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Table 1 Main features of included studies (animal studies)

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

  PMID Year Author Country Sample size Model features Comparison Stem cell species Intervention Observed indicators Duration
1 18,489,988 2008 Ezquer et al. Chile 16 STZ was injected intraperitoneally at a dose of 40 mg/kg, for 5 consecutive days. STZ + MSCs vs STZ + vehicle C57BL/6 mouse bone marrow (allogeneic transplantation) Twenty-five days after the first STZ dose, mice received 0.5 × 106 MSCs or the vehicle via the tail vein. Blood glucose; urinary glucose; intraperitoneal glucose tolerance test; urine albumin/creatinine ratio; pancreas and kidney histopathology 62 days
2 19,822,294 2009 Ezquer et al. Chile 16 C57BL/6 mice received intraperitoneally 200 mg/kg STZ. STZ + MSCs vs STZ + vehicle C57BL/6 mouse bone marrow (allogeneic transplantation) Thirty and 51 days after STZ injection, animals received via the tail vein the vehicle (untreated) or 0.5 × 106 MSC (MSC treated). Blood glucose; urinary glucose; insulinemia; serum creatinine; urine albumin/creatinine ratio; pancreas and kidney histopathology; kidney weight/body mass ratio 90 days
3 19,951,572 2009 Zhou et al. China 32 The male rats received a single intraperitoneal injection of STZ (60 mg/kg). STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) 2 × 106 labeled MSCs per animal in 0.2 mL SFM were given via the left cardiac ventricle. Control diabetic animals were treated identically but infused with 0.2 mL SFM instead of cells. Blood glucose; kidney weight/body mass ratio; urine albumin/creatinine ratio; blood pressure; creatinine clearance rate; kidney histopathology 2 months
4 20,067,112 2009 Zhou et al. China 24 A single intraperitoneal injection of STZ (60 mg/kg) was given to SD rats. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) 2 × 106/200 μL MSCs were given via the left cardiac ventricle. A week later, the second intracardiac injection of the MSCs was performed. Control diabetic animals received 200 μL serum-free DMEM-LG. Blood glucose; body mass; urine protein; kidney/body mass ratio; creatinine clearance rate; kidney histopathology 2 months
5 22,552,764 2012 Fang et al. China 24 Rats were injected intraperitoneally with 40 mg/kg body weight of STZ for 5 consecutive days. STZ + MSCs vs STZ + vehicle SD rat adipose tissue (autologous transplantation) Intravenous infusion of autologous ADMSCs (1.0 × 107) was performed 4 weeks after the onset diabetes via the tail vein. Animals in the vehicle group received an equal volume of culture medium at the same time. Blood glucose; insulinemia; cholesterol; triglycerides; BUN; creatinine; malondialdehyde; TNF-α; IL-1β; IL-6; renal morphology 12 weeks
6 22,564,642 2012 Park et al. Korea 14 Experimental diabetes was induced by intravenous injection of STZ (50 mg/kg). STZ + MSCs vs STZ + vehicle Human umbilical cord blood (xenoplastic transplantation) hUCB-SC (1 × 106 cells/rat) were infused through the tail vein 4 weeks after the STZ injection. Both diabetic and diabetic rats treated with hUCB-SC were injected subcutaneously with insulin (2 U/day/rat) to maintain blood glucose levels of 350 to 500 mg/dL. Blood glucose; body mass; kidney weight; creatinine; urinary protein; fibronectin; α-SMA; E-cadherin 1 month
7 23,026,513 2012 Park et al. Korea 14 Experimental diabetes was induced by injecting 50 mg/kg STZ through the tail vein. STZ + MSCs vs STZ + vehicle Human umbilical cord blood (xenoplastic transplantation) hUCB-MSC were infused at a dose of 5 × 105 cells/rat through the tail vein 2 days after the STZ injection when blood glucose was > 350 mg/dL. Blood glucose; body mass; kidney weight; creatinine; urinary protein; kidney histopathology; BMP-7; TGF-β1; fibronectin; α-SMA; E-cadherin 1 month
8 23,295,166 2013 Wang et al. China 17 Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) in the rats following overnight fasting. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) MSC-treated DN rats were injected with 2 × 106 MSC via the left renal artery. All the diabetic rats received daily injections of insulin to maintain blood glucose levels between 16 and 28 mmol/L. Blood glucose; body mass; kidney weight; kidney/body mass ratio; creatinine clearance rate; urine albumin/creatinine ratio; creatinine; renal morphology; nephrin; podocin; VEGF; BMP-7 2 months
9 23,762,850 2013 Zhang et al. China 20 SD rats were anesthetized and received a single intraperitoneal injection of 60 mg/kg STZ. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) MSCs (1 × 106) were resuspended in 2 mL of PBS and administrated to anesthetized rats through tail vein. Blood glucose; insulinemia; urine albumin/creatinine ratio; kidney and pancreas histopathology; VCAM-1; TGF-β1; IL-10; synaptopodin 8 weeks
10 23,791,972 2013 Lv et al. China 32 Diabetes was induced in the female Wistar rats by a single intraperitoneal injection of STZ (60 mg/kg) after one-night fasting. STZ + MSCs vs STZ + vehicle Wistar rat bone marrow (allogeneic transplantation) MSCs were transplanted via the tail vein at a concentration of 2 × 106 in 0.5 mL serum-free media once a week for 2 continuous weeks. Blood glucose; urinary albumin excretion; creatinine clearance rate; kidney/body mass ratio; kidney histopathology; ED-1; MCP-1; collagen I; fibronectin; IL-1β; IL-6; TNFα; HGF 8 weeks
11 24,513,119 2013 Lv et al. China 24 Following one night of fasting, a single injection of STZ (60 mg/kg) was given intraperitoneally to induce diabetes. STZ + MSCs vs STZ + vehicle Wistar rat bone marrow (allogeneic transplantation) MSCs were transplanted via the tail vein at a concentration of 2 × 106 in 0.5 mL serum-free media once a week for 2 continuous weeks. Blood glucose; urinary albumin excretion; creatinine clearance rate; kidney/body mass ratio; renal histopathology; collagen I; FN; TGF-β; MDA; SOD; ROS 8 weeks
12 24,606,996 2014 Abdel Aziz et al. Egypt 40 Diabetes of female albino rats was induced by a single intraperitoneal injection of STZ (60 mg/kg body weight). STZ + MSCs vs STZ + vehicle White albino rat bone marrow (allogeneic transplantation) DN rats received MSCs in a single dose of 106 cells per rat by intravenous injection in the rat tail vein. Blood glucose; BUN; creatinine; urinary albumin excretion; body weight; renal histopathology; TGF β; TNFα; bcl2; Bax; VEGF 4 weeks
13 24,845,071 2015 Lv et al. China 24 A single injection of STZ (60 mg/kg) was given via intraperitoneal injection to induce diabetes following one-night fasting. STZ + MSCs vs STZ + vehicle Wistar rat bone marrow (allogeneic transplantation) MSCs were transplanted via the tail vein at a concentration of 2 × 106 in 0.5 mL serum-free media once a week for two continuous weeks. Blood glucose; urinary albumin excretion; creatinine clearance rate; kidney/body mass ratio; renal histopathology; TGF-β; collagen I; collagen IV; α-SMA; E-cadherin; BMP7; Smad2; Smad3 8 weeks
14 27,018,336 2016 Lang et al. China 20 After fasting 12 h, SD rats were given STZ 55 mg/kg by i.p. injection. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) For rats in the MSC group, intravenous infusion of autologous MSCs (2 × 106/mL) was performed 4 weeks after the onset of diabetes via the tail vein. Blood glucose; body weight; urinary protein; creatinine; renal mass index; kidney histopathology; MMP- 9; PAI-1; TGF-β1; Smad3 12 weeks
15 27,721,418 2016 Nagaishi et al. Japan 12 Diabetes was induced via an HFD containing 60% lard (high-fat diet 32) for 28 weeks. HFD + MSCs vs HFD + vehicle C57BL/6-GFP-transgenic mouse bone marrow (allogeneic transplantation) C57BL/6J mice were administered 1.0 × 104 MSCs/g body weight 4 times (HFD-MSC) every 2 weeks. Blood glucose; urine albumin/creatinine ratio; kidney histopathology; ICAM-1; TNF-α; megalin; TGF-β; ZO-1 8 weeks
16 27,721,418 2016 Nagaishi et al. Japan 12 Diabetes was induced by a single intraperitoneal injection of STZ (150 mg/kg). STZ + MSCs vs STZ + vehicle C57BL/6-GFP-transgenic mouse bone marrow (allogeneic transplantation) C57BL/6J mice were administered 1.0 × 104 MSCs/g body weight 2 times (STZ-MSC) every 4 weeks. Blood glucose; urine albumin/creatinine ratio; kidney histopathology; ICAM-1; TNF-α; megalin; TGF-β; ZO-1 8 weeks
17 27,774,826 2016 Hamza et al. Egypt 20 Albino Wistar rats were given a single intraperitoneal injection of a mixture of 70 mg/kg STZ. STZ + MSCs vs STZ Albino rat bone marrow (allogeneic transplantation) Rats were given a single-dose intravenous treatment of 1.0 × 106 cells per subject. Blood glucose; insulinemia; BUN; creatinine; uric acid; serum total protein; serum albumin; urinary urea, urinary creatinine; microalbumin; kidney histopathology; HO-1; AGEP; FGF; PDGF; TGF-β; IL-8; MCP-1 3 weeks
18 28,814,814 2016 Nagaishi et al. Japan 8 C57BL/6 mice were given a single intraperitoneal administration high dose (150 mg/kg) of STZ. STZ + MSCs vs STZ + vehicle SD rat bone marrow (xenoplastic transplantation) Mice were administered 4 times with 1 × 104 MSCs/g body weight via the tail vein every 2 weeks. Blood glucose; urine albumin/creatinine ratio; kidney histopathology 8 weeks
19 28,814,814 2016 Nagaishi et al. Japan 10 SD rats were given a single tail vein injection of 55 mg/kg of STZ. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) Rats were administered 1 × 104 MSCs/g body weight via the tail vein. Blood glucose; urine albumin/creatinine ratio; kidney histopathology 8 weeks
20 28,814,814 2016 Nagaishi et al. Japan 16 OLETF rats developed diabetes and DN with natural course. OLETF + MSCs vs OLETF + vehicle LETF rat bone marrow (allogeneic transplantation) Rats were administered 1 × 104 MSCs/g body weight via the tail vein. Blood glucose; urine albumin/creatinine ratio; kidney histopathology 8 weeks
21 29,425,466 2018 Rashed et al. Egypt 20 Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). STZ + vehicle vs STZ + MSCs Wistar strain Albino rat bone marrow (allogeneic transplantation) DN rats treated with a single injection of 1 × 106 labeled MSCs per animal in 0.5 mL serum-free medium into the tail vein. Blood glucose; insulinemia; BUN; creatinine; creatinine clearance rate; urinary albumin excretion; kidney histopathology; TNF-α; IL-10; SOD; TGF-β; Beclin-1 2 weeks
22 29,484,379 2018 Li et al. China 25 Diabetes was induced by a single intraperitoneal injection of 55 mg/kg STZ. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) 2, 4, 5, and 7 weeks after successful establishment of the diabetes model, MSCs were transplanted via the tail vein at a concentration of 5 × 106 cells. Microalbumin; urine albumin/creatinine ratio; BUN; kidney histopathology; MCP-1; IL-1β; TNF- α; ICAM-1; CD68; TGF- β; fibronectin; IL-1 α; IL-2; IL-6; EGF; IL-10; TNF- α; IFN- γ; GRO; VEGF 8 weeks
23 31,023,998 2019 Bai et al. China 24 Diabetes was induced by a single intraperitoneal injection of 60 mg/kg STZ after 1-night fasting. STZ + MSCs vs STZ + vehicle SD rat bone marrow (allogeneic transplantation) MSCs were transplanted via the tail vein at a concentration of 5 × 106 in 0.5 mL PBS once a week for 2 continuous weeks. Blood glucose; creatinine; BUN; urinary glucose; microalbumin; albumin/creatinine ratio; kidney histopathology; TGF-β; Smad2/3; phosphorylated Smad2; phosphorylated Smad3; IFN- γ; IL-8; IL-6; TNF-α 12 weeks
24 31,150,720 2019 Xian et al. China 19 Healthy female NOD mice were purchased. When two consecutive tests showed a blood glucose level > 16.6 mmol/L, the mouse was diagnosed with T1DM. NOD-T1DM + MSCs vs NOD-T1DM Human umbilical cord-derived MSCs (xenoplastic transplantation) 1 × 106 hUCMSCs suspended in 0.3 mL of phosphate-buffered saline (PBS) were injected into the tail vein on the 3rd day after diabetes onset (only once). Blood glucose; weight; creatinine; BUN; urinary albumin excretion; MCP-1; RAGE; nephrin; WT1; NF-κB 8 weeks
25 31,190,436 2019 Cai et al. China 20 Wistar rats were provided with a prepared HFD for 6 weeks and then injected with 60 mg/kg STZ for 2 weeks. HFD + STZ + MSCs vs HFD + STZ + vehicle Rat bone marrow stromal cells (allogeneic transplantation) Rats treated with 2 × 106 labeled MSCs per animal via the tail vein. Blood glucose; creatinine; BUN; alanine aminotransferase; 24 h urine volume; urine protein; urinary albumin excretion; renal histopathology; p-cadherin; synaptopodin; FSP-1; α-SMA; snail; fibronectin; collagen I 12 weeks
26 31,285,429 2019 Lee et al. Korea 14 CD1 mice were intraperitoneally injected with STZ 80 mg/kg for 3 days. STZ + MSCs vs STZ + vehicle Human umbilical cord-derived MSCs (xenoplastic transplantation) Five weeks after the induction of diabetes, human umbilical cord blood-derived MSCs were administered to mice three times. Blood glucose; creatinine; BUN; urine albumin/creatinine ratio 19 weeks
27 31,622,047 2019 Takemura et al. Japan 10 SDT fatty rats formed a spontaneously obese type 2 diabetes model and were subjected to right nephrectomy. Nephrectomy + MSCs vs nephrectomy EGFP rat subcutaneous adipose tissue (allogeneic transplantation) 1 mL of the adipose-derived mesenchymal stem cell suspension (6.0 × 106 cells/mL) was administered via the femoral vein. Albuminuria; proteinuria; urinary creatinine; podocalyxin; L-FABP; KIM-1; TNF-α; IL-6; renal histopathology 2 weeks
28 31,622,047 2019 Takemura et al. Japan 11 SDT fatty rats formed a spontaneously obese type 2 diabetes model and were subjected to right nephrectomy. Nephrectomy + MSCs vs nephrectomy EGFP rat subcutaneous adipose tissue (allogeneic transplantation) Adipose-derived mesenchymal stem cell sheets were laminated in three layers under the renal capsule using a cell sheet transfer device. Albuminuria; proteinuria; urinary creatinine; podocalyxin; L-FABP; KIM-1; TNF-α; IL-6; renal histopathology 2 weeks
29 31,747,961 2019 Yu et al. China 12 SD rats were fed a HFD for 8 weeks, followed by an STZ injection at a single dose of 25 mg/kg. HFD feeding was maintained in the newly diabetic rats for 24 weeks. HFD + STZ + MSCs vs HFD + STZ + vehicle SD rat adipose tissue (allogeneic transplantation) Rats were treated through the tail vein with a single infusion of 3 × 106 ADSCs once a week for 24 weeks. Blood glucose; creatinine; BUN; urine albumin/creatinine ratio; ALT; AST; ALP; LDL-C; TC; TG; renal histopathology; insulin; glucagon; collagen I; α-SMA; CD163; albumin; SP-C; CD206; PI3K; p-AKT; IL-1β; IL-6; IL-10; TNF-α 25 weeks
30 31,791,397 2019 An et al. China 12 Rhesus macaques were administered a single high dose of STZ (80 mg/kg) intravenously. Insulin was used to maintain the FBG level at 15–20 mmol/L. STZ + MSCs vs STZ + vehicle Human umbilical cord-derived MSCs (xenoplastic transplantation) MSCs from a single donor were suspended in 100 mL normal saline and delivered at a density of 2 × 106 cells/kg to one DN rhesus macaque at an infusion rate of 45–50 drops/min. A total of four times of MSC transplantation were performed during 2 months. Blood glucose; serum creatinine; BUN; uric acid; LDL-C; HDL-C; TC; TG; HbA1c; eGFR; microalbumin; urinary creatinine; urine albumin/creatinine ratio; body weight; renal histopathology; IL-1β; IL-16; IL-8; IL-6; IL-10; TNF-α; TGF-β; CCL-5; SGLT-2 1 year
31 31,871,464 2019 Rao et al. China 18 GK rats were given a HFD for 2–4 weeks. HFD + MSCs vs HFD + vehicle Human bone marrow MSCs from donors aged 16–20 (xenoplastic transplantation) A total of 4 × 106 MSC cells were administered via the tail vein to each rat. Blood glucose; body weight; serum cholesterol; serum triglycerides; urinary albumin; kidney/body mass ratio; renal histopathology; α-SMA; Col I; fibronectin; lamininβ; nephrin; synaptopodin; IL-1β; IL-6; IL-10; TNF-α; TGF-β; HGF 8 weeks
32 31,871,464 2019 Rao et al. China 20 GK rats were given HFD for 2–4 weeks. HFD + MSCs vs HFD + vehicle Human exfoliated deciduous tooth stem cells from donors aged 6–8 (xenoplastic transplantation) A total of 4 × 106 MSC cells were administered via the tail vein to each rat. Blood glucose; body weight; serum cholesterol; serum triglycerides; urinary albumin; kidney/body mass ratio; renal histopathology; α-SMA; Col I; fibronectin; lamininβ; nephrin; synaptopodin; IL-1β; IL-6; IL-10; TNF-α; TGF-β; HGF 8 weeks
  1. SD Sprague-Dawley, SFM serum-free medium, HFD high-fat diet, BUN blood urea nitrogen, NOD non-obesity diabetes, OLETF Otsuka Long-Evans Tokushima Fatty, LETO Long-Evans Tokushima Otsuka, MDA malondialdehyde, SOD superoxide dismutase, ICAM-1 intracellular adhesion molecule-1, ZO-1 zona occludens protein-1, HO-1 heme-oxygenase-1, AGEP advanced glycation end product, FGF fibroblast growth factor, PDGF platelet-derived growth factor, EGF epidermal growth factor, RAGE advanced glycation end products, FSP-1 fibroblast-specific protein-1, L-FABP liver-type fatty acid-binding protein, KIM-1 kidney injury molecule-1, ALT alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase, LDL-C low-density lipoprotein cholesterol, TC total cholesterol, TG triglyceride, SP-C pro-surfactant protein C, eGFR estimated glomerular filtration rate, SGLT-2 Na + -glucose cotransporter 2