Skip to main content

Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases


Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.


End-stage liver diseases (ESLD), including decompensated liver cirrhosis, liver failure, and hepatocellular carcinoma, have high mortality rates, and their prevalence has increased in recent years [1]. ESLD is characterized by severely abnormal liver functions including hepatic decompensation, portal hypertension, coagulation dysfunction, jaundice, hepatorenal syndrome, hepatic encephalopathy, and ascites. Although liver transplantation can effectively treat these diseases [2], most patients die waiting for transplant surgery because of a shortage of donor organs. Mesenchymal stem cells (MSCs) are adult multipotent cells with self-renewal, multi-directional differentiation, immunoregulator, and paracrine functions [3]. Recent findings have demonstrated that MSC transplantation can improve liver function in acute or chronic liver diseases, offering an alternative strategy for patients with ESLD to prolong their life [4,5,6,7,8,9]. The therapeutic functions of MSC transplantation are attributed to the following aspects. First, MSCs serve as substitutes for hepatocytes via transdifferentiation or cell fusion for liver tissue repair and regeneration. Second, MSCs exhibit paracrine functions by releasing growth factors and cytokines that inhibit hepatocyte apoptosis and stimulate liver regeneration. Third, MSCs possess immunomodulatory properties related to adaptive and innate immune responses [10].

According to the potential therapeutic mechanisms of MSC therapy, the paracrine or immunoregulatory actions of MSCs depend on their survival rate in vivo, and the hepatic differentiation or fusion function of MSCs depends on the number of viable MSCs that reached the injured liver tissues. Thus, MSC engraftment efficiency is closely related to cell survival or viability and sufficient delivery of cells to the liver. Actually, Kuo et al. found that survival of MSCs in liver tissues was less than 5% 4 weeks after transplantation [11]. Our previous work showed that a large number of MSCs die within 1 day after transplantation in fibrotic liver of mice, and the surviving MSCs almost completely disappeared 11 days after transplantation [12], indicating an extremely low MSC survival rate in vivo, leading to insufficient cell engraftment efficiency for liver diseases. Therefore, cell attrition has become a major bottleneck in MSC therapy for liver diseases. Improving cell survival and MSC homing capability to enhance cell engraftment efficiency is needed to maximize the therapeutic potential of MSC transplantation in liver diseases.

Various biological, biochemical, and biophysical factors tightly influence MSC survival and homing capabilities through reciprocal interactions between cells, the extracellular matrix, and bioactive factors both in vitro and in vivo [13]. Dramatically different conditions between in vitro and in vivo severely affect MSC survival or viability after transplantation. During in vitro expansion of MSCs, the conditions are optimally controlled including oxygen partial pressure, whereas MSCs encounter a variety of conditions in vivo, including hypoxia and oxidative stress, that affect their ability to home and effectively repopulated liver tissue during transplantation (Fig. 1). Each part of the homing process comprising rolling, activation, adhesion, crawling, and migration (Fig. 2) affects the number of the homing of MSCs to parenchymal liver tissues. Therefore, regulation of biological, biochemical, and/or biophysical factors to reduce cell injuries induced by an unfavorable environment in vivo can improve MSC survival, increase MSC homing capability, and enhance MSC engraftment efficiency. In this review, we discuss the current status of MSC therapy, the detailed cell-homing process, strategies to improve MSC survival, and homing capability to enhance MSC engraftment efficiency in liver diseases.

Fig. 1
figure 1

The dramatic difference between in vitro and in vivo conditions in MSC transplantation for liver diseases. The MSC engraftment process is tortuous, and the transplanted MSCs would encounter dramatic changes ranging from in vitro comfortable growing conditions to in vivo inclement environment (such as hypoxia, oxidative stress, and inflammation), leading to the low cell survival of MSC therapy for liver diseases. Figure designed by Adobe Illustrator CC 2018

Fig. 2
figure 2

The systemic homing process during MSC therapy. Systemic administration of MSCs must undergo a multistep process including rolling, activation, and adhesion, as well as crawling and migration. Figure designed by Adobe Illustrator CC 2018

Current status and challenges of MSC transplantation for ESLD

MSCs are adult and multipotent stromal cells that can be isolated from the bone marrow, adipose tissues, umbilical cord, dental tissue, synovium, placenta, and dermis [14]. According to the International Society for Cell and Gene Therapy, MSCs are defined by the following criteria: (1) the cells are adherent under standard culture conditions and grow intrinsically during in vitro expansion or culture; (2) the cell surface makers are positive for CD73, CD90, and CD105, but negative for CD14, CD34, CD45, and HLA-DR; and (3) the cells can differentiate into adipocytes, osteoblasts, or chondrocytes in vitro. In addition to the above properties, MSCs also have immune evasion ability due to low MHC-I antigen expression and lack of MHC-II antigen expression [15], which is a congenital factor for allogeneic or autogenous MSC transplantation [16]. MSC transplantation has been widely used in preclinical studies, for treating ESLD, including liver failure and cirrhosis, indicating its potential for ESLD in humans. A growing number of clinical trials have confirmed the therapeutic potential of MSC transplantation for ESLD, particularly for decompensated liver cirrhosis (DLC) and acute-on-chronic liver failure (ACLF) (Table 1). Li et al. found that the overall survival at 3-year (83.3% vs 61.8%) and 5-year (63.9% vs 43.6%) during the 13- to 75-month follow-up was significantly improved by human umbilical cord blood-derived MSC therapy for DLC patients (n = 36) [17]. In a randomized controlled clinical trial, MSC transplantation improved overall survival and liver function biomarkers (albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up) during a 13–75-month follow-up in patients with DLC (n = 108) [18]. No significant side effects or cell-related complications have been observed after MSC therapy in patients with DLC. A randomized controlled trial conducted by Lin et al. found that MSC therapy could increase 24-week survival rates (73.2% vs 55.6%) by improving liver function (total bilirubin and MELD scores) and decreasing the incidence of severe infections (16.1% vs 33.3%) in ACLF patients (n = 56) [19]. However, Mohamadnejad et al. found that in a randomized controlled trial (n = 27, 12 months of follow-up) involving patients with cirrhosis, MSC transplantation did not improve child scores, MELD scores, serum albumin, INR, serum transaminases, or liver volumes [20]. Given the fact that the background and guidelines for liver diseases worldwide are not fully uniform, some large, multicenter clinical trials with long-term follow-up in MSC therapy for subcategories of liver diseases should be conducted to further confirm the clinical benefit of MSC therapy.

Table 1 Clinical trials of MSC transplantation for ESLD

More importantly, cell engraftment efficiency, including the survival and number of MSC targeted deliveries into parenchymal liver tissues, should be considered when interpreting the therapeutic efficacy of MSC transplantation for liver diseases. Notably, by performing a series of liver biopsies after 6 months of MSC therapy in patients with cirrhosis (n = 25), Kantarcıoğlu et al. found that MSCs could not be delivered into liver tissues in sufficient amounts [21]. Therefore, a low cell engraftment efficiency severely affects the long-term therapeutic outcomes of MSC therapy for liver diseases. Next, we describe the cell-homing process and how to improve cell engraftment efficiency to enhance the therapeutic efficacy of MSCs for liver diseases.

MSC transplantation and homing process in vivo

Following previous reviews, MSC homing can be divided into systemic and non-systemic [22, 23]. For non-systemic homing, MSCs were locally injected into the targeted sites. In systemic homing, MSCs are administered into the bloodstream, pass through the circulatory system, and finally, transmigrate to targeted sites. In liver diseases, MSC homing is systemic, as MSC transplantation is commonly achieved by intravenous (IV) injection via different routes, including the peripheral and hepatic portal veins. After IV transplantation, MSC are initially retained in the lungs and then, delivered to the liver, spleen, and kidney. Very few MSCs are located in other organs [24]. Although the delivery route affects travel of MSCs to the injured sites, the number of cells that could transmigrate into parenchymal liver tissues was not significantly different between portal and peripheral vein administrations [25,26,27]. Additionally, there were no differences in the therapeutic efficacy of MSCs between peripheral and portal vein administration in acute liver failure [25] or cirrhosis models [26]. Considering that MSC survival and homing capabilities are closely related to the therapeutic efficacy of MSC therapy, IV-injected MSC, regardless of injection site, undergo similar microenvironments in vivo and the same systemic homing process. Correlatively, it has been confirmed that systemic homing is inevitable after IV injection and involves active or passive MSC extravasation followed by chemokine-guided interstitial migration toward injured sites [23]. Similar to endogenous leukocyte migration to inflammatory sites [28, 29], systemically administered MSCs undergo rolling, activation, adhesion, crawling, and migration (Fig. 2).

As an initial step, MSC rolling is commonly facilitated by selectins expressed on endothelial cells. In 2006, Rüster et al. first found that the rolling behavior of MSCs bound to endothelial cells occurred in a P-selectin-dependent manner [30]. However, MSCs do not express P-selectin glycoprotein ligand 1 (PSGL-1), implying that other MSC ligands interact with P-selectin in the endothelial cells. Bailey et al. have identified CD24 as a candidate P-selectin ligand in adipose tissue-derived MSCs [31]. Therefore, engineering MSC surfaces with PSGL-1 and Sialyl-Lewis could increase the effectiveness of MSC therapy in multiple sclerosis [32]. Liver sinusoidal endothelial cells (LSECs) are the only gatekeepers of MSCs that homes to parenchymal liver tissue. Previously, MSC rolling was abolished by blocking CD29 (also known as VLA4, a β1-integrin) on MSCs and vascular cell adhesion molecule-1 (VCAM-1) on LSECs [33]. Hence, cell rolling during MSC therapy for liver diseases depends on CD29/VCAM-1.

Cell activation during MSC homing is usually facilitated by G protein-coupled chemokine receptors (GPCRs), which couple with cytokines secreted by wounds. Extensive evidence has shown that stromal cell-derived factor1 (SDF-1, also known as CXCL-12) in endothelial cells plays a crucial role in cell activation during MSC homing [34]. SDF-1 is also a ligand of the chemokine receptor, CXCR-4, which is commonly expressed in MSCs. Significantly, overexpression of CXCR-4 in MSCs enhanced the therapeutic effect of MSC transplantation on acute liver failure by activating the PI3K/Akt signaling pathway [35]. The number of MSC homing is closely related to SDF-1 expression in injured liver tissues [36]. Therefore, SDF-1 is an important attractant for the targeted delivery of MSCs and the SDF-1/CXCR-4 axis plays a pivotal role in MSC activation and homing. In addition to the SDF-1/CXCR-4 axis, direct interaction between other chemokines and receptors, including CCL-2/CCR-2 [37] and cannabinoid receptor-1 [38], is also involved in the cell engraftment process of MSC therapy for liver diseases. Hence, the expression of the GPCRs plays an important role in cell activation during MSC therapy for liver diseases, but the details of the underlying mechanisms require further exploration.

MSC adhesion is facilitated by integrins. Semon et al. showed that MSC adhesion to endothelial cells, including those in the pulmonary artery, cardiac-derived microvasculature, and umbilical veins, is markedly reduced by β5-integrin antibodies [39]. In liver diseases, Aldridge et al. found that blocking the β1-integrin (CD29) on MSCs significantly reduced their adhesiveness to LSECs, whereas GPCRs, including CCR-4, CCR-5, and CXCR-3, made little contribution to MSC adhesion [33]. Therefore, integrin expression in MSCs affects their adhesion capability during MSC homing.

MSCs crawl on the surface of endothelial cells along with the establishment of firm endothelial adhesion. Cell crawling, the movement along extracellular substrates or matrices (e.g., inner vessel walls), requires exogenous factors, including fluid force, and chemokines at targeted sites [23, 40]. Chamberlain et al. found that shear stress and CXCL-9 significantly enhanced MSC crawling capability on endothelial cells in vitro [29]. Lateral cell crawling is accompanied by MSC polarization, which is initiated by the crosstalk between FROUNT and CCR-2, followed by CCR-2 clustering, leading to cytoskeletal reorganization and further endothelial migration [41].

To accomplish endothelial migration, MSCs must penetrate the barriers of the endothelial cell layers by secreting MMPs (including MMP-1, MMP-2, MMP-9, and MT1-MMP), which can degrade the basement membrane of endothelial cells [42, 43]. The MMP activity is commonly regulated by TIMP-1 [44], microRNAs [45], and inflammatory factors (e.g., IL-1β [46], TGF-β1 [47], and TNFα [43]). Apart from MMPs, other cytokines including CXCR-3 and urokinase-type plasminogen activator induced by inflammatory factors such as IL-1β and IL-17, are also involved in the trans-endothelial migration of MSCs [48, 49].

Strategies for enhancing MSC survival and homing capability in liver diseases

After administration into the bloodstream, MSC will encounter a range of conditions that can influence their survival. The optimal constant conditions that support growth in vitro give way to more inclement, complex conditions in vivo, including low oxygen tensions, fluid pressure stress, and interaction with whole blood components. As a result, many MSCs die in the blood circulation after IV transplantation. Furthermore, following the tortuous homing process, the existing surviving MSCs continue to be subjected to challenging conditions such as hypoxia, oxidative stress, and inflammation in the targeted sites, leading to continuous cell death, such that only a small number of viable MSCs populate the parenchymal liver tissues. The cell attrition dramatically reduces theoretical functions of MSC transplantation in liver diseases. Considering that cell survival and cell-homing capability are closely related to MSC engraftment efficacy, it is necessary to further improve MSC survival and homing capabilities and to maximize the therapeutic efficiency of MSC therapy in liver diseases. Next, we summarized the current strategies for enhancing cell survival and homing capability of MSC transplantation (Fig. 3).

Fig. 3
figure 3

Strategies for enhancing MSC survival and homing capability. The current strategies including hypoxic priming, drug pretreatment, gene modification, cell surface engineering, cytokine pretreatment, splenectomy, nanoparticle labeling, and local irradiation have been used to improve MSC survival and cell-homing capability. Figure designed by Adobe Illustrator CC 2018

Strategies for enhancing MSC survival in vivo

Hypoxic priming

Generally, human arterial blood contains 12.3% O2, venous blood contains 5.3% O2, and the liver tissue contains approximately 4.04% O2 (30.7 mmHg of O2) [50]. Comparing in vitro expansion of normoxic cultured MSCs (NC-MSCs, approximately 19.95% O2), the oxygen dissolution in vivo and the oxygen content in liver tissues and the circulatory system are extremely low. After short-term hypoxic exposure, NC-MSCs were prone to death due to upregulation of Sug1, and the inactivation of 26S proteasome, leading to increased immunogenicity [51, 52], and inducing cell apoptosis [53]. Additionally, NC-MSC stemness is easily lost during extensive amplification in vitro [54]. Hence, it is difficult to adapt in vivo expansion of NC-MSCs to dramatic changes in oxygen pressure. To improve the ability of MSCs to adapt to changes in oxygen, hypoxic priming, an in vitro preconditioning method, has been used to increase their survival in vivo [55, 56]. Hypoxic priming can increase autocrine or paracrine factor secretion by MSCs, including IL-6, TNFα, HGF, VEGF, and prostaglandin E synthase, which promotes liver regeneration and reduces hepatocyte apoptosis [57]. In addition, it prevents MSC senescence by promoting autophagy [58], and downregulating p16, p53, and p21 [59, 60]. Therefore, hypoxic priming has been used to enhance the outcomes of MSC therapy for liver diseases [61] (Table 2).

Table 2 Hypoxic preconditioning improves therapeutic outcomes of MSC transplantation for liver diseases

Drug pretreatment

Accumulating evidence suggests that oxidative stress characterized by the excess generation of reactive oxygen species is a key factor in the low cell survival rate of transplanted MSCs [62]. Antioxidant drugs have been used to overcome oxidative stress and enhance MSC survival in vitro (Table 3). Indeed, our group found that a low dose of reduced glutathione (GSH) and melatonin could be used to preserve MSC functions (including cell proliferation, and stemness) and to reduce cell senescence during long-term in vitro passaging [63]. Importantly, antioxidant pretreatment increased MSC survival by reducing cell apoptosis in an H2O2 injury model [64] and enhanced therapeutic outcomes of MSC therapy for liver fibrosis [64, 65]. Pretreatment with other antioxidants, including edaravone [66], zeaxanthin dipalmitate [67], and vitamin E [68], can also be used to enhance MSC survival and therapeutic efficacy for liver failure.

Table 3 Antioxidant drug pretreatment improves MSC survival

Similar to oxidative stress, inflammation is another factor affecting MSC survival in vivo. We previously used a ratiometric near infrared-II fluorescence probe to track MSC viability and found that dexamethasone pretreatment could improve MSC cell survival and enhance the hepatic protection of MSC transplantation for liver fibrosis [12]. Moreover, juzentaihoto, a chemical drug with both anti-inflammatory and anti-oxidative functions, has also been used to improve cell survival and to enhance the therapeutic efficiency of MSC transplantation for liver cirrhosis [69]. Considering that some antioxidant and anti-inflammatory drugs (e.g., GSH) have been used clinically in patients with ESLD, drug pretreatment is a promising clinical strategy for enhancing MSC survival and therapeutic efficacy for liver diseases.

Gene modification

Given that miR-210 is closely involved in cell survival under hypoxia or oxidative stress, its overexpression has been used to enhance MSC survival under hypoxic conditions [67] or oxidative stress induced by H2O2 [70], thereby improving the repair function of MSC transplantation. Overexpression of anti-apoptotic, antioxidant, or pro-survival genes including BCL-2 [71, 72], Akt1 [73], HGF [74], GATA-4 [75], and erythropoietin (EPO) [76], significantly enhanced MSC survival in vitro and in vivo. In addition, down-regulation of miR-34a [77], and miR-16 [78] enhanced MSC survival by reducing apoptosis. Therefore, modifying gene expression to reduce cell apoptosis and/or improve the adaptability to hypoxia and oxidative stress is an alternative method for enhancing MSC survival in vivo.

Strategies for enhancing MSC homing capability in vivo

MSC modification in vitro

Gene modification

The entire process of MSC homing is medicated by the crosstalk between ligands and receptors. Increasing the expression ligands or receptors on MSCs improves their homing capability. Overexpression migration-related genes, including CXCR-4 [79], CCR-2 [80], CXCL-9 [81], and c-Met [82], have been used to increase MSC homing. Gene modification also significantly enhances the therapeutic efficacy of MSCs for acute or chronic liver diseases (Table 4).

Table 4 Gene modification for enhancing cell-homing capability of MSC transplantation in liver diseases

Cell surface engineering

Cell surface engineering to decorate a targeted molecule on the cell surface has been used to enhance MSC delivery to the target sites [83]. Previously, human adipose tissue-derived MSC surfaces were engineered with lipid-conjugated heparin to increase hepatic homing of MSCs and improve MSC therapy for acute liver failure [84,85,86]. Given that LSECs are a specific permeable barrier of the hepatic sinusoidal endothelium for trans-endothelial migration of MSC transplantation, we used bioorthogonal click chemistry to modify the MSC surface with an LSEC-targeted peptide (RLTRKRGLK) to increase MSC homing capability to enhance MSC therapy for acute liver failure and liver fibrosis [87]. Importantly, neither heparin-functionalization nor the bioorthogonal click chemistry approach affected the biological characteristics of the MSCs. Therefore, these cell surface engineering strategies are a promising for enhancing MSC homing capability.

Cytokine pretreatment

Pretreatment with cytokines, including IL-17 [88] and HGF [89], improved MSC migration and homing ability in vivo. Recently, Nie et al. found that IL-1β pretreatment increased CXCR-4 expression and enhanced MSC homing capability and therapeutic outcomes for acute liver failure [46]. Pretreatment with TGFβ1 enhanced the homing and engraftment of MSCs to human and murine hepatic sinusoidal endothelia in vivo and in vitro, which was mediated by increased expression of CXCR-3. In particular, pretreatment with cytokine can enhance the anti-inflammatory effects of MSC therapy in acute liver injury [90]. Because cytokines can be easily controlled within the GMP grade, cytokine pretreatment provides translational potential for improving the MSC homing capacity for liver diseases.

Nanoparticle labeling

Nanoparticle-based imaging has been widely used for in vivo assessment of MSC biodistribution. Huang et al. developed an iron-based nanocluster for MSC labeling and found that it enhanced MSC migration by promoting CXCR-4 expression [91]. Similarly, Vitale et al. developed silica nanoparticles (SiO2-NPs) for MSC tracking and found that their internalization enhanced MSC migration by increasing CXCR-4 expression [92]. Hence, silica nanoparticle labeling is a novel method for improving the homing capabilities of MSCs. Nevertheless, the detailed mechanism and safety profile of nanoparticle labeling for increasing CXCR-4 expression remain unknown.

Host environment regulation


Portal hypertension is a typical physical condition aggravated by cirrhosis. Previously, it was suggested that the flow shear stress benefits the osteogenic, cardiovascular, chondrogenic, adipogenic, and neurogenic differentiation of MSCs [93]. However, high shear stress and portal hypertension hamper the adhesion and migration of MSCs. Splenectomy is a therapeutic option for increasing platelet count and promoting liver regeneration in patients with portal hypertension and cirrhosis. In particular, Tang et al. found that splenectomy enhanced MSC homing capability and therapeutic efficacy for cirrhosis of the liver in rats by upregulating of SDF-1 and HGF [94]. Nevertheless, the detailed mechanism and safety of this approach still need to be verified before clinical application.

Transient local irradiation

Considering that transient local irradiation (TLR) can disturb the LSEC barrier and inhibit the phagocytic function of Kupffer cells, TLR has been used to enhance hepatocyte engraftment in hepatectomized mice [95]. Inspired by this, Shao et al. used hepatic TLR to enhance MSC homing and therapeutic outcomes for thioacetamide-induced fibrosis in rats [96]. Hence, TLR is an alternative method for improving the MSC homing capability. However, this approach increases the risk of tissue injury, and its clinical benefits should be fully evaluated before further application.

Conclusions and future directions

Here, we review the whole cell-homing process of MSC transplantation and the current clinical status of MSC therapy for liver diseases, emphasizing that low cell engraftment efficiency is a major challenge to the use and the long-term therapeutic efficacy of MSC therapy. We also highlighted that cell survival and MSC transmigration into the parenchymal liver tissues is closely related to the efficiency of MSC engraftment. Therefore, we summarized the current strategies to enhance cell survival and homing capability for MSC transplantation in liver diseases. Nevertheless, there are many unanswered questions regarding the safety and the clinical potential of these strategies. First, although pretreatment with drugs, hypoxia, and cytokines can improve MSC survival or homing capability, they also affect the paracrine functions of MSCs; hence, future studies are still needed. Second, modifying MSCs to enhance their homing capability through gene editing, nanoparticle labeling, or chemical methods is an alternative approach for enhancing MSC engraftment efficiency; however, biosafety issues and how to achieve GMP-grade cell production requires further exploration. Third, splenectomy or TLR poses an external risk to patients, and the clinical benefit should be fully verified before implementation in clinical settings. Finally, the current strategies are supported by in vitro and animal studies, but their clinical translational potentials for improving cell survival and homing capability of MSC therapy in liver diseases remain to be tested.

Apart from cell survival and homing capability, there are a large number of variables, including the heterogeneity of MSCs derived from different tissues and individual differences in patients, which affect cell engraftment efficiency and personalized MSC therapy for liver diseases. There is a clear need to develop personalized models to address therapeutic efficacy of MSC transplantation in liver diseases.

Availability of data and materials

Not applicable.



α-Smooth muscle actin


Acute-on-chronic liver failure


Adipose-derived MSC


Amniotic-fluid-derived MSC




Acute liver failure


Alanine aminotransferase


Protein kinase B


Amniotic mesenchymal stem cell


Aspartate transaminase


Branched‐chain amino acid transaminase‐1


Bone marrow-derived MSC


CC Chemokine receptor 2






Central intravenous


Cellular-mesenchymal epithelial transition factor


C-X-C chemokine receptor type 4


C-X-C chemokine ligand 2


C-X-C chemokine ligand 9


Decompensated liver cirrhosis


End-stage liver diseases




Fibroblast growth factor 4


Forkhead box O




Hepatic B virus


Hepatocellular carcinoma


Hepatic C virus


Human Forkhead box A2


Hepatocyte growth factor


Hepatic stellate cell


Intrahepatic arterial injection


Interleukin-1-receptor antagonist




Interleukin 10


International normalized ratio


Intrasplenic injection


Intravenous injection


Liver cirrhosis


Liver failure




Liver transplantation


Liver sinusoidal endothelial cells


Model for end-stage liver disease


Matrix metalloproteinase 9


Mesenchymal stem cell


Nuclear factor erythroid 2-related factor 2


Overall survival


Primary biliary cirrhosis


Prothrombin concentration


Proliferating cell nuclear antigen


Prostaglandin E2


Placenta-derived MSC


Portal injection


Phosphatase of regenerating liver-1


P-selectin glycoprotein ligand 1


Prothrombin time


Peripheral vein injection


Reactive oxygen species


Stromal cell-derived factor1


Total bilirubin


Transforming growth factorβ1


Transient local irradiation


Tumor necrosis factor α


Umbilical cord-derived mesenchymal stem cell


Vascular cell adhesion molecule-1


Vascular endothelial growth factor

VEGF165 :

Vascular endothelial growth factor 165


  1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70:151–71.

    PubMed  Google Scholar 

  2. Forbes SJ, Gupta S, Dhawan A. Cell therapy for liver disease: from liver transplantation to cell factory. J Hepatol. 2015;62:S157–69.

    CAS  PubMed  Google Scholar 

  3. Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell Biosci. 2020;10:123.

    PubMed  PubMed Central  Google Scholar 

  4. Zhang L, Ma XJ, Fei YY, Han HT, Xu J, Cheng L, et al. Stem cell therapy in liver regeneration: focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther. 2022;232:108004.

    CAS  PubMed  Google Scholar 

  5. Hu X-H, Chen L, Wu H, Tang Y-B, Zheng Q-M, Wei X-Y, et al. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther. 2023;14:141.

    PubMed  PubMed Central  Google Scholar 

  6. Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver disease and cell therapy: advances made and remaining challenges. Stem Cells. 2023;41:739–61.

    PubMed  Google Scholar 

  7. Cardinale V, Lanthier N, Baptista PM, Carpino G, Carnevale G, Orlando G, et al. Cell transplantation-based regenerative medicine in liver diseases. Stem Cell Rep. 2023;18:1555–72.

    CAS  Google Scholar 

  8. Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep. 2023.

  9. Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, et al. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol. 2023;20:583–99.

    CAS  PubMed  Google Scholar 

  10. Liu WH, Song FQ, Ren LN, Guo WQ, Wang T, Feng YX, et al. The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases. J Cell Mol Med. 2014;19:511–20.

    PubMed  PubMed Central  Google Scholar 

  11. Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134:2111–21.

    PubMed  Google Scholar 

  12. Liao NS, Su L, Cao Y, Qiu L, Xie R, Peng F, et al. Tracking cell viability for adipose-derived mesenchymal stem cell-based therapy by quantitative fluorescence Imaging in the second near-Infrared window. ACS Nano. 2022;16:2889–900.

    CAS  PubMed  Google Scholar 

  13. Noronha NC, Mizukami A, Caliari-Oliveira C, Cominal JG, Rocha JLM, Covas DT, et al. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther. 2019;10:131.

    PubMed  Google Scholar 

  14. Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012;10:709–16.

    CAS  PubMed  Google Scholar 

  15. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med. 2012;18:128–34.

    CAS  PubMed  Google Scholar 

  17. Li Z, Zhou X, Han L, Shi M, Xiao H, Lin M, et al. Human umbilical cord blood-derived mesenchymal stem cell transplantation for patients with decompensated liver cirrhosis. J Gastrointest Surg. 2023;27:926–31.

    PubMed  PubMed Central  Google Scholar 

  18. Shi M, Li YY, Xu RN, Meng FP, Yu SJ, Fu JL, et al. Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial. Hepatol Int. 2021;15:1431–41.

    PubMed  Google Scholar 

  19. Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial. Hepatology. 2017;66:209–19.

    CAS  PubMed  Google Scholar 

  20. Mohamadnejad M, Alimoghaddam K, Bagheri M, Ashrafi M, Abdollahzadeh L, Akhlaghpoor S, et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis. Liver Int. 2013;33:1490–6.

    CAS  PubMed  Google Scholar 

  21. Kantarcioglu M, Demirci H, Avcu F, Karslioglu Y, Babayigit MA, Karaman B, et al. Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis. Turk J Gastroenterol. 2015;26:244–50.

    PubMed  Google Scholar 

  22. Ullah M, Liu DD, Thakor AS. Mesenchymal stromal cell homing: mechanisms and strategies for improvement. iScience. 2019;15:421–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Nitzsche F, Muller C, Lukomska B, Jolkkonen J, Deten A, Boltze J. Concise review: MSC adhesion cascade-insights into homing and transendothelial migration. Stem Cells. 2017;35:1446–60.

    PubMed  Google Scholar 

  24. Sanchez-Diaz M, Quinones-Vico MI, Sanabria de la Torre R, Montero-Vilchez T, Sierra-Sanchez A, Molina-Leyva A, et al. Biodistribution of mesenchymal stromal cells after administration in animal models and humans: a systematic review. J Clin Med. 2021;10:2925.

    PubMed  PubMed Central  Google Scholar 

  25. Sun L, Fan X, Zhang L, Shi G, Aili M, Lu X, et al. Bone mesenchymal stem cell transplantation via four routes for the treatment of acute liver failure in rats. Int J Mol Med. 2014;34:987–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Truong NH, Nguyen NH, Le TV, Vu NB, Huynh N, Nguyen TV, et al. Comparison of the treatment efficiency of bone marrow-derived mesenchymal stem cell transplantation via tail and portal veins in CCl4-induced mouse liver fibrosis. Stem Cells Int. 2016;2016:5720413.

    PubMed  Google Scholar 

  27. Idriss NK, Sayyed HG, Osama A, Sabry D. Treatment efficiency of different routes of bone marrow-derived mesenchymal stem cell injection in rat liver fibrosis model. Cell Physiol Biochem. 2018;48:2161–71.

    CAS  PubMed  Google Scholar 

  28. Uchida N, Nassehi T, Drysdale CM, Gamer J, Yapundich M, Bonifacino AC, et al. Busulfan combined with immunosuppression allows efficient engraftment of gene-modified cells in a rhesus macaque model. Mol Ther. 2019;27:1586–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chamberlain G, Smith H, Rainger GE, Middleton J. Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: effects of chemokines and shear. PLoS ONE. 2011;6:e25663.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ruster B, Gottig S, Ludwig RJ, Bistrian R, Muller S, Seifried E, et al. Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood. 2006;108:3938–44.

    PubMed  Google Scholar 

  31. Bailey AM, Lawrence MB, Shang H, Katz AJ, Peirce SM. Agent-based model of therapeutic adipose-derived stromal cell trafficking during ischemia predicts ability to roll on P-selectin. PLoS Comput Biol. 2009;5:e1000294.

    PubMed  PubMed Central  Google Scholar 

  32. Liao W, Pham V, Liu L, Riazifar M, Pone EJ, Zhang SX, et al. Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis. Biomaterials. 2016;77:87–97.

    CAS  PubMed  Google Scholar 

  33. Aldridge V, Garg A, Davies N, Bartlett DC, Youster J, Beard H, et al. Human mesenchymal stem cells are recruited to injured liver in a beta1-integrin and CD44 dependent manner. Hepatology. 2012;56:1063–73.

    CAS  PubMed  Google Scholar 

  34. Liepelt A, Tacke F. Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases. Am J Physiol Gastrointest Liver Physiol. 2016;311:G203–9.

    PubMed  Google Scholar 

  35. Xiu G, Li X, Yin Y, Li J, Li B, Chen X, et al. SDF-1/CXCR4 augments the therapeutic effect of bone marrow mesenchymal stem cells in the treatment of lipopolysaccharide-induced liver injury by promoting their migration through PI3K/Akt signaling pathway. Cell Transplant. 2020;29:1–12.

    Google Scholar 

  36. Jin W, Liang X, Brooks A, Futrega K, Liu X, Doran MR, et al. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ. 2018;6:e6072.

    PubMed  PubMed Central  Google Scholar 

  37. Xu R, Ni B, Wang L, Shan J, Pan L, He Y, et al. CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure. Stem Cell Res Ther. 2022;13:55.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang L, Yang L, Tian L, Mai P, Jia S, Yang L, et al. Cannabinoid receptor 1 mediates homing of bone marrow-derived mesenchymal stem cells triggered by chronic liver injury. J Cell Physiol. 2017;232:110–21.

    CAS  PubMed  Google Scholar 

  39. Semon JA, Nagy LH, Llamas CB, Tucker HA, Lee RH, Prockop DJ. Integrin expression and integrin-mediated adhesion in vitro of human multipotent stromal cells (MSCs) to endothelial cells from various blood vessels. Cell Tissue Res. 2010;341:147–58.

    CAS  PubMed  Google Scholar 

  40. Bershadsky AD, Kozlov MM. Crawling cell locomotion revisited. Proc Natl Acad Sci U S A. 2011;108:20275–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Belema-Bedada F, Uchida S, Martire A, Kostin S, Braun T. Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2. Cell Stem Cell. 2008;2:566–75.

    CAS  PubMed  Google Scholar 

  42. Kim HY, Yoon HS, Lee Y, Kim YH, Cho KA, Woo SY, et al. Matrix metalloproteinase 1 as a marker of tonsil-derived mesenchymal stem cells to assess bone marrow cell migration. Tissue Eng Regen Med. 2023;20:271–84.

    CAS  PubMed  Google Scholar 

  43. Almalki SG, Agrawal DK. Effects of matrix metalloproteinases on the fate of mesenchymal stem cells. Stem Cell Res Ther. 2016;7:129.

    PubMed  PubMed Central  Google Scholar 

  44. Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood. 2007;109:4055–63.

    CAS  PubMed  Google Scholar 

  45. Lv C, Yang S, Chen X, Zhu X, Lin W, Wang L, et al. MicroRNA-21 promotes bone mesenchymal stem cells migration in vitro by activating PI3K/Akt/MMPs pathway. J Clin Neurosci. 2017;46:156–62.

    CAS  PubMed  Google Scholar 

  46. Nie H, An F, Mei J, Yang C, Zhan Q, Zhang Q. IL-1beta pretreatment improves the efficacy of mesenchymal stem cells on acute liver failure by enhancing CXCR4 expression. Stem Cells Int. 2020;2020:1498315.

    PubMed  PubMed Central  Google Scholar 

  47. Zhao W, Wang C, Liu R, Wei C, Duan J, Liu K, et al. Effect of TGF-beta1 on the migration and recruitment of mesenchymal stem cells after vascular balloon injury: involvement of matrix metalloproteinase-14. Sci Rep. 2016;6:21176.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Krstic J, Obradovic H, Jaukovic A, Okic-Dordevic I, Trivanovic D, Kukolj T, et al. Urokinase type plasminogen activator mediates Interleukin-17-induced peripheral blood mesenchymal stem cell motility and transendothelial migration. Biochim Biophys Acta. 2015;1853:431–44.

    CAS  PubMed  Google Scholar 

  49. Guo YC, Chiu YH, Chen CP, Wang HS. Interleukin-1beta induces CXCR3-mediated chemotaxis to promote umbilical cord mesenchymal stem cell transendothelial migration. Stem Cell Res Ther. 2018;9:281.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med. 2011;15:1239–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Abu-El-Rub E, Sareen N, Lester Sequiera G, Ammar HI, Yan W, ShamsEldeen AM, et al. Hypoxia-induced increase in Sug1 leads to poor post-transplantation survival of allogeneic mesenchymal stem cells. FASEB J. 2020;34:12860–76.

    CAS  PubMed  Google Scholar 

  52. Abu-El-Rub E, Sequiera GL, Sareen N, Yan W, Moudgil M, Sabbir MG, et al. Hypoxia-induced 26S proteasome dysfunction increases immunogenicity of mesenchymal stem cells. Cell Death Dis. 2019;10:90.

    PubMed  PubMed Central  Google Scholar 

  53. Zhang F, Luo H, Peng W, Wang L, Wang T, Xie Z, et al. Hypoxic condition induced H3K27me3 modification of the LncRNA Tmem235 promoter thus supporting apoptosis of BMSCs. Apoptosis. 2022;27:762–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Choi W, Kwon SJ, Jin HJ, Jeong SY, Choi SJ, Oh W, et al. Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells. Clin Transl Med. 2017;6:38.

    PubMed  PubMed Central  Google Scholar 

  55. Hu C, Wu Z, Li L. Pre-treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases. J Cell Mol Med. 2020;24:40–9.

    PubMed  Google Scholar 

  56. Zhang Z, Yang C, Shen M, Yang M, Jin Z, Ding L, et al. Autophagy mediates the beneficial effect of hypoxic preconditioning on bone marrow mesenchymal stem cells for the therapy of myocardial infarction. Stem Cell Res Ther. 2017;8:89.

    PubMed  PubMed Central  Google Scholar 

  57. Kojima Y, Tsuchiya A, Ogawa M, Nojiri S, Takeuchi S, Watanabe T, et al. Mesenchymal stem cells cultured under hypoxic conditions had a greater therapeutic effect on mice with liver cirrhosis compared to those cultured under normal oxygen conditions. Regen Ther. 2019;11:269–81.

    PubMed  PubMed Central  Google Scholar 

  58. Liu J, He J, Ge L, Xiao H, Huang Y, Zeng L, et al. Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the mir-326-mediated autophagy. Stem Cell Res Ther. 2021;12:413.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim Y, Jin HJ, Heo J, Ju H, Lee HY, Kim S, et al. Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease. Leukemia. 2018;32:2672–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu H, Xue W, Ge G, Luo X, Li Y, Xiang H, et al. Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1alpha in MSCs. Biochem Biophys Res Commun. 2010;401:509–15.

    CAS  PubMed  Google Scholar 

  61. Yu J, Yin S, Zhang W, Gao F, Liu Y, Chen Z, et al. Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model. Stem Cell Res Ther. 2013;4:83.

    PubMed  PubMed Central  Google Scholar 

  62. Yang YX, Fei WY, Liu MS, Zhang YC, Gao RS, Hu YY, et al. Molecular hydrogen promotes adipose-derived stem cell myogenic differentiation via regulation of mitochondria. Curr Stem Cell Res Ther. 2022;18:864–75.

    Google Scholar 

  63. Liao N, Shi Y, Zhang C, Zheng Y, Wang Y, Zhao B, et al. Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion. Stem Cell Res Ther. 2019;10:306.

    PubMed  PubMed Central  Google Scholar 

  64. Liao N, Shi Y, Wang Y, Liao F, Zhao B, Zheng Y, et al. Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model. Stem Cell Res Ther. 2020;11:237.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Mortezaee K, Khanlarkhani N, Sabbaghziarani F, Nekoonam S, Majidpoor J, Hosseini A, et al. Preconditioning with melatonin improves therapeutic outcomes of bone marrow-derived mesenchymal stem cells in targeting liver fibrosis induced by CCl4. Cell Tissue Res. 2017;369:303–12.

    CAS  PubMed  Google Scholar 

  66. Zeng W, Xiao J, Zheng G, Xing F, Tipoe GL, Wang X, et al. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep. 2015;5:11100.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu Y, Xiong Y, Xing F, Gao H, Wang X, He L, et al. Precise regulation of mir-210 is critical for the cellular homeostasis maintenance and transplantation efficacy enhancement of mesenchymal stem cells in acute liver failure therapy. Cell Transplant. 2017;26:805–20.

    PubMed  PubMed Central  Google Scholar 

  68. Baig MT, Ghufran H, Mehmood A, Azam M, Humayun S, Riazuddin S. Vitamin E pretreated Wharton’s jelly-derived mesenchymal stem cells attenuate CCl(4)-induced hepatocyte injury in vitro and liver fibrosis in vivo. Biochem Pharmacol. 2021;186:114480.

    CAS  PubMed  Google Scholar 

  69. Iwasawa T, Nojiri S, Tsuchiya A, Takeuchi S, Watanabe T, Ogawa M, et al. Combination therapy of Juzentaihoto and mesenchymal stem cells attenuates liver damage and regresses fibrosis in mice. Regen Ther. 2021;18:231–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu J, Huang Z, Lin L, Fu M, Gao Y, Shen Y, et al. miR-210 over-expression enhances mesenchymal stem cell survival in an oxidative stress environment through antioxidation and c-Met pathway activation. Sci China Life Sci. 2014;57:989–97.

    CAS  PubMed  Google Scholar 

  71. Jin S, Li H, Han M, Ruan M, Liu Z, Zhang F, et al. Mesenchymal stem cells with enhanced Bcl-2 expression promote liver recovery in a rat model of hepatic cirrhosis. Cell Physiol Biochem. 2016;40:1117–28.

    CAS  PubMed  Google Scholar 

  72. Ni X, Ou C, Guo J, Liu B, Zhang J, Wu Z, et al. Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro. Int J Mol Med. 2017;40:418–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhou L, Liu S, Wang Z, Yao J, Cao W, Chen S, et al. Bone marrow-derived mesenchymal stem cells modified with Akt1 ameliorates acute liver GVHD. Biol Proced Online. 2019;21:24.

    PubMed  PubMed Central  Google Scholar 

  74. Zhao L, Liu X, Zhang Y, Liang X, Ding Y, Xu Y, et al. Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction. Exp Cell Res. 2016;344:30–9.

    CAS  PubMed  Google Scholar 

  75. Yu B, Gong M, He Z, Wang YG, Millard RW, Ashraf M, et al. Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family. Int J Biochem Cell Biol. 2013;45:2724–35.

    CAS  PubMed  Google Scholar 

  76. Wang X, Wang H, Lu J, Feng Z, Liu Z, Song H, et al. Erythropoietin-modified mesenchymal stem cells enhance anti-fibrosis efficacy in mouse liver fibrosis model. Tissue Eng Regen Med. 2020;17:683–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu Y, Zhang X, Chen J, Li T. Inhibition of mircoRNA-34a enhances survival of human bone marrow mesenchymal stromal/stem cells under oxidative stress. Med Sci Monit. 2018;24:264–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Prakash A, Garcia-Moreno JF, Brown JAL, Bourke E. Clinically applicable inhibitors impacting genome stability. Molecules. 2018;23:1166.

    PubMed  PubMed Central  Google Scholar 

  79. Du Z, Wei C, Yan J, Han B, Zhang M, Peng C, et al. Mesenchymal stem cells overexpressing C-X-C chemokine receptor type 4 improve early liver regeneration of small-for-size liver grafts. Liver Transpl. 2013;19:215–25.

    PubMed  Google Scholar 

  80. Zheng J, Li H, He L, Huang Y, Cai J, Chen L, et al. Preconditioning of umbilical cord-derived mesenchymal stem cells by rapamycin increases cell migration and ameliorates liver ischaemia/reperfusion injury in mice via the CXCR4/CXCL12 axis. Cell Prolif. 2019;52:e12546.

    CAS  PubMed  Google Scholar 

  81. Li Y, Dong J, Zhou Y, Ye X, Cai Z, Zhang X, et al. Therapeutic effects of CXCL9-overexpressing human umbilical cord mesenchymal stem cells on liver fibrosis in rats. Biochem Biophys Res Commun. 2021;584:87–94.

    CAS  PubMed  Google Scholar 

  82. Wang K, Li Y, Zhu T, Zhang Y, Li W, Lin W, et al. Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure. Stem Cell Res Ther. 2017;8:162.

    PubMed  PubMed Central  Google Scholar 

  83. Won YW, Patel AN, Bull DA. Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. Biomaterials. 2014;35:5627–35.

    CAS  PubMed  Google Scholar 

  84. Hwang Y, Kim JC, Tae G. Significantly enhanced recovery of acute liver failure by liver targeted delivery of stem cells via heparin functionalization. Biomaterials. 2019;209:67–78.

    CAS  PubMed  Google Scholar 

  85. Liao L, Shi B, Chang H, Su X, Zhang L, Bi C, et al. Heparin improves BMSC cell therapy: anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy. Theranostics. 2017;7:106–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kim J, Tae G. The modulation of biodistribution of stem cells by anchoring lipid-conjugated heparin on the cell surface. J Control Release. 2015;217:128–37.

    CAS  PubMed  Google Scholar 

  87. Liao N, Zhang D, Wu M, Yang H, Liu X, Song J. Enhancing therapeutic effects and in vivo tracking of adipose tissue-derived mesenchymal stem cells for liver injury using bioorthogonal click chemistry. Nanoscale. 2020;13:1813–22.

    Google Scholar 

  88. Ma T, Wang X, Jiao Y, Wang H, Qi Y, Gong H, et al. Interleukin 17 (IL-17)-induced mesenchymal stem cells prolong the survival of allogeneic skin grafts. Ann Transplant. 2018;23:615–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu J, Pan G, Liang T, Huang P. HGF/c-Met signaling mediated mesenchymal stem cell-induced liver recovery in intestinal ischemia reperfusion model. Int J Med Sci. 2014;11:626–33.

    PubMed  PubMed Central  Google Scholar 

  90. Garg A, Khan S, Luu N, Nicholas DJ, Day V, King AL, et al. TGFbeta(1) priming enhances CXCR3-mediated mesenchymal stromal cell engraftment to the liver and enhances anti-inflammatory efficacy. J Cell Mol Med. 2023;27:864–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Huang X, Zhang F, Wang Y, Sun X, Choi KY, Liu D, et al. Design considerations of iron-based nanoclusters for noninvasive tracking of mesenchymal stem cell homing. ACS Nano. 2014;8:4403–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Vitale E, Rossin D, Perveen S, Miletto I, Lo Iacono M, Rastaldo R, et al. Silica nanoparticle internalization improves chemotactic behaviour of human mesenchymal stem cells acting on the SDF1alpha/CXCR4 axis. Biomedicines. 2022;10:336.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Arora S, Srinivasan A, Leung CM, Toh YC. Bio-mimicking shear stress environments for enhancing mesenchymal stem cell differentiation. Curr Stem Cell Res Ther. 2020;15:414–27.

    CAS  PubMed  Google Scholar 

  94. Tang WP, Akahoshi T, Piao JS, Narahara S, Murata M, Kawano T, et al. Splenectomy enhances the therapeutic effect of adipose tissue-derived mesenchymal stem cell infusion on cirrhosis rats. Liver Int. 2016;36:1151–9.

    CAS  PubMed  Google Scholar 

  95. Yamanouchi K, Zhou H, Roy-Chowdhury N, Macaluso F, Liu L, Yamamoto T, et al. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology. 2009;49:258–67.

    PubMed  Google Scholar 

  96. Shao CH, Chen SL, Dong TF, Chai H, Yu Y, Deng L, et al. Transplantation of bone marrow-derived mesenchymal stem cells after regional hepatic irradiation ameliorates thioacetamide-induced liver fibrosis in rats. J Surg Res. 2014;186:408–16.

    CAS  PubMed  Google Scholar 

  97. Alimoghaddam K, Mohamadnejad M, Mohyedin Bonab M, Bagheri M, Bashtar M, Ghanati H, et al. Phase 1 Trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med. 2008;10:459–66.

    Google Scholar 

  98. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–8.

    CAS  PubMed  Google Scholar 

  99. Amin MA, Sabry D, Rashed LA, Aref WM, el-Ghobary MA, Farhan MS, et al. Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant. 2013;27:607–12.

    PubMed  Google Scholar 

  100. Jang YO, Kim YJ, Baik SK, Kim MY, Eom YW, Cho MY, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int. 2014;34:33–41.

    CAS  PubMed  Google Scholar 

  101. Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 2013;28(Suppl 1):85–92.

    CAS  PubMed  Google Scholar 

  102. Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012;27(Suppl 2):112–20.

    CAS  PubMed  Google Scholar 

  103. Wang L, Han Q, Chen H, Wang K, Shan GL, Kong F, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev. 2014;23:2482–9.

    CAS  PubMed  Google Scholar 

  104. El-Ansary M, Abdel-Aziz I, Mogawer S, Abdel-Hamid S, Hammam O, Teaema S, et al. Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev Rep. 2012;8:972–81.

    CAS  PubMed  Google Scholar 

  105. Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009;21:1199–205.

    CAS  PubMed  Google Scholar 

  106. Terai S, Tanimoto H, Maeda M, Zaitsu J, Hisanaga T, Iwamoto T, et al. Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy. J Gastroenterol. 2012;47:491–7.

    PubMed  Google Scholar 

  107. Salama H, Zekri AR, Medhat E, Al Alim SA, Ahmed OS, Bahnassy AA, et al. Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease. Stem Cell Res Ther. 2014;5:70.

    PubMed  PubMed Central  Google Scholar 

  108. Xue HL, Zeng WZ, Wu XL, Jiang MD, Zheng SM, Zhang Y, et al. Clinical therapeutic effects of human umbilical cord-derived mesenchymal stem cells transplantation in the treatment of end-stage liver disease. Transplant Proc. 2015;47:412–8.

    PubMed  Google Scholar 

  109. Suk KT, Yoon JH, Kim MY, Kim CW, Kim JK, Park H, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology. 2016;64:2185–97.

    CAS  PubMed  Google Scholar 

  110. Rajaram R, Subramani B, Abdullah BJJ, Mahadeva S. Mesenchymal stem cell therapy for advanced liver cirrhosis: a case report. JGH Open. 2017;1:153–5.

    PubMed  PubMed Central  Google Scholar 

  111. Fang X, Liu L, Dong J, Zhang J, Song H, Song Y, et al. A study about immunomodulatory effect and efficacy and prognosis of human umbilical cord mesenchymal stem cells in patients with chronic hepatitis B-induced decompensated liver cirrhosis. J Gastroenterol Hepatol. 2018;33:774–80.

    CAS  PubMed  Google Scholar 

  112. Sakai Y, Fukunishi S, Takamura M, Kawaguchi K, Inoue O, Usui S, et al. Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy. Regen Ther. 2021;18:97–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Sakai Y, Takamura M, Seki A, Sunagozaka H, Terashima T, Komura T, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell. Regen Ther. 2017;6:52–64.

    PubMed  PubMed Central  Google Scholar 

  114. Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011;54:820–8.

    PubMed  Google Scholar 

  115. Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N, et al. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. Eur J Gastroenterol Hepatol. 2011;23:936–41.

    PubMed  Google Scholar 

  116. Detry O, Vandermeulen M, Delbouille MH, Somja J, Bletard N, Briquet A, et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I–II, open-label, clinical study. J Hepatol. 2017;67:47–55.

    PubMed  Google Scholar 

  117. Li Y, Xu Y, Wu HM, Yang J, Yang LH, Yue-Meng W. Umbilical cord-derived mesenchymal stem cell transplantation in hepatitis B virus related acute-on-chronic liver failure treated with plasma exchange and entecavir: a 24-month prospective study. Stem Cell Rev Rep. 2016;12:645–53.

    PubMed  Google Scholar 

  118. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1:725–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Nolta JA, Meyerrose TE, Rosova I. Working toward better tissue repair therapies: exposure of MSC to hypoxic conditions in vitro increases levels of the hepatocyte growth factor receptor c-met, improves motility, and induces phosphorylation of the pro-survival protein AKT. Blood. 2005;106:2313.

    Google Scholar 

  120. Wang Z, Wang L, Jiang R, Li C, Chen X, Xiao H, et al. Ginsenoside Rg1 prevents bone marrow mesenchymal stem cell senescence via NRF2 and PI3K/Akt signaling. Free Radic Biol Med. 2021;174:182–94.

    CAS  PubMed  Google Scholar 

  121. Li X, Wang T, Liu J, Liu Y, Zhang J, Lin J, et al. Effect and mechanism of wedelolactone as antioxidant-coumestan on OH-treated mesenchymal stem cells. Arab J Chem. 2020;13:184–92.

    CAS  Google Scholar 

  122. Mohammadi S, Barzegari A, Dehnad A, Barar J, Omidi Y. Astaxanthin protects mesenchymal stem cells from oxidative stress by direct scavenging of free radicals and modulation of cell signaling. Chem Biol Interact. 2021;333:109324.

    CAS  PubMed  Google Scholar 

  123. Zhou H, Yang J, Xin T, Li D, Guo J, Hu S, et al. Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free Radic Biol Med. 2014;77:363–75.

    CAS  PubMed  Google Scholar 

  124. Li X, Xie H, Jiang Q, Wei G, Lin L, Li C, et al. The mechanism of (+) taxifolin’s protective antioxidant effect for *OH-treated bone marrow-derived mesenchymal stem cells. Cell Mol Biol Lett. 2017;22:31.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Li S, Bian H, Liu Z, Wang Y, Dai J, He W, et al. Chlorogenic acid protects MSCs against oxidative stress by altering FOXO family genes and activating intrinsic pathway. Eur J Pharmacol. 2012;674:65–72.

    CAS  PubMed  Google Scholar 

  126. Huang CK, Lee SO, Lai KP, Ma WL, Lin TH, Tsai MY, et al. Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis. Hepatology. 2013;57:1550–63.

    CAS  PubMed  Google Scholar 

  127. Zheng YB, Zhang XH, Huang ZL, Lin CS, Lai J, Gu YR, et al. Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure. PLoS ONE. 2012;7:e41392.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kim JY, Jun JH, Park SY, Yang SW, Bae SH, Kim GJ. Dynamic regulation of miRNA expression by functionally enhanced placental mesenchymal stem cells promotes hepatic regeneration in a rat model with bile duct ligation. Int J Mol Sci. 2019;20:5299.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang J, Xu L, Chen Q, Zhang Y, Hu Y, Yan L. Bone mesenchymal stem cells overexpressing FGF4 contribute to liver regeneration in an animal model of liver cirrhosis. Int J Clin Exp Med. 2015;8:12774–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Lai L, Chen J, Wei X, Huang M, Hu X, Yang R, et al. Transplantation of MSCs overexpressing HGF into a rat model of liver fibrosis. Mol Imaging Biol. 2016;18:43–51.

    CAS  PubMed  Google Scholar 

  131. Cho JW, Lee CY, Ko Y. Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues. J Gastroenterol Hepatol. 2012;27:1362–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Choi JS, Jeong IS, Han JH, Cheon SH, Kim SW. IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity. Biomater Sci. 2019;7:1078–87.

    CAS  PubMed  Google Scholar 

  133. Hu G, Cui Z, Chen X, Sun F, Li T, Li C, et al. Suppressing mesenchymal stromal cell ferroptosis via targeting a metabolism-epigenetics axis corrects their poor retention and insufficient healing benefits in the injured liver milieu. Adv Sci (Weinh). 2023;10(13):e2206439.

    PubMed  Google Scholar 

  134. Chen H, Tang S, Liao J, Liu M, Lin Y. VEGF165 gene-modified human umbilical cord blood mesenchymal stem cells protect against acute liver failure in rats. J Gene Med. 2021;23(10):e3369.

    CAS  PubMed  Google Scholar 

Download references


Not applicable.


This study was supported by the National Natural Science Foundation of Fujian (No. 2020J011152), Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province,China (No. 2021ZQNZD014),  and the Project of Fuzhou Science and Technology Department (No. 2020-WS-56).

Author information

Authors and Affiliations



SY, SaY and HL searched literatures, collected data. SY and NL and wrote the initial draft of the manuscript. NL and XL designed tables and revised the manuscript. All the authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Naishun Liao or Xiaolong Liu.

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 The Creative Commons Public Domain Dedication waiver ( 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

Yu, S., Yu, S., Liu, H. et al. Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases. Stem Cell Res Ther 14, 235 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: