Table 1.
Preclinical studies of mesenchymal stem cell therapy on animal models of diabetic nephropathy.
| MSC types | Experimental models | Treatment | Effects on DN | Reverse the hyperglycemia or not | Reference | |
|---|---|---|---|---|---|---|
| Injection methods | Frequency and Dose | |||||
| BM-MSCs | ||||||
| Human BM-MSCs | STZ-induced type I NOD/SCID mice | Intracardiac infusion |
Days 10 and 17 2.5 × 106 |
➢ Pancreatic islets and cells producing mouse insulin has increased ➢ A decrease in mesangial thickening and in macrophage infiltration |
Yes | Lee et al.19 |
| Mice BM-MSCs | STZ-induced type I C57BL/6 mice | Tail vein injection |
Two doses (interval of 21 days) 0.5 × 106 |
➢ MSC-treated mice showed only slight tubular dilatation ➢ Small number of donor cells homed and persisted in the kidney |
No | Ezquer et al.78 |
| STZ-induced type I C57BL/6 mice | Tail vein injection |
Single dose 0.5 × 106 |
➢ Increase in morphologically normal beta-pancreatic islets ➢ Ameliorate glomerular hyalinosis and mesangial expansion |
Yes | Ezquer et al.24 | |
| Rat BM-MSCs | STZ-induced type I female Wistar rats | Tail vein injection |
Once a week for twice 2 × 106 |
➢ Inhibit TGF-β/Smad signaling pathway ➢ Secreted a significant amount of BMP7 ➢ Attenuate the renal function and the glomerulosclerosis |
Yes | Lv et al.31 |
| STZ-induced type I Sprague Dawley rats | Tail vein injection |
Single-dose (4 weeks after the onset) 2 × 106 |
➢ Inhibit TGF-b1/Smad3 pathway ➢ Decrease the expression of PAI-1 ➢ Reduce the accumulation of extracellular matrix ➢ Inhibit renal fibrosis in rats with DN |
No | Lang et al.79 | |
| STZ-induced type I Sprague Dawley rats | Tail vein injection |
Single-dose (4 weeks after the onset) 3 × 106 |
➢ BMSCs differentiate into islet-like cells with miR-124a ➢ MSCs combined with miR-124a enhance proliferation and inhibit apoptosis of podocytes ➢ Protected kidney tissue from impairment and inhibit nephroncyte apoptosis |
Yes | Sun et al.81 | |
| STZ-induced type I Sprague Dawley rats | Tail vein injection |
Four doses (2, 4, 5, and 7 weeks after the onset) 5 × 106 |
➢ Upregulate serum anti-inflammatory cytokines IL-10 and EGF ➢ Downregulate inflammatory-related cytokines such as IL-6, MCP-1, TNF-α, and IL-1β ➢ Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs |
No | Li et al.14 | |
| STZ-induced type I female Wistar rats | Tail vein injection |
Once a week for twice 2 × 106 |
➢ Suppress the expression of MCP-1 and the number of infiltrated macrophages in the kidney ➢ Up-regulate the expression of HGF ➢ Downregulate the expressions of IL-1β, IL-6, and TNFα |
Yes | Lv et al.83 | |
|
HFD-induced type 2 C57BL/6J mice STZ-induced type I C57BL/6 J mice |
Tail vein injection |
1.0 × 104 MSCs/g (4 times every 2 weeks) for HFD-induced mice 1.0 × 104 MSCs/g (2 times every 4 weeks) for STZ-induced mice |
➢ Inhibit the exacerbation of albuminuria ➢ Inhibit the increase of glomerular mesangium substrate in HFD diabetic mice ➢ Exosomes purified from MSC-CM exert an anti-apoptotic effect and protect tight junction structure in TECs |
No | Nagaishi et al.39 | |
| STZ-induced type I Sprague Dawley rats | Tail vein injection |
Single-dose with ultrasound-targeted microbubble destruction (UTMD) technique 1 × 106 |
➢ UTMD increase the permeability of renal interstitial capillaries and VCAM-1 expression ➢ Inhibit TGF-β1 expression and upregulate synaptopodin and IL-10 expression |
Yes | Yi et al.32 | |
| STZ-induced type I Sprague Dawley rats | Left renal artery injection |
Single dose 2 × 106 |
➢ Suppress creatinine clearance rate and urinary albumin to creatinine ratio ➢ Reduce the dysfunction of podocytes ➢ Express higher levels of BMP-7 but not of VEGF |
No | Shuai et al.86 | |
| Tree shrew BM-MSCs | STZ-induced type I tree shrews | Intravenous injection |
Two doses (interval of 14 days) 5 × 106 |
➢ Biological indexes were significantly lowered ➢ Home to the kidney and pancreas of DN tree shrews |
Yes | Pan et al.80 |
| AD-MSCs | ||||||
| Human AD-MSCs | STZ-induced type I Sprague Dawley rats | Tail vein injection |
Five doses (at 4 weekly intervals) 5 × 106 |
➢ Attenuate glomerulus hypertrophy and tubular interstitial jury ➢ Downregulate the expression of WT -1 and synaptopodin ➢ The cells were detected in lung, spleen, and peritubular regions, but rarely in the pancreas |
No | Zhang et al.96 |
| Autologous AD-MSCs | STZ-induced type I Sprague Dawley rats | Tail vein injection |
Single-dose (4 weeks after the onset) 1 × 107 |
➢ Minimize pathological alterations, reduce oxidative damage, and suppress the expression of pro-inflammatory cytokines ➢ Decrease molecules of the MAPK signaling pathway. |
Yes | Fang et al.97 |
| Rat AD-MSCs | STZ-induced type I Sprague Dawley rats | Tail vein injection |
Single dose 1 × 107 |
➢ Reduce the rate of cellular apoptosis ➢ Decrease Bax and Wnt/β-catenin levels ➢ Elevate Bcl-2 and klotho levels |
Not Mentioned | Ni et al.92 |
| UCB-MSCs | ||||||
| Human UCB-MSCs |
STZ-induced type I Sprague Dawley rats |
Tail vein injection |
Single-dose (4 weeks after the onset) 1 × 106 |
➢ Reduce proteinuria and renal fibronectin ➢ Up-regulate α-SMA and down-regulate renal E-cadherin ➢ Engraft human UCB-MSC in diabetic kidneys |
No | Park et al.10 |
|
STZ-induced type I Sprague Dawley rats |
Tail vein injection |
Single dose 5 × 105 |
➢ A few engraftments of hUCB-MSC in diabetic kidneys ➢ hUCB-MSC conditioned media inhibit TGF-b1-induced extra-cellular matrix upregulation and epithelial-to-mesenchymal transition ➢ Prevent diabetic renal injury |
No | Park et al.16 | |