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Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis

Stem Cell Research & Therapy volume 12, Article number: 43 (2021) Cite this article

Abstract

Background

Mesenchymal stem cell (MSC) therapy shows great promise for diabetic kidney disease (DKD) patients. Research has been carried out on this topic in recent years. The main goals of this paper are to evaluate the therapeutic effects of MSCs on DKD through a meta-analysis and address the mechanism through a systematic review of the literature.

Method

An electronic search of the Embase, Cochrane Library, ISI Web of Science, PubMed, and US National Library of Medicine (NLM) databases was performed for all articles about MSC therapy for DKD, without species limitations, up to January 2020. Data were pooled for analysis with Stata SE 12.

Result

The MSC-treated group showed a large and statistically significant hypoglycemic effect at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, and 6 months. Total hypoglycemic effect was observed (SMD = − 1.954, 95%CI − 2.389 to − 1.519, p < 0.001; I2 = 85.1%). The overall effects on serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed, suggesting that MSC decreased SCr and BUN and mitigated the impairment of renal function (SCr: SMD = − 4.838, 95%CI − 6.789 to − 2.887, p < 0.001; I2 = 90.8%; BUN: SMD = − 4.912, 95%CI − 6.402 to − 3.422, p < 0.001; I2 = 89.3%). Furthermore, MSC therapy decreased the excretion of urinary albumin. Fibrosis indicators were assessed, and the results showed that transforming growth factor-β, collagen I, fibronectin, and α-smooth muscle actin were significantly decreased in the MSC-treated group compared to the control group.

Conclusion

MSCs might improve glycemic control and reduce SCr, BUN, and urinary protein. MSCs can also alleviate renal fibrosis. MSC therapy might be a potential treatment for DKD.

Introduction

Diabetes mellitus (DM) is a chronic metabolic disease with a rising incidence rate, and its microvascular and macrovascular complications are associated with a large global burden of morbidity and mortality [1]. Diabetic kidney disease (DKD) is a serious kidney-related complication that is present in approximately 40% of patients with DM [2], and patients with DKD have an increased risk of cardiovascular events and all-cause mortality [3]. Abnormal blood glucose status leads to oxidative stress and induces the release of inflammatory mediators, resulting in glomerular lesions in DM patients. The current evidence indicates that it is very difficult to prevent the progression of DKD. The creatinine clearance rate (CCr), serum creatinine (SCr), blood urea nitrogen (BUN), microalbuminuria, urinary albumin excretion, etc. are important indicators to assess the renal damage associated with DKD.

Mesenchymal stem cells (MSCs) are being used systemically or locally to treat many diseases, as they exhibit great self-renewal and differentiation potential [4, 5]. Stem cells are self-renewing, self-replicating pluripotent cells and can be classified according to their origin: embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Among them, adult stem cells, the undifferentiated cells in differentiated tissues, can be isolated from the bone marrow, adipose tissue, umbilical cord blood, and deciduous teeth. MSCs have been used for tissue regeneration and repair [6], treatment of inflammatory disease [7], prevention of transplant rejection [8], and other clinical applications.

At present, there are some data indicating that MSCs might improve complications from DM [9,10,11]. We conducted this systematic review and meta-analysis to evaluate the effects of MSC therapy on DKD.

Search strategy

We searched the Embase, Cochrane Library, ISI Web of Science, PubMed, and US National Library of Medicine (NLM) databases through January 2020 for original papers that assessed the effects of MSC administration on DKD animal models or patients without language restrictions. Keywords in this research included the following: (mesenchymal stem cells OR MSC OR multipotent stromal cells OR mesenchymal stromal cells OR mesenchymal progenitor cells OR Wharton jelly cells OR adipose-derived mesenchymal stem cells OR bone marrow stromal stem cells) AND (diabetic nephropathy OR DN OR diabetic kidney disease OR DKD).

Randomized controlled trials, comparative studies, or controlled trials that assessed the efficacy or safety of MSC therapy for treatment as an intervention in DKD animal models (without species limitations) or patients with DKD were included. The included studies were required to contain biochemical data on renal function or adverse events and to report albuminuria and impaired renal function in patients or animals with DM. The precise distinction between DKD and diabetic nephropathy (DN) was outside the scope of this paper, and both were included. Reviews, case reports, meta-analyses, comments, and letters were excluded. Articles that studied embryonic stem cells, induced pluripotent stem cells, or MSC components (rather than actual MSCs) for the treatment of DKD were excluded. In addition, studies that lacked a control arm or did not provide essential data such as renal function and sample size were excluded. We also searched for additional relevant reports by browsing the references of the articles.

Data extraction

The main features of the included studies were summarized, and the data were extracted independently by two authors using a standardized datasheet. Adverse events and biochemical indicator data were extracted from the articles, such as blood glucose, CCr, SCr, BUN, U-albumin/U-creatinine ratio (U-ACR), microalbuminuria, urinary albumin excretion, urine protein/Cr, kidney weight, body weight, and kidney weight/body weight ratio. If a paper contained no specific information, data were obtained by measuring the chart in the paper or by contacting the primary authors. Any disagreements in the extracted data were resolved by the third author.

Validity and quality assessment

For clinical trials, quality assessment was performed using 4 items based on the Jadad scale [12]: randomization, concealment of allocation, blinding method, and description of withdrawals and dropouts. A total score of ≥ 3 was considered high quality.

For animal studies, the methodological quality assessment was carried out using a risk of bias (RoB) tool by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE), which is based on the Cochrane RoB tool and adjusted for animal experiments. The following ten items were assessed. (1) Sequence generation: Were the subjects randomly assigned to the case or control groups with an adequately generated allocation sequence? (2) Baseline characteristics: Were the baseline characteristics of the two groups comparable? (3) Allocation concealment: Was the allocation of all the subjects adequately concealed? (4) Random housing: Were all the subjects randomly housed in the same environment during the experiment? (5) Researcher blinding: Were the researchers blinded to which subjects had received treatment (in this case, MSC treatment)? (6) Random outcome assessment: Were the animals selected in random order for outcome assessment? (7) Blinding of outcome assessors: Were the outcome assessors blinded to the group information? (8) Incomplete outcome data: Were incomplete outcome data or dropouts adequately addressed? (9) Selective outcome reporting: Was the study free of selective outcome reporting for significant results? (10) Other sources of bias: Was the study apparently free of other problems that could result in a high risk of bias, such as contamination of MSCs, inappropriate influence of the funder, errors in units of analysis, design-specific risk of bias, and additional animals to replace dropouts? An answer of “yes” means a low risk of bias, while “no” means a high risk of bias, and “unclear” means the risk of bias cannot be assessed for the lack of sufficient information. Disagreements were resolved by consensus-oriented discussion.

Statistical analysis

Stata SE 12 was used for statistical analysis. For continuous variables, standard mean differences (SMDs) were obtained by pooling the mean values, standard deviations, and sample sizes. For binary data, the odds ratio (OR) was calculated. Moreover, 95% confidence intervals (95%CIs) were calculated between the MSC-treated groups and the control groups. If there were multiple MSC-treated groups in an article, the data in the control group were reused. Heterogeneity across studies was quantified using I2 and was considered significant at a p value of < 0.1. The data were pooled using a fixed-effect model without heterogeneity or a random-effect model. A p value of < 0.05 was regarded as statistically significant for all analyses. Potential publication bias was assessed with Begg’s test, Egger’s test, and the trim-and-fill method.

Results

Search results

In total, 33 studies in 29 publications were included, among which 28 publications were based on animal studies [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40] and 1 was based on a clinical trial [41]. In addition, there are 4 ongoing clinical trials registered with the NLM.

Among 32 animal studies, 24 studies used rat models, 7 used mouse models, and 1 used a rhesus macaque model. A single method or a combination of multiple methods was used to induce DM, including streptozotocin (STZ) injection, high-fat diet dietary induction, nephrectomy, and natural development of models. However, the dosage and frequency of STZ injection and the time when the animals were tested for the establishment of DN were different. Although MSCs were used in all the included studies, the details of the source, dosage, frequency, administration, and point in time varied. The sources of MSCs were bone marrow mesenchymal stem cells (BM-MSCs) in 22 studies, adipose-derived stem cells (ADSCs) in 4 studies, human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in 5 studies, and stem cells from exfoliated deciduous teeth in 1 study. Allogeneic administration was used in 23 studies, xenoplastic administration was used in 8 studies, and autologous administration was used in 1 study. The characteristics of the included animal studies are summarized in Table 1.

Table 1 Main features of included studies (animal studies)
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The only clinical trial was a multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled study, finished in 2016. Thirty patients were randomized to receive one of two doses of mesenchymal precursor cells or placebo, and the efficacy and adverse events were observed. The main features of the clinical trial are shown in Table 2.

Table 2 Main features of included studies (clinical trials)
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None of the animal experiments reported the occurrence of graft rejection after administration, but 2 MSC-treated human patients developed antibodies specific to the donor HLA in the clinical trial, one of these cases occurred transiently, whereas the other presented at baseline and persisted throughout the observation period without the appearance of adverse events. Strangely, however, antibodies specific to the donor HLA were also found in one placebo-treated patient. Six animal experiments specified the deaths or dropouts. Lang and Dai [27] reported the deaths of 6 model rats during the construction of the diabetes model (21.4%, 6/28), and Wang et al. [21] reported 1 death each in the MSC-treated group (8.3%, 1/14) and the DN group (10%, 1/10) as well as 2 deaths because of anesthesia. In the study of Li et al. [32], no rat died in the DN group (0.0%, 0/14), and 2 died in the MSC-treated group (18.2%, 2/11). During a 12-week observation, the MSC-treated group (25%, 3/12) had lower mortality than the DN-treated group (66.7%, 8/12) [33]. Similarly, Xian et al. [34] found 2 deaths in the hUCB-MSC group (16.7%, 2/12), making for a markedly lower mortality rate than the T1DM group (40%, 6/15) at the end of the study. An et al. [39] found no marked change in the immune system of rhesus macaque DN models in response to hUCB-MSC treatment.

Quality assessment

Quality assessments of animal experiments and clinical trials were performed (Tables 3 and 4). Table 3 shows a number of “unclear” judgments in the quality assessment of animal experiments; in particular, outcome assessment in a random order, concealment of allocation and blinding of outcome assessors in all included experiments were rated “unclear,” largely due to a lack of awareness of randomization and blinding methods in animal experiments. As shown in Table 4, a total score of 7 suggested the high methodological quality of the included clinical trial.

Table 3 Quality assessment of animal intervention studies by SYRCLE
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Table 4 Quality assessment of clinical trials by Jadad score
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Assessment of glucose

Glucose was detected after MSC treatment in all but 2 studies [32, 37]. Sixteen studies measured glucose once at the end of the experiment [18,19,20,21, 23,24,25,26,27,28,29, 31, 33,34,35,36]. Seven studies conducted blood glucose monitoring at several points in time [14,15,16,17, 22, 30, 40]. Five studies, 7 studies, 5 studies, 12 studies, 17 studies, 7 studies, and 2 studies were included to assess the effect of treatment on blood glucose levels at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, and 6 months, respectively, all of which showed a highly significant hypoglycemic effect in the MSC-treated group (1 week: SMD = − 1.484, 95%CI − 2.586 to − 0.381, p < 0.001; I2 = 80.6%; 2 weeks: SMD = − 2.312, 95%CI − 3.743 to − 0.882, p = 0.002, I2 = 89.6%; 3 weeks: SMD = − 4.007, 95%CI − 6.472 to − 1.541, p = 0.001, I2 = 92.1%; 1 month: SMD = − 1.740, 95%CI − 2.660 to − 0.821, p < 0.001, I2 = 83.8%; 2 months: SMD = − 1.830, 95%CI − 2.633 to − 1.028, p < 0.001; I2 = 86.0%; 3 months: SMD = − 1.649, 95%CI − 2.838 to − 0.461, p = 0.007; I2 = 84.6%; 6 months: SMD = − 3.045, 95%CI − 5.895 to − 0.195, p = 0.036; I2 = 76.4%). The total hypoglycemic effect was also analyzed (SMD = − 1.954, 95%CI − 2.389 to − 1.519, p < 0.001; I2 = 85.1%) (Fig. 1).

Fig. 1
figure 1

The effect of MSC treatment on glycemic control. 1w, 1 week; 2w, 2 weeks; 3w, 3 weeks; 1m, 1 month; 2m, 2 months; 3m, 3 months; 6m, 6 months

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Assessment of serum creatinine

There were 4 studies, 2 studies, and 5 studies that assessed SCr at 1 month, 2 months, and 3 months, respectively. All of them showed significantly reduced creatinine values in the MSC-treated group (1 month: SMD = − 4.126, 95%CI − 7.936 to − 0.315, p = 0.034; I2 = 94.9%; 2 months: SMD = − 3.505, 95%CI − 4.746 to − 2.264, p < 0.001; I2 = 1.8%; 3 months: SMD = − 6.736, 95%CI − 10.311 to − 3.162, p < 0.001; I2 = 89.0%). The total effect on SCr was also analyzed, suggesting that MSCs decreased SCr and improved renal function (SMD = − 4.838, 95%CI − 6.789 to − 2.887, p < 0.001; I2 = 90.8%) (Fig. 2).

Fig. 2
figure 2

The effect of MSC treatment on serum creatinine. 1m, 1 month; 2m, 2 months; 3m, 3 months

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Assessment of blood urea nitrogen

BUN was evaluated at 5 different time points, each of which was used by relatively few studies. At 2 weeks (2 studies included), 3 weeks (2 studies included), 1 month (2 studies included), 2 months (3 studies included), and 3 months (4 studies included), BUN decreased in the MSC-treated group, although no statistical significance was seen at 3 weeks or 1 month (2 weeks: SMD = − 2.514, 95%CI − 3.582 to − 1.447, p < 0.001; I2 = 37.3%; 3 weeks: SMD = − 4.432, 95%CI − 9.220 to − 0.356, p = 0.070; I2 = 92.0%; 1 month: SMD = − 10.392, 95%CI − 21.247 to 0.464, p = 0.061; I2 = 95.6%; 2 months: SMD = − 3.389, 95%CI − 6.679 to − 0.099, p = 0.044; I2 = 89.8%; 3 months: SMD = − 5.902, 95%CI − 8.988 to − 2.815, p < 0.001; I2 = 85.0%). The total effect on BUN was also analyzed, suggesting that MSCs decreased BUN (SMD = − 4.912, 95%CI − 6.402 to − 3.422, p < 0.001; I2 = 89.3%) (Fig. 3).

Fig. 3
figure 3

The effect of MSC treatment on blood urea nitrogen (BUN). 2w, 2 weeks; 3w, 3 weeks; 1m, 1 month; 2m, 2 months; 3m, 3 months

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Assessment of creatinine clearance rate

The data of six studies were pooled to evaluate CCr at 2 months after MSC treatment; CCr was significantly decreased in the MSC-treated group compared to the DKD group (2 months: SMD = − 1.881, 95%CI − 2.842 to − 0.921, p < 0.001; I2 = 79.7%) (Fig. 4).

Fig. 4
figure 4

The effect of MSC treatment on a 2-month clearance of creatine rate (CCr)

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Assessment of blood insulin level

Two studies assessed insulinemia. The insulin level increased at 3 months after MSC treatment, although the significance was not notable (3 months: SMD = 3.051, 95%CI − 0.091 to 6.193, p = 0.057; I2 = 90.3%).

Assessment of urine protein

The measurement of urine protein varied in the included studies. Microalbuminuria, urinary albumin excretion, the urinary albumin/urinary creatinine ratio, and the urinary protein/creatinine ratio were used to assess urine protein excretion in the DKD animals.

Urinary albumin excretion levels at 1 month (2 studies included) and at 2 months (7 studies included) were observed to be lower in the MSC-treated group than in the DKD group, although no significance at 1 month was observed (1 month: SMD = − 6.507, 95%CI − 17.935 to 4.921, p = 0.264; I2 = 98.3%; 2 months: SMD = − 4.386, 95%CI − 5.891 to − 2.881, p < 0.001; I2 = 85.5%). The total effect on urinary albumin excretion was also analyzed, suggesting that MSCs decreased urinary albumin excretion (SMD = − 4.830, 95%CI − 6.602 to − 3.058, p < 0.001; I2 = 92.5%).

Microalbuminuria was detected at 3 weeks and 3 months; each of these time points was addressed by 2 studies that satisfied the inclusion criteria. Microalbuminuria was found to be decreased in the MSC-treated group at 3 months (3 weeks: SMD = − 9.112, 95%CI − 21.627 to 3.404, p = 0.154; I2 = 95.3%; 3 months: SMD = − 4.431, 95%CI − 5.771 to − 3.091, p < 0.001; I2 = 0.0%). The total effect on microalbuminuria was analyzed, suggesting that microalbuminuria was significantly lower in the MSC-treated group than in the DKD group (SMD = − 5.791, 95%CI − 8.681 to − 2.901, p < 0.001; I2 = 86.3%).

The urinary albumin/urinary creatinine ratios at 1 month (6 studies included) and at 2 months (10 studies included) were observed to be significantly lower in the MSC-treated group than in the untreated DKD group (1 month: SMD = − 2.419, 95%CI − 3.070 to − 1.769, p < 0.001; I2 = 0.0%; 2months: SMD = − 2.648, 95%CI − 3.454 to − 1.842, p < 0.001; I2 = 58.9%). The total effect on the urinary albumin/urinary creatinine ratio was analyzed, and the analysis suggested that the urinary albumin/urinary creatinine ratio was significantly lower in the MSC-treated group than in the DKD group (SMD = − 2.539, 95%CI − 3.075 to − 2.003, p < 0.001; I2 = 42.6%).

Urinary protein/creatinine ratios were not significantly different between the groups at 2 weeks (2 studies included) after MSC treatment (SMD = − 2.779, 95%CI − 7.617 to 2.059, p = 0.260; I2 = 92.6%).

Assessment of kidney weight

Kidney weight and the kidney weight/body weight ratio were used to assess kidney hypertrophy. No significant intergroup difference in kidney weight was found between the MSC and untreated DKD groups at 1 month (2 studies included; SMD = − 0.674, 95%CI − 2.052 to 0.704, p = 0.337; I2 = 67.0%).

The kidney weight/body weight ratio was found to be significantly decreased in the MSC-treated group at 2 months (8 studies included, SMD = − 1.364, 95%CI − 2.164 to − 0.565, p = 0.001; I2 = 79.7%), while no significant difference was found between the two groups at 3 months (2 studies included, SMD = − 10.012, 95%CI − 29.753 to 9.729, p = 0.320; I2 = 97.0%). The total effect on the kidney weight/body weight ratio was analyzed, and the analysis suggested that a reduced kidney weight/body weight ratio was found in the MSC-treated group (SMD = − 1.624, 95%CI − 2.594 to − 0.655, p = 0.001; I2 = 86.9%).

Assessment of body weight

There were 3 studies and 5 studies that assessed body weight at the 1-month and 2-month time points, respectively. No significant difference in 1-month body weight was found between the two groups (SMD = 2.634, 95%CI − 0.730 to 5.999, p = 0.125; I2 = 95.5%). At 2 months, the body weight of the MSC-treated groups significantly increased compared to that of the DKD groups (SMD = 0.903, 95%CI 0.346 to 1.459, p = 0.001; I2 = 40.2%). An overall effect of MSC treatment on body weight was also found (SMD = 1.499, 95%CI 0.461 to 2.536, p = 0.005; I2 = 87.3%).

Assessment of renal fibrosis

Four included studies evaluated the percentage of glomerulosclerosis at 2 months after MSC treatment, and no significant difference was found (SMD = − 0.350, 95%CI − 4.173 to 3.473, p = 0.858; I2 = 96.2%).

Transforming growth factor-β (TGF-β) was measured at different time points using different methods. According to polymerase chain reaction (PCR) assays at 1 month (2 studies included) and 2 months (3 studies included) as well as western blot (WB) assays at 2 months (2 studies included), TGF-β was significantly decreased in the MSC-treated group (1-month PCR: SMD = − 3.281, 95%CI − 4.225 to − 2.337, p < 0.001; I2 = 4.2%; 2-month PCR: SMD = − 7.594, 95%CI − 13.274 to − 1.915, p = 0.009; I2 = 93.6%; 2-month WB: SMD = − 9.329, 95%CI − 11.569 to − 7.089, p < 0.001; I2 = 16.2%). The same was true for the total expression of TGF-β (SMD = − 6.839, 95%CI − 9.367 to − 4.312, p < 0.001; I2 = 90.5%).

Collagen I (Col-I) was detected by immunohistochemistry (IHC) and PCR. According to PCR at 2 months (3 studies included), Col-I was significantly decreased (SMD = − 11.856, 95%CI − 14.887 to − 8.826, p < 0.001, I2 = 41.3%) in the MSC-treated group, although no significant intergroup difference was found by IHC at 2 months (2 studies included; SMD = − 4.714, 95%CI − 10.670 to 1.242, p = 0.121; I2 = 95.3%). An overall effect on Col-I expression was also found (SMD = − 9.081, 95%CI − 14.233 to − 3.929, p = 0.001; I2 = 95.1%).

Three included studies evaluated fibronectin (FN) by IHC at 2 months after MSC treatment, and a statistically significant decrease was found in the MSC-treated group (SMD = − 7.781, 95%CI − 10.680 to − 4.881, p < 0.001; I2 = 71.3%).

Two studies evaluated α-smooth muscle actin (α-SMA) by WB at 1 month after MSC treatment, and 3 studies quantified its expression by PCR at 2 months. Both measures of α-SMA expression were significantly decreased in the MSC-treated group (1-month WB: SMD = − 2.514, 95%CI − 3.550 to − 1.479, p < 0.001; I2 = 0.0%; 2-month PCR: SMD = − 2.098, 95%CI − 3.721 to − 0.476, p = 0.011; I2 = 83.4%). An overall effect of MSC treatment on the expression of α-SMA was found (SMD = − 2.249, 95%CI − 3.311 to − 1.186, p < 0.001; I2 = 72.1%).

E-cadherin was quantified by WB at 1 month (2 studies included) after MSC treatment; the treatment was associated with a significant and notable decrease in E-cadherin deposition (SMD = 3.600, 95%CI 2.338 to 4.861, p < 0.001; I2 = 0.0%).

Assessment of inflammatory mediators

Monocyte chemokine protein-1 (MCP-1) was detected by IHC at 2 months (2 studies included) after MSC treatment, and no significant difference was found between the two groups (SMD = − 8.913, 95%CI − 20.994 to 3.167, p = 0.148; I2 = 93.1%).

Tumor necrosis factor-α (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA) at 2 weeks (3 studies included) and by PCR at 1 month (2 studies included) after MSC treatment, both of which showed statistically significant decreases in the MSC-treated group (2-week ELISA: SMD = − 3.853, 95%CI − 7.207 to − 0.499, p = 0.024; I2 = 90.4%; 1-month PCR: SMD = − 4.369, 95%CI − 6.835 to − 1.903, p = 0.001; I2 = 57.5%). An overall effect of MSC treatment on the expression of TNF-α was found (SMD = − 4.027, 95%CI − 5.955 to − 2.098, p < 0.001; I2 = 84.9%).

Risk of bias

Given sufficient data to assess publication bias, 2-month blood glucose was used for measurement. There was some degree of bias, indicated by a moderate asymmetry of the funnel plot, and Egger’s test showed p = 0.013. However, the trim-and-fill method did not identify any missing studies (Fig. 5).

Fig. 5
figure 5

Publication bias. a Funnel plot. b Egger’s test. c Trim-and-fill method

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Discussion

Meta-analysis of medication in clinical trials is essential for clinical decisions in evidence-based medicine. Before medications are put into clinical use, preclinical experiments to explore their efficacy and safety must be performed, and these studies can be costly. In addition, in the absence of compelling evidence, testing directly on humans is both highly risky and unethical. A meta-analysis based on animals may provide a good reference to predict the outcomes of clinical trials. To evaluate the therapeutic effects of MSCs on DKD and review the mechanisms involved, we carried out this study. In this study, we performed a literature search with no species restrictions, yielding 32 animal studies in 28 publications and 1 clinical trial; on this basis, we conducted a meta-analysis of the animal studies and a systematic review.

The concept of DKD was proposed to replace DN in the Kidney Disease Outcomes Quality Initiative (K/DOQI) by the National Kidney Foundation (NKF) in 2007 and has been used to specify renal lesions caused by DM. DN is characterized by proteinuria ≥ 300 mg/day in a diabetic patient, with or without diabetic retinopathy and hypertension. However, with a new pathological classification of diabetic kidney lesions involving lesions of the tubules, interstitium, and/or vessels as determined by renal biopsy, the concept of DN has shifted to DKD in recent years focusing on clinical diagnosis. Because of the conceptual update, the precise distinction between DN and DKD was considered outside the scope of this study to avoid confusion, and both clinical entities were included.

In this paper, we found that MSCs might improve diabetic status, islet function, and glucose levels, as well as provide reno-protection. MSCs appeared to be effective in the treatment of diabetes, mitigating diabetic symptoms such as weight gain and decreased urine output and enhancing pancreatic islet function to improve inclusion secretion and glycemic control. Regarding the therapeutic effect of DKD, reductions in SCr, BUN, CCr, urinary protein, and renal hypertrophy were found in the MSC-treated group. In addition, molecular detection showed that MSCs might reduce the expression of renal fibrosis-related indicators, such as TGF-β, Col-I, FN, α-SMA, and E-cadherin, and the expression of inflammatory mediators such as MCP-1 and TNF-α.

To the best of our knowledge, this study is the first attempt to systemically evaluate MSC administration in DKD without species limitations. El-Badawy and El-Badri [42] conducted a meta-analysis of the therapeutic effects of different sources of stem cells in T1DM and T2DM by evaluating C-peptide, HbA1c, insulin requirements, and adverse effects, showing improved outcomes with stem cell therapy, especially CD34+ hematopoietic stem cell therapy. According to the study, the incidence of adverse effects was 21.72%, and no deaths were reported. To assess and quantify stem cells in animal studies of chronic kidney disease (CKD). Papazova et al. [43] performed a systematic review and meta-analysis and reported notable improvements in plasma creatinine, plasma urea, urinary protein, glomerular filtration rate (GFR), and blood pressure. Wang et al. [44] screened and pooled the data from small animal models of acute kidney injury (AKI) and CKD treated with MSCs and confirmed that impaired renal function was improved.

For glucose at 2 months, the moderate funnel plot asymmetry suggested the presence of bias, and Egger’s test showed p = 0.013; however, the trim-and-fill method did not show any missing studies. We detected significant heterogeneity, one of the inevitable drawbacks of animal meta-analyses; its causes may have included the following: different construction methods of animal models, different MSC treatment schemes, and different detection methods.

The therapeutic effects of MSC treatment seemed to be promising in animal studies, but the lone human investigation appeared to tell another story. That trial, a randomized, double-blind, placebo-controlled study of MSCs published in 2016, primarily assessed the safety over a 60-week follow-up and the efficacy over a 12-week follow-up. Regarding safety and tolerance, neither adverse events associated with MSCs nor persistent donor-specific anti-HLA antibodies were observed in the trial. However, except for interleukin-6 values and GFR stabilization, no significant difference from placebo was found in any other treatment outcome: urinary protein, CCr, lipid profile, HbA1c, blood pressure, TNF-α, adiponectin, TGF-β, uric acid, and fibroblast growth factor 23. Nevertheless, the results are not convincing, as they come from a single trial with a small sample size (N = 30).

Previous studies have indicated that MSCs can improve some other renal diseases. Chang et al. [45] assessed the effects of MSCs in an anti-Thy1.1-induced rat model of glomerulonephritis and found that intrarenal transplantation of MSCs with hypoxic preconditioning could reduce glomerular apoptosis, autophagy, and inflammation. Barbado et al. [46] conducted a clinical study in patients with lupus nephritis and found that MSC treatment dramatically improved proteinuria levels at the end of the first month, and the ameliorations were sustained throughout the follow-up period. Song et al. [47] conducted a study in rats with nephropathy induced by adriamycin (ADR) and showed that MSCs attenuated ADR-induced nephropathy by inhibiting NF-kB to diminish oxidative stress and inflammation and improve glomerulosclerosis and interstitial fibrosis.

How do MSCs improve renal lesions? MSC therapy has been reported to exert beneficial effects on renal impairment in animal models and patients [48,49,50]. However, the exact mechanisms of nephroprotection of MSCs remain unclear at present. To date, several potential mechanisms have been proposed. Immunoregulation is one important aspect, encompassing anti-inflammatory, antiapoptotic, and antioxidant action [51, 52]. In addition, one cannot ignore the inhibition of extracellular matrix accumulation, which may be achieved by promoting the secretion of antifibrotic factors and reducing the expression of renal fibrosis-related indicators [27, 53]. Protection of renal cells such as podocytes [51] and renal tubular epithelial cells [52] also deserves a place on the list. Proangiogenic potential is one of the functional characteristics of MSCs and may play a part in kidney repair [54]. Furthermore, attention should be paid to the homing of exogenously administered MSCs to specific parts or organs owing to the number of cells that come into play [15], and with the dedifferentiation of tubular cells into stem-like cells, there is a possibility of organ regeneration in AKI with MSC therapy [52].

In this study, a sensitivity analysis was performed, and we found that the results for sensitivity analysis were similar to those of non-sensitivity analyses. It might indicate that the results might be robust to some extent.

Limitations

Only one clinical trial was included in this study, meaning that human data were seriously lacking. As for animal experiments, notable heterogeneity and bias left the conclusions uncertain. Because of the limited longevity of animals, the included animal experiments generally had short observation periods. Heterogeneity was observed in this meta-analysis due to the factors such as the experimental models of DM (e.g., animal species, method used to induce diabetes, and type of diabetes) and MSC treatment (e.g., source, dosage, frequency and route of administration, and timing of administration in relation to the onset of diabetic kidney disease). Sensitivity analysis should be performed by omitting each individual study. Concomitant effects of glycemia confound interpretations about direct therapeutic effects on renal injury. MSC-related adverse events were also limited. Overall poor quality of the experimental studies incorporated in the meta-analysis was found, and further attention should be paid to the design methodology as well as animal experiments with higher quality and larger samples in the future. If preclinical experiments yield sufficient evidence of efficacy and safety, it is expected that more human investigations will be conducted in the future.

Conclusions

In animal models of DKD, MSCs might improve body weight, glycemic control, and pancreatic islet function to secrete insulin and reduce the SCr, BUN, CCr, urinary protein, and renal hypertrophy. MSCs can reduce the expression of inflammatory mediators and alleviate renal fibrosis. MSC therapy might be a potential treatment for DKD.

Availability of data and materials

Not applicable.

Abbreviations

MSC:

Mesenchymal stem cell

DKD:

Diabetic kidney disease

NLM:

National Library of Medicine

SYRCLE:

Systematic Review Centre for Laboratory Animal Experimentation

SCr:

Serum creatinine

BUN:

Blood urea nitrogen

CCr:

Creatinine clearance rate

UACR:

Urinary albumin/urinary creatinine ratio

TGF-β:

Transforming growth factor-β

Col-I:

Collagen I

FN:

Fibronectin

α-SMA:

α-Smooth muscle actin

TNF-α:

Tumor necrosis factor-α

PCR:

Polymerase chain reaction

WB:

Western blot

IHC:

Immunohistochemical

ELISA:

Enzyme-linked immunosorbent assay

GFR:

Glomerular filtration rate

DM:

Diabetes mellitus

DN:

Diabetic nephropathy

RoB:

Risk of bias

SMDs:

Standard mean differences

OR:

Odds ratio

CIs:

Confidence intervals

STZ:

Streptozotocin

BM-MSCs:

Bone marrow mesenchymal stem cells

ADSCs:

Adipose-derived stem cells

hUCB-MSCs:

Human umbilical cord blood-derived mesenchymal stem cells

K/DOQI:

Kidney Disease Outcomes Quality Initiative

NKF:

National Kidney Foundation

CKD:

Chronic kidney disease

References

  1. Daios S, Kaiafa G, Pilalas D, Nakou I, Kanellos I, Kirdas K, Despoudi K, Papanas N, Savopoulos C. Endothelial dysfunction and platelet hyperaggregation in type 2 diabetes mellitus: the era of novel anti-diabetic agents. Curr Med Chem. 2020. https://doi.org/10.2174/0929867327666201009143816.

  2. Ebaid H, Bashandy SAE, Abdel-Mageed AM, Al-Tamimi J, Hassan I, Alhazza IM. Folic acid and melatonin mitigate diabetic nephropathy in rats via inhibition of oxidative stress. Nutr Metab. 2020;17:6.

    Article  CAS  Google Scholar 

  3. Roy A, Maiti A, Sinha A, Baidya A, Basu AK, Sarkar D, Sanyal D, Biswas D, Maisnam I, Pandit K, et al. Kidney disease in type 2 diabetes mellitus and benefits of sodium-glucose cotransporter 2 inhibitors: a consensus statement. Diab Ther. 2020;11(12):2791–827.

    Article  CAS  Google Scholar 

  4. Fazal N, Khawaja H, Naseer N, Khan AJ, Latief N. Daphne mucronata enhances cell proliferation and protects human adipose stem cells against monosodium iodoacetate induced oxidative stress in vitro. Adipocyte. 2020;9(1):495–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhou T, Liao C, Lin S, Lin W, Zhong H, Huang S. The efficacy of mesenchymal stem cells in therapy of acute kidney injury induced by ischemia-reperfusion in animal models. Stem Cells Int. 2020;2020:1873921.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xuan K, Li B, Guo H, Sun W, Kou X, He X, Zhang Y, Sun J, Liu A, Liao L, et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci Transl Med. 2018;10(455):3227.

    Article  CAS  Google Scholar 

  7. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154(5):1334–1342.e1334.

    Article  PubMed  Google Scholar 

  8. Jurado M, De La Mata C, Ruiz-García A, López-Fernández E, Espinosa O, Remigia MJ, Moratalla L, Goterris R, García-Martín P, Ruiz-Cabello F, et al. Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: a phase I/II study. Cytotherapy. 2017;19(8):927–36.

    Article  CAS  PubMed  Google Scholar 

  9. Yu M, Liu W, Li J, Lu J, Lu H, Jia W, Liu F. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res Ther. 2020;11(1):350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen S, Du K, Zou C. Current progress in stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther. 2020;11(1):275.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yue C, Guo Z, Luo Y, Yuan J, Wan X, Mo Z. c-Jun overexpression accelerates wound healing in diabetic rats by human umbilical cord-derived mesenchymal stem cells. Stem Cells Int. 2020;2020:7430968.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  13. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A. 2006;103(46):17438–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ, Conget PA. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant. 2008;14(6):631–40.

    Article  CAS  PubMed  Google Scholar 

  15. Ezquer F, Ezquer M, Simon V, Pardo F, Yañez A, Carpio D, Conget P. Endovenous administration of bone-marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice. Biology Blood Marrow Transplant. 2009;15(11):1354–65.

    Article  CAS  Google Scholar 

  16. Zhou H, Tian HM, Long Y, Zhang XX, Zhong L, Deng L, Chen XH, Li XQ. Mesenchymal stem cells transplantation mildly ameliorates experimental diabetic nephropathy in rats. Chin Med J. 2009;122(21):2573–9.

    PubMed  Google Scholar 

  17. Zhou H, Gao Y, Tian HM. Bone marrow mesenchymal stem cell therapy on diabetic nephropathy in rats. Sichuan da xue xue bao Yi xue ban. 2009;40(6):1024–8.

    PubMed  Google Scholar 

  18. 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 

  19. Park JH, Hwang I, Hwang SH, Han H, Ha H. Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. Diabetes Res Clin Pract. 2012;98(3):465–73.

    Article  CAS  PubMed  Google Scholar 

  20. Park JH, Park J, Hwang SH, Han H, Ha H. Delayed treatment with human umbilical cord blood-derived stem cells attenuates diabetic renal injury. Transplant Proc. 2012;44(4):1123–6.

    Article  CAS  PubMed  Google Scholar 

  21. Wang S, Li Y, Zhao J, Zhang J, Huang Y. Mesenchymal stem cells ameliorate podocyte injury and proteinuria in a type 1 diabetic nephropathy rat model. Biology Blood Marrow Transplant. 2013;19(4):538–46.

    Article  CAS  Google Scholar 

  22. Zhang Y, Ye C, Wang G, Gao Y, Tan K, Zhuo Z, Liu Z, Xia H, Yang D, Li P. Kidney-targeted transplantation of mesenchymal stem cells by ultrasound-targeted microbubble destruction promotes kidney repair in diabetic nephropathy rats. Biomed Res Int. 2013;2013:526367.

    PubMed  PubMed Central  Google Scholar 

  23. Lv SS, Liu G, Wang JP, Wang WW, Cheng J, Sun AL, Liu HY, Nie HB, Su MR, Guan GJ. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. Int Immunopharmacol. 2013;17(2):275–82.

    Article  CAS  PubMed  Google Scholar 

  24. Lv S, Cheng J, Sun A, Li J, Wang W, Guan G, Liu G, Su M. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting oxidative stress. Diabetes Res Clin Pract. 2014;104(1):143–54.

    Article  CAS  PubMed  Google Scholar 

  25. Abdel Aziz MT, Wassef MA, Ahmed HH, Rashed L, Mahfouz S, Aly MI, Hussein RE, Abdelaziz M. The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diab Metab Syndrome. 2014;6(1):34.

    Article  CAS  Google Scholar 

  26. Lv S, Liu G, Sun A, Wang J, Cheng J, Wang W, Liu X, Nie H, Guan G. Mesenchymal stem cells ameliorate diabetic glomerular fibrosis in vivo and in vitro by inhibiting TGF-β signalling via secretion of bone morphogenetic protein 7. Diab Vasc Dis Res. 2014;11(4):251–61.

    Article  CAS  PubMed  Google Scholar 

  27. Lang H, Dai C. Effects of bone marrow mesenchymal stem cells on plasminogen activator Inhibitor-1 and renal fibrosis in rats with diabetic nephropathy. Arch Med Res. 2016;47(2):71–7.

    Article  CAS  PubMed  Google Scholar 

  28. Nagaishi K, Mizue Y, Chikenji T, Otani M, Nakano M, Konari N, Fujimiya M. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep. 2016;6:34842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamza AH, Al-Bishri WM, Damiati LA, Ahmed HH. Mesenchymal stem cells: a future experimental exploration for recession of diabetic nephropathy. Ren Fail. 2017;39(1):67–76.

    Article  PubMed  Google Scholar 

  30. Nagaishi K, Mizue Y, Chikenji T, Otani M, Nakano M, Saijo Y, Tsuchida H, Ishioka S, Nishikawa A, Saito T, et al. Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy. Sci Rep. 2017;7(1):8484.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rashed LA, Elattar S, Eltablawy N, Ashour H, Mahmoud LM, El-Esawy Y. Mesenchymal stem cells pretreated with melatonin ameliorate kidney functions in a rat model of diabetic nephropathy. Biochem Cell Biol. 2018;96(5):564–71.

    Article  CAS  PubMed  Google Scholar 

  32. Li Y, Liu J, Liao G, Zhang J, Chen Y, Li L, Li L, Liu F, Chen B, Guo G, et al. Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment. Int J Mol Med. 2018;41(5):2629–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bai Y, Wang J, He Z, Yang M, Li L, Jiang H. Mesenchymal stem cells reverse diabetic nephropathy disease via Lipoxin A4 by targeting transforming growth factor β (TGF-β)/smad pathway and pro-inflammatory cytokines. Med Sci Monit. 2019;25:3069–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xian Y, Lin Y, Cao C, Li L, Wang J, Niu J, Guo Y, Sun Y, Wang Y, Wang W. Protective effect of umbilical cord mesenchymal stem cells combined with resveratrol against renal podocyte damage in NOD mice. Diabetes Res Clin Pract. 2019;156:107755.

    Article  CAS  PubMed  Google Scholar 

  35. Cai X, Wang L, Wang X, Hou F. miR-124a enhances therapeutic effects of bone marrow stromal cells transplant on diabetic nephropathy-related epithelial-to-mesenchymal transition and fibrosis. J Cell Biochem. 2020;121(1):299–312.

    Article  CAS  PubMed  Google Scholar 

  36. Lee SE, Jang JE, Kim HS, Jung MK, Ko MS, Kim MO, Park HS, Oh W, Choi SJ, Jin HJ, et al. Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells. Exp Mol Med. 2019;51(7):77.

    Article  PubMed Central  CAS  Google Scholar 

  37. Takemura S, Shimizu T, Oka M, Sekiya S, Babazono T. Transplantation of adipose-derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model. J Diab Invest. 2020;11(3):545–53.

    Article  CAS  Google Scholar 

  38. 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  PubMed Central  CAS  Google Scholar 

  39. An X, Liao G, Chen Y, Luo A, Liu J, Yuan Y, Li L, Yang L, Wang H, Liu F, et al. Intervention for early diabetic nephropathy by mesenchymal stem cells in a preclinical nonhuman primate model. Stem Cell Res Ther. 2019;10(1):363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rao N, Wang X, Xie J, Li J, Zhai Y, Li X, Fang T, Wang Y, Zhao Y, Ge L. Stem cells from human exfoliated deciduous teeth ameliorate diabetic nephropathy in vivo and in vitro by inhibiting advanced glycation end product-activated epithelial-mesenchymal transition. Stem Cells Int. 2019;2019:2751475.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Packham DK, Fraser IR, Kerr PG, Segal KR. Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: a randomized, placebo-controlled, dose escalation study. EBioMedicine. 2016;12:263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  42. El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis. PLoS One. 2016;11(4):e0151938.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Papazova DA, Oosterhuis NR, Gremmels H, van Koppen A, Joles JA, Verhaar MC. Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis. Dis Model Mech. 2015;8(3):281–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang Y, He J, Pei X, Zhao W. Systematic review and meta-analysis of mesenchymal stem/stromal cells therapy for impaired renal function in small animal models. Nephrology (Carlton). 2013;18(3):201–8.

    Article  CAS  Google Scholar 

  45. Chang HH, Hsu SP, Chien CT. Intrarenal transplantation of hypoxic preconditioned mesenchymal stem cells improves glomerulonephritis through anti-oxidation, anti-ER stress, anti-inflammation, anti-apoptosis, and anti-autophagy. Antioxidants (Basel). 2019;9(1):2.

    Article  CAS  Google Scholar 

  46. Barbado J, Tabera S, Sánchez A, García-Sancho J. Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis. Lupus. 2018;27(13):2161–5.

    Article  CAS  PubMed  Google Scholar 

  47. Song IH, Jung KJ, Lee TJ, Kim JY, Sung EG, Bae YC, Park YH. Mesenchymal stem cells attenuate adriamycin-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of the NF-kB. Nephrology (Carlton). 2018;23(5):483–92.

    Article  CAS  Google Scholar 

  48. Rosselli DD, Mumaw JL, Dickerson V, Brown CA, Brown SA, Schmiedt CW. Efficacy of allogeneic mesenchymal stem cell administration in a model of acute ischemic kidney injury in cats. Res Vet Sci. 2016;108:18–24.

    Article  CAS  PubMed  Google Scholar 

  49. Ashour RH, Saad MA, Sobh MA, Al-Husseiny F, Abouelkheir M, Awad A, Elghannam D, Abdel-Ghaffar H, Sobh M. Comparative study of allogenic and xenogeneic mesenchymal stem cells on cisplatin-induced acute kidney injury in Sprague-Dawley rats. Stem Cell Res Ther. 2016;7(1):126.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Ruiz-Argüelles GJ, León-Peña AA, León-González M, Nuñez-Cortes AK, Olivares-Gazca JC, Murrieta-Alvarez I, Vargas-Espinosa J, Medina-Ceballos E, Cantero-Fortiz Y, Ruiz-Argüelles A, et al. A feasibility study of the full outpatient conduction of hematopoietic transplants in persons with multiple sclerosis employing autologous non-cryopreserved peripheral blood stem cells. Acta Haematol. 2017;137(4):214–9.

    Article  PubMed  CAS  Google Scholar 

  51. Ko SF, Chen KH, Wallace CG, Yang CC, Sung PH, Shao PL, Li YC, Chen YT, Yip HK. Protective effect of combined therapy with hyperbaric oxygen and autologous adipose-derived mesenchymal stem cells on renal function in rodent after acute ischemia-reperfusion injury. Am J Transl Res. 2020;12(7):3272–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Tsuji K, Kitamura S, Sang Y, Fukushima K, Wada J. Adult kidney stem/progenitor cells contribute to regeneration through the secretion of trophic factors. Stem Cell Res. 2020;46:101865.

    Article  CAS  PubMed  Google Scholar 

  53. Kholia S, Herrera Sanchez MB, Cedrino M, Papadimitriou E, Tapparo M, Deregibus MC, Brizzi MF, Tetta C, Camussi G. Human liver stem cell-derived extracellular vesicles prevent aristolochic acid-induced kidney fibrosis. Front Immunol. 2018;9:1639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Tögel F, Zhang P, Hu Z, Westenfelder C. VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. J Cell Mol Med. 2009;13(8b):2109–14.

    Article  PubMed  Google Scholar 

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This study was supported by Guangdong Medical Science and Technology Research Fund Project (no. A2018336).

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  1. Wenshan Lin and the Hong-Yan Li authors should be regarded as joint first authors.

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  1. Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China

    Wenshan Lin, Qian Yang, Guangyong Chen, Shujun Lin, Chunling Liao & Tianbiao Zhou

  2. Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou, China

    Hong-Yan Li

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TBZ contributed to the conception and design of the study. WSL, HYL, and TBZ were responsible for the collection of data and performed the statistical analysis and manuscript preparation. SJL, QY, GYC, and CLL were responsible for checking the data. All authors were responsible for the drafting of the manuscript and read and approved the final version.

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Lin, W., Li, HY., Yang, Q. et al. Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis. Stem Cell Res Ther 12, 43 (2021). https://doi.org/10.1186/s13287-020-02108-5

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Keywords

  • Mesenchymal stem cell
  • Diabetic kidney disease
  • Animal study
  • Clinical trial
  • Meta-analysis
  • Systematic review

Stem Cell Research & Therapy

ISSN: 1757-6512