds [97], which is clinically manifested as peripheral neuropathy and lower limb ischemia, leading to sensory disorders, muscle atrophy, rest pain, and necrosis [98]. Moreover, if diabetic wounds are not treated properly, they may lead to amputation or even death [99]. Peripheral neuropathy can decrease the skin elasticity and secretion function of diabetic wounds, making patients with diabetes more prone to form wounds on the skin [100]. At the cellular level, DM damages macrophage function and prevents keratinocytes and fibroblasts from playing their roles in epithelial healing [101]. In addition, hyperglycemia causes endothelial damage in peripheral blood vessels, which further reduces skin perfusion and promotes the formation of skin ulcers [101].

Currently, numerous animal and clinical human experiments have been carried out on the application of ADSCs in the treatment of diabetic wounds, as shown in Table 4 and Table 5.

Table 4 Animal experiments of application of ADSCs in diabetic wounds
Full size table
Table 5 Clinical trials using ADSCs in diabetic wounds
Full size table

In one study, at 6 months, the diabetic foot ulcer closure rate was 100% for 51 subjects and ≥ 75% for 8 subjects. At 12 months, 100% of the DFUs in 50 subjects had healed, and ≥ 85% had healed in 4 subjects [122]. In another study, 59 patients with diabetic foot ulcers were randomly divided into an ADSCs treatment group and a polyurethane film control group. At week 8, the complete closure rate of wounds in the ADSCs treatment group was 73%, while in the control group was 47%. At week 12, the complete closure rate of wounds in the ADSCs treatment group was 82%, while in the control group was 53%. The median time for wound closure in the ADSCs treatment group and the control group was 28.5 days and 63.0 days, respectively [125]. The healing time of wounds in the group receiving allogeneic ADSC injection was 31 days, which was significantly shorter than that of the control group [126].

According to existing research, there are several possible mechanisms proposed for ADSCs therapy in the treatment of diabetic wounds. ADSCs have paracrine function and can secrete various cytokines, such as VEGF, fibroblast growth factor2, keratinocyte growth factor, TGF-β, platelet-derived growth factor, HGF, and collagen [127]. ADSCs also have the ability to directly differentiate into epithelial components and endothelial cells, playing an important role in dermal remodeling and wound healing [128]. In addition, ADSCs can inhibit the inflammatory response in diabetic wounds through paracrine function. After applying ADSCs, the expression of IL-6, IL-8 [129], and TNF-α [112] in diabetic wounds is significantly downregulated, and inflammatory cell infiltration is reduced [102].

Existing studies have confirmed that ADSCs can promote regulation, neovascularization, and fibrosis, and can be used as a potential therapy for the treatment of diabetic wounds. However, there are still relatively few clinical experiments on the application of ADSCs in the human body [122,123,124,125,126]. Further research is needed to determine more efficient methods of utilizing ADSCs for the treatment of trauma or surgical wounds in diabetic patients, in order to achieve the goal of treating diabetic wounds.

Diabetic retinopathy

Diabetic retinopathy is a microvascular disease of the retina caused by retinal ischemia [130]. Increasing evidence suggests that diabetes-related neurodegeneration occurs prior to retinal vascular endothelial changes, indicating that diabetic retinopathy should be considered a neurovascular degenerative disease [131, 132].

The self-renewal ability of pericytes and endothelial cells in the eyes of patients with diabetes is impaired, and the repair ability of these two cell types is continuously depleted [133]. Subsequently, the blood flow of capillaries decreases, resulting in hypoxia in adjacent areas of the retina. This hypoxic environment causes upregulation of VEGF, leading to increased vascular permeability [134] and the development of diabetic macular edema, ultimately resulting in loss of visual function [135]. Continuous hyperglycemia leads to abnormal function of ganglion cells, resulting in changes in retinal electrical activity before vascular endothelial changes occur [136]. In addition, hypoxia-inducible factor-1α is induced by hypoxia in the retina, which increases the expression of VEGF regulated by hypoxia, causing intraretinal microvascular abnormalities in the retina [137]. Proliferation and migration of vascular endothelial cells can eventually lead to the formation of neovascularization in the retina, characterized by proliferative diabetic retinopathy.

Currently, the primary treatment for diabetic retinopathy is still aimed at controlling blood sugar to slow down the progression of the disease [138,139,140,141]. When the disease progresses to macular edema or proliferative diabetic retinopathy that threatens vision, laser therapy can be used clinically to destroy the surrounding retina and reduce oxygen demand to help alleviate the disease [142]; however, laser therapy may cause many complications, such as decreased visual acuity, thickening of the retina, and loss of visual field [143].

Recently, some studies explored a new method for treating diabetic retinopathy by using ADSCs. This method is based on the ability of ADSCs to differentiate into pericytes, which can prevent neurovascular damage and promote the regeneration of damaged retinas, thereby achieving treatment for diabetic retinopathy [144, 145].

Thomas A. Mendel et al. founded in animal experiments that ADSCs injected into the vitreous body of OIR mice can differentiate into pericytes and integrate into retinal blood vessels, delaying the breakdown of the blood-retinal barrier. After two months of injection, approximately 80% of capillary loss can be prevented. Injection of ADSCs before vascular instability in OIR mice can reduce capillary loss by approximately 50% [146]. In another study, the histopathology of retinal tissue in T1DM nude mice showed a significant reduction in vascular leakage and apoptosis of retinal vascular cells around the eyes that received ADSCs injection compared to those that received saline injection. Additionally, the expression of inflammatory genes related to diabetic retinopathy was downregulated. Furthermore, in vitro experiments confirmed that co-culturing ADSCs with retinal endothelial cells can improve the survival rate of endothelial cells. These findings suggest that ADSCs have a protective effect against retinal damage caused by diabetes [147].

Overall, based on current perspectives, ADSCs can be a potential method for the future treatment of diabetic retinopathy. However, determining the optimal transplantation method and localization of ADSCs remains a challenge. Current research mainly focuses on local or intravenous injection of ADSCs, and further studies are needed to ensure the accurate location of cells in the damaged retinal area after injection into the eye. Additionally, although current research suggests that adipose-derived stem cells can protect retinal blood vessels, the specific therapeutic mechanisms are still unclear and require further investigation. Furthermore, the current research on the use of ADSCs for the treatment of diabetic retinopathy is limited to animal experiments, and there is still a long way to go before ADSCs can be used as an actual treatment method.

Diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and the main cause of death for patients with T1DM and T2DM [148]. The main feature of DN is the abnormality of kidney function and morphology. Abnormalities in the morphology of glomeruli include increased glomerular size, podocyte injury, gradual accumulation of ECM, mesangial matrix expansion, thickening of the glomerular basement membrane, and the appearance of glomerulosclerosis and interstitial fibrosis. Functional abnormalities include proteinuria, decreased glomerular filtration rate, and increased glomerular perfusion and filtration [149]. Long-term high blood sugar, high blood pressure, and local inflammation can lead to progressive and irreversible damage to the glomeruli and renal tubulointerstitium, ultimately resulting in renal dysfunction and eventually progressing to renal failure [148].

Under special conditions, podocytes and mesangial cells release various mediators to promote functional and morphological changes in glomeruli [150]. Mediators such as VEGFA, TGF-β1, angiotensin II, angiotensin-converting enzyme, inflammatory cytokines, and glomerular capillary remodeling cytokines can induce pathological changes in the kidneys. They activate cell remodeling signaling pathways, increase ECM synthesis, or activate NADPH oxidase, leading to increased oxidative stress levels. These changes can alter cell morphology and contribute to the development of kidney disease [151]. Furthermore, persistent hyperglycemia can generate advanced glycation end products (AGEs) in plasma and tissues, which can exacerbate DN via two mechanisms. AGEs can bind to matrix proteins like laminin and type IV collagen, inhibiting their breakdown by matrix metalloproteinases. This leads to an accumulation of excessive ECM proteins and fibrosis [152]. AGEs can bind to receptors on podocytes and mesangial cells, causing the secretion of fibrosis-promoting factors like VEGF, connective tissue growth factor, and TGF-β1, and an increase in NADPH oxidase expression. These factors promote the proliferation, expansion, and hypertrophy of glomerular cells [153]. Inflammation plays a significant role in the development of DN. As glomerular function deteriorates, inflammatory cells infiltrate the renal interstitium and release factors that worsen the progression of DN, including TNF-α, IFN-γ, IL-1, IL-6, and MCP-1. Inflammatory cells can also activate NADPH oxidase, leading to local oxidative stress responses [154].

Increasing evidence suggests that exosomes derived from stem cells are relatively safe and effective in treating kidney diseases in rat or mouse models [155]. The exosomes secreted by MSCs play a significant protective role in acute kidney injury and chronic kidney disease [156]. Exosomes are nanoscale membrane vesicles released by various types of cells, including mesenchymal stem cells [157]. The microRNAs can be enclosed in exosomes and serve as potential paracrine regulatory factors involved in the regulation of many diseases, such as ischemic diseases and degenerative eye diseases [158, 159]. The microRNAs produced by MSCs, such as miR-150 and miR-134, play a crucial role in the treatment of DN [160]. Exosomes secreted by human urine-derived stem cells alleviate DN and high glucose-induced podocyte injury through the transfer of miR16-5p [161]. Therefore, some researchers have attempted to use ADSCs-Exos to achieve the goal of treating DN, and have successfully improved the functional impairments of foot cells and symptoms of DN to varying degrees.

In vivo studies have also shown that ADSC-Exo can inhibit high glucose-induced podocyte apoptosis in mice [162]. According to the research of Duan Y et al., exosomes produced by ADSCs contain miR-26a-5p, which can be transferred to glomerular podocytes and improve DN in diabetic mice. In vitro studies have shown that ADSCs-Exo-miR-26a-5p can prevent podocyte apoptosis caused by high glucose by targeting TLR4, reducing the expression of VEGFA, inhibiting the pathway of NF-κB, and suppressing oxidative stress reactions [163]. In the experiment conducted by Jin et al. ADSC-Exo-miR-486 can inhibit high glucose-induced podocyte apoptosis by targeting Smad1, downregulating its expression, and suppressing the mTOR pathway which promotes autophagy flux and reduces podocyte apoptosis [162]. Besides they also founded that ADSCs-Exo-miR-215-5P can inhibit the expression of zinc finger E-box-binding homeobox 2, alleviate the progression of epithelial-mesenchymal transition, and foot cell migration [164].

In summary, according to the current results, ADSCs-Exo have potential therapeutic effects in the treatment of diabetic nephropathy, and in the future, they may be a relatively good choice for the treatment of DN. However, there are still some issues that need to be addressed, such as optimizing the preparation methods of ADSC extracellular vesicles, determining the active molecules in the extracellular vesicles, and exploring methods to accurately deliver the extracellular vesicles to the kidneys. These will contribute to the translation of adipose-derived stem cells into clinical applications.

Recent studies have shown that liver changes is another complication of DM [165]. Hyperglycemia caused by DM increases the risk of liver damage and liver fibrosis [166], severely affecting the health and quality of life of patients. DM is closely associated with liver diseases [165, 167], but the pathological and physiological basis and progression of liver changes in DM are not yet fully understood, and effective early intervention is lacking. Some studies have attempted to transplant ADSCs into animals to alleviate diabetes-induced liver damage and fibrosis, and have achieved certain positive results [168, 169]. This provides an important theoretical and experimental basis for further research and development of ADSCs for the treatment of DM-related liver diseases. However, clinical trials have not yet been conducted, and the explanation of the therapeutic mechanisms and pathways of ADSCs is not sufficiently detailed, requiring further research for clarification.

The potential mechanisms of ADSCs application in complication of DM are summarized in Fig. 2.

Fig. 2
figure 2

The application and mechanism of ADSCs in the complications of Diabetes Mellitus. ADSCs adipose-derived stem cells. All of the elements in the diagram were provided by Figdraw (http://www.fgdraw.com)

Full size image

Current challenges

Although ADSCs have broad prospects for application in disease treatment and tissue engineering, their application still faces some challenges. The following are some possible issues:

Complications issues There are certain difficulties and risks in obtaining and processing adipose tissue, such as the risk of wound infection due to improper handling and the possibility of blood clots from excessive intravenous infusion of ADSCs. Further research and clinical observation are needed to ensure the long-term effectiveness and safety of ADSCs therapy.

Standardization issues ADSCs are derived from various tissues, such as subcutaneous adipose tissue, breast tissue, and bone marrow. The differences in preparation and culture conditions of ADSCs mean that it is not guaranteed to obtain the same cell population in different laboratories. ADSCs from different sources have differences in biological characteristics, differentiation ability, and immunogenicity, which poses a challenge to the stability of ADSCs application. ADSCs have different abilities and functions, and standardized methods have not been established. More researches are needed to develop good quality control standards to ensure the consistency and stability of cells and achieve the desired therapeutic effects. In addition, it is also necessary to determine the number of cells needed for transplantation to cure diabetes mellitus and its complications in order to reduce the number of transplantations and patient suffering.

Transplantation efficiency issues During the in vitro culture process, some ADSCs may be lost, and similarly, some ADSCs may be lost during the transplantation process, which may affect the transplantation effect. The survival rate of adipose-derived stem cells after transplantation is an important issue, and optimization of long-term preservation and storage conditions of ADSCs needs to be addressed. More effective methods need to be explored to ensure the purity and stability of cells during the cell culture and expansion process.

Plasticity issues ADSCs need to undergo differentiation to generate insulin-secreting cells. ADSCs may be unstable during the differentiation process, leading to inconsistent results in differentiation products. The efficiency and stability of the differentiation process are key issues, therefore, further research and exploration are needed to optimize the stability of ADSCs differentiation.

It should be noted that the above issues are just some potential challenges mentioned in this article, and there may be other issues in actual applications.

Conclusions

In summary, an increasing amount of research suggests that ADSCs may serve as a new therapeutic approach for DM. Treatment with ADSCs has the potential to improve high blood glucose levels and alleviate symptoms of related complications in both animals and humans. However, there is still much work to be done in order to translate ADSCs into practical clinical applications. Further research and clinical observation are needed to assess the long-term effects of ADSCs treatment and minimize potential risks associated with their usage, in order to achieve more reliable and effective benefits in future clinical applications.

Availability of data and materials

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Abbreviations

ADSCs:

Adipose-derived stem cells

AGE:

Advanced glycation end products

AMPK:

AMP-activated protein kinase

BM-MSC :

Bone marrow-derived MSCs

DFU:

Diabetic foot ulcer

DM:

Diabetes mellitus

DN:

Diabetic nephropathy

ECM :

Extracellular matrix

GLP-1:

Glucagon-like peptide-1

HGF:

Hepatocyte growth factor

HLA:

Human leukocyte antigen

IFN-γ:

Interferon-gamma

IL:

Interleukin

INSR:

Insulin receptors

IPC:

Insulin-producing cells

MSC:

Mesenchymal stem cell

PDX1:

Pancreatic and duodenal homeobox 1

PI3K:

Phosphatidylinositol 3-kinase

STZ:

Streptozotocin

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

TGF-β:

Transforming growth factor-β

Th1:

T helper 1

TIMP-1:

Tissue inhibitor of metalloproteinase 1

TNF-α:

Tumor necrosis factor-alpha

vWF:

Von Willebrand factor

References

  1. Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020;16(7):377–90.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002;51(Suppl 3):S455-461.

    Article  CAS  PubMed  Google Scholar 

  3. Eirin A, Zhu X-Y, Krier JD, Tang H, Jordan KL, Grande JP, Lerman A, Textor SC, Lerman LO. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30(5):1030–41.

    Article  CAS  PubMed  Google Scholar 

  4. Shah GN, Morofuji Y, Banks WA, Price TO. High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: implications for cerebral microvascular disease in diabetes. Biochem Biophys Res Commun. 2013;440(2):354–8.

    Article  CAS  PubMed  Google Scholar 

  5. Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, Li Y, Zhao Z, Qin X, Jin D, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA J Am Med Assoc. 2017;317(24):2515–23.

    Article  Google Scholar 

  6. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6(5):568–72.

    Article  CAS  PubMed  Google Scholar 

  7. Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, Manfioletti G, Barbetti F, Brunetti A, Croce CM, et al. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med. 2005;11(7):765–73.

    Article  CAS  PubMed  Google Scholar 

  8. Volarevic V, Arsenijevic N, Lukic ML, Stojkovic M. Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells. 2011;29(1):5–10.

    Article  CAS  PubMed  Google Scholar 

  9. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Seaquist FJ. Evaluation and management of adult hypoglycemic disorders: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709–28.

    Article  CAS  PubMed  Google Scholar 

  10. Monnier L, Dunseath GJ, Colette C, Owens DR. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care. 2007;30(2):263–9.

    Article  PubMed  Google Scholar 

  11. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA J Am Med Assoc. 2018;320(1):53–62.

    Article  CAS  Google Scholar 

  12. Dominguez-Bendala J, Lanzoni G, Inverardi L, Ricordi C. Concise review: mesenchymal stem cells for diabetes. Stem Cells Transl Med. 2012;1(1):59–63.

    Article  CAS  PubMed  Google Scholar 

  13. Chan T-M, Harn H-J, Lin H-P, Chiu S-C, Lin P-C, Wang H-I, Ho L-I, Chuu C-P, Chiou T-W, Hsieh A-C, et al. The use of ADSCs as a treatment for chronic stroke. Cell Transplant. 2014;23(4–5):541–7.

    Article  PubMed  Google Scholar 

  14. Mizuno H, Tobita M, Uysal AC. Concise review: adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells. 2012;30(5):804–10.

    Article  CAS  PubMed  Google Scholar 

  15. Vanikar AV, Dave SD, Thakkar UG, Trivedi HL. Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int. 2010. https://doi.org/10.4061/2010/582382.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Gir P, Oni G, Brown SA, Mojallal A, Rohrich RJ. Human adipose stem cells: current clinical applications. Plast Reconstr Surg. 2012;129(6):1277–90.

    Article  CAS  PubMed  Google Scholar 

  17. Bhansali A, Upreti V, Khandelwal N, Marwaha N, Gupta V, Sachdeva N, Sharma RR, Saluja K, Dutta P, Walia R, et al. Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev. 2009;18(10):1407–15.

    Article  CAS  PubMed  Google Scholar 

  18. Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain A, Sachdeva N, Sharma RR, Marwaha N, Khandelwal N. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2014;23(9):1075–85.

    Article  PubMed  Google Scholar 

  19. Bhansali S, Dutta P, Kumar V, Yadav MK, Jain A, Mudaliar S, Bhansali S, Sharma RR, Jha V, Marwaha N, et al. Efficacy of autologous bone marrow-derived mesenchymal stem cell and mononuclear cell transplantation in type 2 diabetes mellitus: a randomized, placebo-controlled comparative study. Stem Cells Dev. 2017;26(7):471–81.

    Article  CAS  PubMed  Google Scholar 

  20. Kinnaird T, Stabile E, Burnett MS, Epstein SE. Bone-marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res. 2004;95(4):354–63.

    Article  CAS  PubMed  Google Scholar 

  21. Kong D, Zhuang X, Wang D, Qu H, Jiang Y, Li X, Wu W, Xiao J, Liu X, Liu J, et al. Umbilical cord mesenchymal stem cell transfusion ameliorated hyperglycemia in patients with type 2 diabetes mellitus. Clin Lab. 2014;60(12):1969–76.

    CAS  PubMed  Google Scholar 

  22. Jiang R, Han Z, Zhuo G, Qu X, Li X, Wang X, Shao Y, Yang S, Han ZC. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med. 2011;5(1):94–100.

    Article  PubMed  Google Scholar 

  23. Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Zhou H, Yin Z, Chen Y, Zhang Y, Wang S, et al. Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial. BMC Med. 2013;11:1–13.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.

    Article  CAS  PubMed  Google Scholar 

  25. Tobita M, Orbay H, Mizuno H. Adipose-derived stem cells: current findings and future perspectives. Discov Med. 2011;11(57):160–70.

    PubMed  Google Scholar 

  26. Varghese J, Griffin M, Mosahebi A, Butler P. Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Res Ther. 2017;8:1–15.

    Article  Google Scholar 

  27. Ding D-C, Chou H-L, Hung W-T, Liu H-W, Chu T-Y. Human adipose-derived stem cells cultured in keratinocyte serum free medium: donor’s age does not affect the proliferation and differentiation capacities. J Biomed Sci. 2013;20:1–11.

    Article  Google Scholar 

  28. Chan T-M, Harn H-J, Lin H-P, Chou P-W, Chen JY-R, Ho T-J, Chiou T-W, Chuang H-M, Chiu S-C, Chen Y-C, et al. Improved human mesenchymal stem cell isolation. Cell Transplant. 2014;23(4–5):399–406.

    Article  PubMed  Google Scholar 

  29. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20(8):1297–308.

    Article  CAS  PubMed  Google Scholar 

  30. Arnalich-Montiel F, Pastor S, Blazquez-Martinez A, Fernandez-Delgado J, Nistal M, Alio JL, De Miguel MP. Adipose-derived stem cells are a source for cell therapy of the corneal stroma. Stem Cells. 2008;26(2):570–9.

    Article  CAS  PubMed  Google Scholar 

  31. Ning H, Liu G, Lin G, Garcia M, Li L-C, Lue TF, Lin C-S. Identification of an aberrant cell line among human adipose tissue-derived stem cell isolates. Differentiation. 2009;77(2):172–80.

    Article  CAS  PubMed  Google Scholar 

  32. Ra JC, Kang SK, Shin IS, Park HG, Joo SA, Kim JG, Kang B-C, Lee YS, Nakama K, Piao M, et al. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. J Transl Med. 2011;9:1–11.

    Article  Google Scholar 

  33. Mundra V, Gerling IC, Mahato RI. Mesenchymal stem cell-based therapy. Mol Pharm. 2013;10(1):77–89.

    Article  CAS  PubMed  Google Scholar 

  34. Jung JW, Kwon M, Choi JC, Shin JW, Park IW, Choi BW, Kim JY. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 2013;54(5):1293–6.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, Horii A, Kanegae K, Utoh R, Iwata T, et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun. 2013;431(2):203–9.

    Article  CAS  PubMed  Google Scholar 

  36. Perlee D, van Vught LA, Scicluna BP, Maag A, Lutter R, Kemper EM, van’t Veer C, Punchard MA, González J, Richard MP, et al. Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group placebo controlled trial. Stem Cells. 2018;36(11):1778–88.

    Article  CAS  PubMed  Google Scholar 

  37. Lue J, Lin G, Ning H, Xiong A, Lin C-S, Glenn JS. Transdifferentiation of adipose-derived stem cells into hepatocytes: a new approach. Liver Int. 2010;30(6):913–22.

    Article  CAS  PubMed  Google Scholar 

  38. Lindroos B, Suuronen R, Miettinen S. The potential of adipose stem cells in regenerative medicine. Stem Cell Rev Rep. 2011;7(2):269–91.

    Article  PubMed  Google Scholar 

  39. Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Yoo H-W, Kim I, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31(11):2575–81.

    Article  CAS  PubMed  Google Scholar 

  40. Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, Teresa Vallejo-Cremades M, Fuentes B, Cerdan S, Diez-Tejedor E. Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther. 2013;4:1–12.

    Article  Google Scholar 

  41. Abdanipour A, Tiraihi T, Delshad A. Trans-differentiation of the adipose tissue-derived stem cells into neuron-like cells expressing neurotrophins by selegiline. Iran Biomed J. 2011;15(4):113–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. van den Broek LJ, Kroeze KL, Waaijman T, Breetveld M, Sampat-Sardjoepersad SC, Niessen FB, Middelkoop E, Scheper RJ, Gibbs S. Differential response of human adipose tissue-derived mesenchymal stem cells, dermal fibroblasts, and keratinocytes to burn wound exudates: potential role of skin-specific chemokine CCL27. Tissue Eng Part A. 2014;20(1–2):197–209.

    Article  PubMed  Google Scholar 

  43. Cho K-S, Park H-K, Park H-Y, Jung JS, Jeon S-G, Kim Y-K, Roh HJ. IFATS collection: immunomodulatory effects of adipose tissue-derived stem cells in an allergic rhinitis mouse model. Stem Cells. 2009;27(1):259–65.

    Article  CAS  PubMed  Google Scholar 

  44. Fang Y, Tian X, Bai S, Fan J, Hou W, Tong H, Li D. Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway. Int J Mol Med. 2012;30(1):85–92.

    CAS  PubMed  Google Scholar 

  45. Chan T-M, Chen JY-R, Ho L-I, Lin H-P, Hsueh K-W, Liu DD, Chen Y-H, Hsieh A-C, Tsai N-M, Hueng D-Y, et al. ADSC therapy in neurodegenerative disorders. Cell Transplant. 2014;23(4):549–57.

    Article  PubMed  Google Scholar 

  46. Marconi S, Bonaconsa M, Scambi I, Squintani GM, Rui W, Turano E, Ungaro D, D’Agostino S, Barbieri F, Angiari S, et al. Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Neuroscience. 2013;248:333–43.

    Article  CAS  PubMed  Google Scholar 

  47. Sandor GK, Numminen J, Wolff J, Thesleff T, Miettinen A, Tuovinen VJ, Mannerstrom B, Patrikoski M, Seppanen R, Miettinen S, et al. Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. stem Cells Transl Med. 2014;3(4):530–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ansaria MJI, Fiorina P, Dada S, Guleria I, Ueno T, Yuan X, Trikudanathan S, Smith RN, Freeman G, Sayegh MH. Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clin Immunol. 2008;126(2):140–7.

    Article  Google Scholar 

  49. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501–13.

    Article  CAS  PubMed  Google Scholar 

  50. Bassi EJ, Moraes-Vieira PMM, Moreira-Sa CSR, Almeida DC, Vieira LM, Cunha CS, Hiyane MI, Basso AS, Pacheco-Silva A, Camara NOS. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes. 2012;61(10):2534–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Takiishi T, Korf H, Van Belle TL, Robert S, Grieco FA, Caluwaerts S, Galleri L, Spagnuolo I, Steidler L, Van Huynegem K, et al. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J Clin Investig. 2012;122(5):1717–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Niclauss N, Morel P, Berney T. Has the gap between pancreas and islet transplantation closed? Transplantation. 2014;98(6):593–9.

    Article  PubMed  Google Scholar 

  53. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care. 2012;35(7):1436–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Kono TM, Sims EK, Moss DR, Yamamoto W, Ahn G, Diamond J, Tong X, Day KH, Territo PR, Hanenberg H, et al. Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors. Stem Cells. 2014;32(7):1831–42.

    Article  CAS  PubMed  Google Scholar 

  55. Karaoz E, Okcu A, Unal ZS, Subasi C, Saglam O, Duruksu G. Adipose tissue-derived mesenchymal stromal cells efficiently differentiate into insulin-producing cells in pancreatic islet microenvironment both in vitro and in vivo. Cytotherapy. 2013;15(5):557–70.

    Article  CAS  PubMed  Google Scholar 

  56. Levi B, Hyun JS, Nelson ER, Li S, Montoro DT, Wan DC, Jia FJ, Glotzbach JC, James AW, Lee M, et al. Nonintegrating knockdown and customized scaffold design enhances human adipose-derived stem cells in skeletal repair. Stem Cells. 2011;29(12):2018–29.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang S, Dai H, Wan N, Moore Y, Dai Z. Promoting long-term survival of insulin-producing cell grafts that differentiate from adipose tissue-derived stem cells to cure type 1 diabetes. PLoS ONE. 2011;6(12): e29706.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Chandra V, Swetha G, Muthyala S, Jaiswal AK, Bellare JR, Nair PD, Bhonde RR. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. PLoS ONE. 2011;6(6):e20615.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Kajiyama H, Hamazaki TS, Tokuhara M, Masui S, Okabayashi K, Ohnuma K, Yabe S, Yasuda K, Ishiura S, Okochi H, et al. Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice. Int J Dev Biol. 2010;54(4):699–705.

    Article  CAS  PubMed  Google Scholar 

  60. Lin G, Wang G, Liu G, Yang L-J, Chang L-J, Lue TF, Lin C-S. Treatment of type 1 diabetes with adipose tissue-derived stem cells expressing pancreatic duodenal homeobox 1. Stem Cells Dev. 2009;18(10):1399–406.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Kang HM, Kim J, Park S, Kim J, Kim H, Kim KS, Lee EJ, Seo SI, Kang SG, Lee J-E, et al. Insulin-secreting cells from human eyelid-derived stem cells alleviate type I diabetes in immunocompetent mice. Stem Cells. 2009;27(8):1999–2008.

    Article  CAS  PubMed  Google Scholar 

  62. Dave SD, Vanikar AV, Trivedi HL, Thakkar UG, Gopal SC, Chandra T. Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells. Clin Exp Med. 2015;15(1):41–5.

    Article  CAS  PubMed  Google Scholar 

  63. Trivedi HL, Vanikar AV, Thakker U, Firoze A, Dave SD, Patel CN, Patel JV, Bhargava AB, Shankar V. Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Transpl Proc. 2008;40(4):1135–9.

    Article  CAS  Google Scholar 

  64. Li Y-Y, Liu H-H, Chen H-L, Li Y-P. Adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes. Bio Med Mater Eng. 2012;22(1–3):97–103.

    Google Scholar 

  65. Lee J, Kim SC, Kim SJ, Lee H, Jung EJ, Jung SH, Han DJ. Differentiation of human adipose tissue-derived stem cells into aggregates of insulin-producing cells through the overexpression of pancreatic and duodenal homeobox gene-1. Cell Transplant. 2013;22(6):1053–60.

    Article  PubMed  Google Scholar 

  66. Sun L-L, Liu T-J, Li L, Tang W, Zou J-J, Chen X-F, Zheng J-Y, Jiang B-G, Shi Y-Q. Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces -cell proliferation in diabetic mice. Int J Mol Med. 2017;39(4):936–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Amer MG, Embaby AS, Karam RA, Amer MG. Role of adipose tissue derived stem cells differentiated into insulin producing cells in the treatment of type I diabetes mellitus. Gene. 2018;654:87–94.

    Article  CAS  PubMed  Google Scholar 

  68. Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, Muller B, Zulewski H. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 2006;341(4):1135–40.

    Article  CAS  PubMed  Google Scholar 

  69. Liu Z, Habener JF. Wnt signaling in pancreatic islets. In: Islam MS, editor. Islets of Langerhans, Vol 654. pp.391–419.

  70. Wang H, Ren Y, Hu X, Ma M, Wang X, Liang H, Liu D. Effect of Wnt signaling on the differentiation of islet beta-cells from adipose-derived stem cells. Biomed Res Int. 2017. https://doi.org/10.1155/2017/2501578.

    Article  PubMed Central  PubMed  Google Scholar 

  71. Anjum MS, Mehmood A, Mahmood F, Ali M, Tarrar MN, Khan SN, Riazuddin S. In vitro preconditioning of insulin-producing cells with growth factors improves their survival and ability to release insulin. J Biosci. 2018;43(4):649–59.

    Article  CAS  PubMed  Google Scholar 

  72. Piran M, Enderami SE, Piran M, Sedeh HS, Seyedjafari E, Ardeshirylajimi A. Insulin producing cells generation by overexpression of miR-375 in adipose-derived mesenchymal stem cells from diabetic patients. Biologicals. 2017;46:23–8.

    Article  CAS  PubMed  Google Scholar 

  73. Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M, Stoffel M. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci. 2009;106(14):5813–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Dayer D, Tabar MH, Moghimipour E, Tabandeh MR, Ghadiri AA, Bakhshi EA, Orazizadeh M, Ghafari MA. Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. Cytotherapy. 2017;19(8):937–46.

    Article  CAS  PubMed  Google Scholar 

  75. Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes: induction of tolerance and islet cell neogenesis. Autoimmun Rev. 2002;1(3):133–8.

    Article  CAS  PubMed  Google Scholar 

  76. Navaei-Nigjeh M, Moloudizargari M, Baeeri M, Gholami M, Lotfibakhshaiesh N, Soleimani M, Vasheghani-Farahani E, Ai J, Abdollahi M. Reduction of marginal mass required for successful islet transplantation in a diabetic rat model using adipose tissue-derived mesenchymal stromal cells. Cytotherapy. 2018;20(9):1124–42.

    Article  CAS  PubMed  Google Scholar 

  77. Bhang SH, Jung MJ, Shin J-Y, La W-G, Hwang YH, Kim MJ, Kim B-S, Lee DY. Mutual effect of subcutaneously transplanted human adipose-derived stem cells and pancreatic islets within fibrin gel. Biomaterials. 2013;34(30):7247–56.

    Article  CAS  PubMed  Google Scholar 

  78. Arzouni AA, Vargas-Seymour A, Rackham CL, Dhadda P, Huang G-C, Choudhary P, Nardi N, King AJF, Jones PM. Mesenchymal stromal cells improve human islet function through released products and extracellular matrix. Clin Sci. 2017;131(23):2835–45.

    Article  CAS  Google Scholar 

  79. Rackham CL, Dhadda PK, Le Lay AM, King AJF, Jones PM. Preculturing islets with adipose-derived mesenchymal stromal cells is an effective strategy for improving transplantation efficiency at the clinically preferred intraportal site. Cell Med. 2014;7(1):37–47.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Ohmura Y, Tanemura M, Kawaguchi N, Machida T, Tanida T, Deguchi T, Wada H, Kobayashi S, Marubashi S, Eguchi H, et al. Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice. Transplantation. 2010;90(12):1366–73.

    Article  CAS  PubMed  Google Scholar 

  81. Tanaka T, Kojima D, Mera T, Matsumoto M, Yasunami Y, Yanase T. Expansion of transplanted islets in mice by co-transplantation with adipose tissue-derived mesenchymal stem cells. Heliyon. 2018;4(5):e00632–e00632.

    Article  PubMed Central  PubMed  Google Scholar 

  82. Ayenehdeh JM, Niknam B, Rasouli S, Hashemi SM, Rahavi H, Rezaei N, Soleimani M, Liaeiha A, Niknam MH, Tajik N. Immunomodulatory and protective effects of adipose tissue-derived mesenchymal stem cells in an allograft islet composite transplantation for experimental autoimmune type 1 diabetes. Immunol Lett. 2017;188:21–31.

    Article  Google Scholar 

  83. Cavallari G, Olivi E, Bianchi F, Neri F, Foroni L, Valente S, La Manna G, Nardo B, Stefoni S, Ventura C. Mesenchymal stem cells and islet cotransplantation in diabetic rats: improved islet graft revascularization and function by human adipose tissue-derived stem cells preconditioned with natural molecules. Cell Transplant. 2012;21(12):2771–81.

    Article  PubMed  Google Scholar 

  84. Golocheikine A, Tiriveedhi V, Angaswamy N, Benshoff N, Sabarinathan R, Mohanakumar T. Cooperative Signaling for angiogenesis and neovascularization by VEGF and HGF following islet transplantation. Transplantation. 2010;90(7):725–31.

    Article  CAS  PubMed  Google Scholar 

  85. Song L, Sun Z, Kim D-S, Gou W, Strange C, Dong H, Cui W, Gilkeson G, Morgan KA, Adams DB, et al. Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function. Stem Cell Res Ther. 2017;8:1–11.

    Article  Google Scholar 

  86. Keane KN, Calton EK, Carlessi R, Hart PH, Newsholme P. The bioenergetics of inflammation: insights into obesity and type 2 diabetes. Eur J Clin Nutr. 2017;71(7):904–12.

    Article  CAS  PubMed  Google Scholar 

  87. Velloso LA, Eizirik DL, Cnop M. Type 2 diabetes mellitus-an autoimmune disease? Nat Rev Endocrinol. 2013;9(12):750–5.

    Article  CAS  PubMed  Google Scholar 

  88. Wang M, Song L, Strange C, Dong X, Wang H. Therapeutic effects of adipose stem cells from diabetic mice for the treatment of type 2 diabetes. Mol Ther. 2018;26(8):1921–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Hu J, Fu Z, Chen Y, Tang N, Wang L, Wang F, Sun R, Yan S. Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats. Endocr J. 2015;62(4):339–52.

    Article  CAS  PubMed  Google Scholar 

  90. Dave SD, Vanikar AV, Trivedi HL. In-vitro generation of human adipose tissue derived insulin secreting cells: up-regulation of Pax-6, Ipf-1 and Isl-1. Cytotechnology. 2014;66(2):299–307.

    Article  CAS  PubMed  Google Scholar 

  91. Chandra V, Swetha G, Phadnis S, Nair PD, Bhonde RR. Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells. Stem Cells. 2009;27(8):1941–53.

    Article  CAS  PubMed  Google Scholar 

  92. Shree N, Bhonde RR. Conditioned media from adipose tissue derived mesenchymal stem cells reverse insulin resistance in cellular models. J Cell Biochem. 2017;118(8):2037–43.

    Article  CAS  PubMed  Google Scholar 

  93. Xie M, Hao HJ, Cheng Y, Xie ZY, Yin YQ, Zhang Q, Gao JQ, Liu HY, Mu YM, Han WD. Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats. Biochem Biophys Res Commun. 2017;483(1):435–41.

    Article  CAS  PubMed  Google Scholar 

  94. Nam JS, Kang HM, Kim J, Park S, Kim H, Ahn CW, Park JO, Kim KR. Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice. Biochem Biophys Res Commun. 2014;443(2):775–81.

    Article  CAS  PubMed  Google Scholar 

  95. Yu S, Cheng Y, Zhang L, Yin Y, Xue J, Li B, Gong Z, Gao J, Mu Y. Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res Ther. 2019;10(1):333.

    Article  PubMed Central  PubMed  Google Scholar 

  96. Pirola L, Ferraz JC. Role of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. World J Biol Chem. 2017;8(2):120–8.

    Article  PubMed Central  PubMed  Google Scholar 

  97. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis. Ann Med. 2017;49(2):106–16.

    Article  PubMed  Google Scholar 

  98. Zhao X, Guo J, Zhang F, Zhang J, Liu D, Hu W, Yin H, Jin L. Therapeutic application of adipose-derived stromal vascular fraction in diabetic foot. Stem Cell Res Ther. 2020;11(1):1–8.

    Article  Google Scholar 

  99. Reardon R, Simring D, Kim B, Mortensen J, Williams D, Leslie A. The diabetic foot ulcer. Aust J Gen Pract. 2020;49(5):250–5.

    Article  PubMed  Google Scholar 

  100. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367–75.

    Article  PubMed  Google Scholar 

  101. Den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Transl Res. 2019;204:39–50.

    Article  Google Scholar 

  102. Kim EK, Li G, Lee TJ, Hong JP. The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. Plast Reconstr Surg. 2011;128(2):387–94.

    Article  CAS  PubMed  Google Scholar 

  103. Lee SH, Lee JH, Cho KH. Effects of human adipose-derived stem cells on cutaneous wound healing in nude mice. Ann Dermatol. 2011;23(2):150–5.

    Article  PubMed Central  PubMed  Google Scholar 

  104. Nie C, Yang D, Xu J, Si Z, Jin X, Zhang J. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20(2):205–16.

    Article  PubMed  Google Scholar 

  105. Cianfarani F, Toietta G, Di Rocco G, Cesareo E, Zambruno G, Odorisio T. Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21(4):545–53.

    Article  PubMed  Google Scholar 

  106. Kato Y, Iwata T, Morikawa S, Yamato M, Okano T, Uchigata Y. Allogeneic transplantation of an adipose-derived stem cell sheet combined with artificial skin accelerates wound healing in a rat wound model of type 2 diabetes and obesity. Diabetes. 2015;64(8):2723–34.

    Article  CAS  PubMed  Google Scholar 

  107. Kuo Y-R, Wang C-T, Cheng J-T, Kao G-S, Chiang Y-C, Wang C-J. Adipose-derived stem cells accelerate diabetic wound healing through the induction of autocrine and paracrine effects. Cell Transplant. 2016;25(1):71–81.

    Article  PubMed  Google Scholar 

  108. Shi R, Jin Y, Cao C, Han S, Shao X, Meng L, Cheng J, Zhang M, Zheng J, Xu J, et al. Localization of human adipose-derived stem cells and their effect in repair of diabetic foot ulcers in rats. Stem Cell Res Ther. 2016;7:1–13.

    Article  Google Scholar 

  109. Hamada M, Iwata T, Kato Y, Washio K, Morikawa S, Sakurai H, Yamato M, Okano T, Uchigata Y. Xenogeneic transplantation of human adipose-derived stem cell sheets accelerate angiogenesis and the healing of skin wounds in a Zucker Diabetic Fatty rat model of obese diabetes. Regen Ther. 2017;6:65–73.

    Article  PubMed Central  PubMed  Google Scholar 

  110. Lin K, Wang S, Fan L, Pan D, Xian CJ, Shen J. Adipose-derived stem cells seeded in Pluronic F-127 hydrogel promotes diabetic wound healing. J Surg Res. 2017;217:63–74.

    Article  CAS  Google Scholar 

  111. Seo E, Lim JS, Jun J-B, Choi W, Hong I-S, Jun H-S. Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing. J Transl Med. 2017;15:1–19.

    Article  Google Scholar 

  112. Irons RF, Cahill KW, Rattigan DA, Marcotte JH, Fromer MW, Chang S, Zhang P, Behling EM, Behling KC, Caputo FJ. Acceleration of diabetic wound healing with adipose-derived stem cells, endothelial-differentiated stem cells, and topical conditioned medium therapy in a swine model. J Vasc Surg. 2018;68(6):115S-125S.

    Article  PubMed  Google Scholar 

  113. Li X, Xie X, Lian W, Shi R, Han S, Zhang H, Lu L, Li M. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 2018;50:1–14.

    PubMed Central  PubMed  Google Scholar 

  114. Chen L, Wang Z-C, Ma J-J, Sun W-J, Wang S-W, Gu Z-C, Yang X. Autologous nanofat transplantation accelerates foot wound healing in diabetic rats. Regen Med. 2019;14(3):231–41.

    Article  CAS  PubMed  Google Scholar 

  115. Liu Z, Xiao S, Tao K, Li H, Jin W, Wei Z, Wang D, Deng C. Synergistic effects of human platelet-rich plasma combined with adipose-derived stem cells on healing in a mouse pressure injury model. Stem Cells Int. 2019. https://doi.org/10.1155/2019/3091619.

    Article  PubMed Central  PubMed  Google Scholar 

  116. Ahmadi H, Amini A, Fathabady FF, Mostafavinia A, Zare F, Ebrahimpour-malekshah R, Ghalibaf MN, Abrisham M, Rezaei F, Albright R, et al. Transplantation of photobiomodulation-preconditioned diabetic stem cells accelerates ischemic wound healing in diabetic rats. Stem Cell Res Ther. 2020;11(1):1–14.

    Article  Google Scholar 

  117. An R, Zhang Y, Qiao Y, Song L, Wang H, Dong X. Adipose stem cells isolated from diabetic mice improve cutaneous wound healing in streptozotocin-induced diabetic mice. Stem Cell Res Ther. 2020;11(1):1–11.

    Article  Google Scholar 

  118. Ding S, Xu Y, Yan X, Lin Y, Tan Q. Effect of collagen scaffold with Bcl-2-modified adipose-derived stem cells on diabetic mice wound healing. Int J Low Extremity Wounds. 2020;19(2):139–47.

    Article  CAS  Google Scholar 

  119. Ahmadi H, Bayat M, Amini A, Mostafavinia A, Ebrahimpour-Malekshah R, Gazor R, Asadi R, Gachkar L, Rezaei F, Shafikhani SH, et al. Impact of preconditioned diabetic stem cells and photobiomodulation on quantity and degranulation of mast cells in a delayed healing wound simulation in type one diabetic rats. Lasers Med Sci. 2022;37(3):1593–604.

    Article  PubMed  Google Scholar 

  120. Ebrahim N, Dessouky AA, Mostafa O, Hassouna A, Yousef MM, Seleem Y, El Gebaly EA, Allam MM, Farid AS, Saffaf BA, et al. Adipose mesenchymal stem cells combined with platelet-rich plasma accelerate diabetic wound healing by modulating the Notch pathway. Stem Cell Res Ther. 2021;12(1):1–24.

    Article  Google Scholar 

  121. Zhou J, Wei T, He Z. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m(6)A modification to improve wound healing of diabetic foot ulcers. Mol Med. 2021;27(1):1–12.

    Article  Google Scholar 

  122. Carstens MH, Quintana FJ, Calderwood ST, Sevilla JP, Rios AB, Rivera CM, Calero DW, Zelaya ML, Garcia N, Bertram KA, et al. Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: safety and evidence of efficacy at 1 year. Stem Cells Transl Med. 2021;10(8):1138–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Moon Y-C, Chung H-Y, Han S-K, Jeong S-H, Dhong E-S. Possibility of injecting adipose-derived stromal vascular fraction cells to accelerate microcirculation in ischemic diabetic feet: a pilot study. Int J Stem Cells. 2019;12(1):107–13.

    Article  PubMed Central  PubMed  Google Scholar 

  124. Nilforoushzadeh MA, Sisakht MM, Amirkhani MA, Seifalian AM, Banafshe HR, Verdi J, Nouradini M. Engineered skin graft with stromal vascular fraction cells encapsulated in fibrin-collagen hydrogel: a clinical study for diabetic wound healing. J Tissue Eng Regen Med. 2020;14(3):424–40.

    Article  CAS  PubMed  Google Scholar 

  125. Moon KC, Suh HS, Kim KB, Han SK, Young KW, Lee JW, Kim MH. Potential of allogeneic adipose-derived stem cell-hydrogel complex for treating diabetic foot ulcers. Diabetes. 2019;68(4):837–46.

    Article  CAS  PubMed  Google Scholar 

  126. Uzun E, Guney A, Gonen ZB, Ozkul Y, Kafadar IH, Gunay M, Mutlu M. Intralesional allogeneic adipose-derived stem cells application in chronic diabetic foot ulcer: phase I/2 safety study. Foot Ankle Surg. 2021;27(6):636–42.

    Article  PubMed  Google Scholar 

  127. Park B-S, Jang KA, Sung J-H, Park J-S, Kwon YH, Kim KJ, Kim W-S. Adipose-derived stem cells and their secretory factors as a promising therapy for skin aging. Dermatol Surg. 2008;34(10):1323–6.

    CAS  PubMed  Google Scholar 

  128. Ul Hassan W, Greiser U, Wang W. Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014;22(3):313–25.

    Article  Google Scholar 

  129. Massee M, Chinn K, Lim JJ, Godwin L, Young CS, Koob TJ. Type I and II diabetic adipose-derived stem cells respond in vitro to dehydrated human amnion/chorion membrane allograft treatment by increasing proliferation, migration, and altering cytokine secretion. Adv Wound Care. 2016;5(2):43–54.

    Article  Google Scholar 

  130. Evans JR, Michelessi M, Virgili G. Laser photocoagulation for proliferative diabetic retinopathy. Cochrane Database Syst Rev. 2014;2014(11):Cd011234.

    PubMed Central  PubMed  Google Scholar 

  131. Ghirlanda G, Di Leo MA, Caputo S, Falsini B, Porciatti V, Marietti G, Greco AV. Detection of inner retina dysfunction by steady-state focal electroretinogram pattern and flicker in early IDDM. Diabetes. 1991;40(9):1122–7.

    Article  CAS  PubMed  Google Scholar 

  132. Carrasco E, Hernández C, Miralles A, Huguet P, Farrés J, Simó R. Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care. 2007;30(11):2902–8.

    Article  CAS  PubMed  Google Scholar 

  133. Ejaz S. Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes Obes Metab. 2008;10(1):53–63.

    Article  CAS  PubMed  Google Scholar 

  134. Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol. 2002;133(3):373–85.

    Article  CAS  PubMed  Google Scholar 

  135. Stitt AW, O’Neill CL, O’Doherty MT, Archer DB, Gardiner TA, Medina RJ. Vascular stem cells and ischaemic retinopathies. Prog Retin Eye Res. 2011;30(3):149–66.

    Article  CAS  PubMed  Google Scholar 

  136. Tzekov R, Arden GB. The electroretinogram in diabetic retinopathy. Surv Ophthalmol. 1999;44(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  137. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000;14(16):1983–91.

    Article  CAS  PubMed  Google Scholar 

  138. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C, Diabetes C, Complications Trial Research G. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86.

    Article  CAS  PubMed  Google Scholar 

  139. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet (London, England). 1998;352(9131):854–65.

    Article  Google Scholar 

  140. Lachin JM, Genuth S, Cleary P, Davis MD, Nathan DM, Diabetes C, Complications Trial/Epidemiology of D, Interventions, Complications Research G. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381–9.

    Article  PubMed  Google Scholar 

  141. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.

    Article  Google Scholar 

  142. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology. 1991;98(5 Suppl):766–85.

    Google Scholar 

  143. Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol. 2003;136(1):122–35.

    Article  PubMed  Google Scholar 

  144. Kojima H, Kim J, Chan L. Emerging roles of hematopoietic cells in the pathobiology of diabetic complications. Trends Endocrinol Metab. 2014;25(4):178–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  145. Megaw R, Dhillon B. Stem cell therapies in the management of diabetic retinopathy. Curr Diabetes Rep. 2014;14(7):1–9.

    Article  CAS  Google Scholar 

  146. Mendel TA, Clabough EBD, Kao DS, Demidova-Rice TN, Durham JT, Zotter BC, Seaman SA, Cronk SM, Rakoczy EP, Katz AJ, et al. Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy. PLoS ONE. 2013;8(5):e65691.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Rajashekhar G, Ramadan A, Abburi C, Callaghan B, Traktuev DO, Evans-Molina C, Maturi R, Harris A, Kern TS, March KL. Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PLoS ONE. 2014;9(1):e84671.

    Article  PubMed Central  PubMed  Google Scholar 

  148. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021;17(5):319–34.

    Article  CAS  PubMed  Google Scholar 

  149. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  150. Abbasi F, Moosaie F, Khaloo P, Firouzabadi FD, Abhari SMF, Atainia B, Ardeshir M, Nakhjavani M, Esteghamati A. Neutrophil gelatinase-associated lipocalin and retinol-binding protein-4 as biomarkers for diabetic kidney disease. Kidney Blood Press Res. 2020;45(2):222–32.

    Article  CAS  PubMed  Google Scholar 

  151. Campion CG, Sanchez-Ferras O, Batchu SN. Potential role of serum and urinary biomarkers in diagnosis and prognosis of diabetic nephropathy. Can J Kidney Health Dis. 2017;4:2054358117705371–2054358117705371.

    Article  PubMed Central  PubMed  Google Scholar 

  152. Bucala R, Vlassara H. Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis. 1995;26(6):875–88.

    Article  CAS  PubMed  Google Scholar 

  153. D’Agati V, Schmidt AM. RAGE and the pathogenesis of chronic kidney disease. Nat Rev Nephrol. 2010;6(6):352–60.

    Article  CAS  PubMed  Google Scholar 

  154. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–40.

    Article  CAS  PubMed  Google Scholar 

  155. Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomarker Res. 2019;7:8.

    Article  Google Scholar 

  156. Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M, Mao F, Yan Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4(2):34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Fiedler T, Rabe M, Mundkowski RG, Oehmcke-Hecht S, Peters K. Adipose-derived mesenchymal stem cells release microvesicles with procoagulant activity. Int J Biochem Cell Biol. 2018;100:49–53.

    Article  CAS  PubMed  Google Scholar 

  158. Li N, Long B, Han W, Yuan S, Wang K. microRNAs: important regulators of stem cells. Stem Cell Res Ther. 2017;8(1):110.

    Article  PubMed Central  PubMed  Google Scholar 

  159. Mead B, Tomarev S. Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms. Stem Cells Transl Med. 2017;6(4):1273–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Yang H, Zhang X, Xin G. Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network. Ren Fail. 2018;40(1):136–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Duan YR, Chen BP, Chen F, Yang SX, Zhu CY, Ma YL, Li Y, Shi J. Exosomal microRNA-16-5p from human urine-derived stem cells ameliorates diabetic nephropathy through protection of podocyte. J Cell Mol Med. 2021;25(23):10798–813.

    Article  CAS  PubMed  Google Scholar 

  162. Jin J, Shi Y, Gong J, Zhao L, Li Y, He Q, Huang H. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res Ther. 2019;10:1–15.

    Article  Google Scholar 

  163. Duan Y, Luo Q, Wang Y, Ma Y, Chen F, Zhu X, Shi J. Adipose mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p target TLR4 and protect against diabetic nephropathy. J Biol Chem. 2020;295(37):12868–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  164. Jin J, Wang Y, Zhao L, Zou W, Tan M, He Q. Exosomal miRNA-215-5p derived from adipose-derived stem cells attenuates epithelial–mesenchymal transition of podocytes by inhibiting ZEB2. Biomed Res Int. 2020;2020:1–14.

    Google Scholar 

  165. Regnell SE, Lernmark Å. Hepatic steatosis in type 1 diabetes. Rev Diabet Stud. 2011;8(4):454–67.

    Article  PubMed  Google Scholar 

  166. Thompson AJ, Patel K. Antifibrotic therapies: Will we ever get there? Curr Gastroenterol Rep. 2010;12(1):23–9.

    Article  PubMed Central  PubMed  Google Scholar 

  167. Targher G, Mantovani A, Pichiri I, Mingolla L, Cavalieri V, Mantovani W, Pancheri S, Trombetta M, Zoppini G, Chonchol M, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care. 2014;37(6):1729–36.

    Article  CAS  PubMed  Google Scholar 

  168. Liao N, Zheng Y, Xie H, Zhao B, Zeng Y, Liu X, Liu J. Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats. Stem Cell Res Ther. 2017;8(1):286.

    Article  PubMed Central  PubMed  Google Scholar 

  169. Hou Y, Ding W, Wu P, Liu C, Ding L, Liu J, Wang X. Adipose-derived stem cells alleviate liver injury induced by type 1 diabetes mellitus by inhibiting mitochondrial stress and attenuating inflammation. Stem Cell Res Ther. 2022;13(1):132.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We want to thank Ms. Jialv Sun for language improving. The figures were prepared by our group, and all of the elements in the diagram were provided by Figdraw (http://www.fgdraw.com).

Funding

This work was supported by the National Natural Science Foundation of China (Grants Nos. 82170336, 82270286 and 82000227), National Key R&D Program of China (2022YFC2402804), Science and Technology Research and Development Program of Shaanxi Province(2023-ZDLSF-39) and the National High Level Talents Special Support Plan.

Author information

Author notes

  1. Dongxu Yan and Yujie Song contributed equally.

Authors and Affiliations

  1. Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi’an, 710032, China

    Dongxu Yan, Guojie Cao, Haitao Zhou, Hong Li, Hao Sun, Meng Deng, Yufeng Qiu & Yang Sun

  2. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi’an, 710032, China

    Yujie Song, Bing Zhang & Wei Yi

Authors
  1. Dongxu Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yujie Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guojie Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haitao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meng Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yufeng Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WY and YS contributed to the conception of the study. BZ, GJC, HTZ and HL organized the relevant literature. DXY and YJS wrote the manuscript. HS, MD and YFQ performed the tables and figures. WY and YS revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wei Yi or Yang Sun.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, D., Song, Y., Zhang, B. et al. Progress and application of adipose-derived stem cells in the treatment of diabetes and its complications. Stem Cell Res Ther 15, 3 (2024). https://doi.org/10.1186/s13287-023-03620-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13287-023-03620-0

Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512