MESENCHYMAL STEM CELLS AND CELLULAR TRANSPLANTATION

H. Tsuda¹, K. Yamahara², K. Yazawa³, N. Ichimaru³, J. Kaimori⁴, Y. Isaka⁵, T. Ikeda², S. Takahara^1
1Department Of Advanced Technology, Osaka University Graduate School of Medicine, suita/JAPAN, ², National Cardiovascular Center Research Institute, suita/JAPAN, ³Urology, Osaka University Graduate School of Medicine, Suita/JAPAN, ⁴Department Of Advanced Technology For Transplantation, Osaka University, Graduate School of Medicine, Suita/JAPAN, ⁵Nephrology, Osaka University Graduate School of Medicine, Suita/JAPAN

Body: Introduction Mesenchymal stem cell (MSC) is an attractive therapeutic cell source for the treatment of renal diseases. Many reports have been described that MSC administration leads to improve renal function although the mechanisms responsible for its protective and regenerative effect are incompletely understood. We have demonstrated that fetal membrane-derived MSC (FM-MSC), which is available non-invasively in large amounts, had similar surface antigen and multipotent potential to bone marrow-derived MSC (BM-MSC). Transplantation of allogenic FM-MSC as well as autologous BM-MSC induced therapeutic angiogenesis in a hindlimb ischemia model, indicating allogeneic FM-MSC is a potential alternative to autologous BM-MSC as a source of protective and regenerative therapy. Using an experimental glomerulonephritis induced by anti-Thy1 antibody, we recently found that allogenic FM-MSC had renoprotecctive effect via complex paracrine actions including anti-inflammatory and anti-fibrotic effects and not by their differentiation into target cells. From these facts, we investigated whether allogenic FM-MSC administration could protect from renal ischemia/reperfusion (I/R) injury. Methods We used an I/R model in 6-wk-old male Lewis rats to induce acute kidney injury (AKI) by clamping left renal artery for 60 minutes with right nephrectomy, followed by 4 or 24 hours of reperfusion. After declamping, FM-MSC (5×10⁵cells) obtained from major histocompatibility complex mismatched ACI rats were intravenously administered. Results At 24 hours after reperfusion, the induction of AKI led to increase of serum creatinine (1.45±0.24mg/dl) and BUN (92.5±10.5mg/dl), whereas FM-MSC administration significantly reduced renal damage as shown by the lowering in creatinin and BUN (0.80±0.11 and 1.45±0.24 mg/dl, respectively, p<0.05). Histological analysis of injured kidney revealed that FM-MSC administered rats showed a marked reduction in CD68-positive monocytes/macrophages infiltration compared to control rats (FM-MSC group 1.57±0.09 vs PBS group 2.09±0.07 % positive-area per field, p<0.05). Similar decrease in the number of CD3-positive T cells were observed between FM-MSC transplanted and control rats (FM-MSC group 5.88±0.34 vs PBS group 8.31±0.41 positive-cells per field, p<0.05). I/R injury induced robust increases in the renal expression of inflammatory related genes such as IL-6, TNF-α and MCP-1, which was markedly reduced by FM-MSC administration .In addition, TUNEL staining demonstrated that I/R of kidneys induced apoptosis in tubular epithelial cells and FM-MSC administration suppressed I/R injury-induced apoptosis compared to PBS treatment. Conclusion In this study, we demonstrated that FM-MSC transplantation provided significant improvement in renal I/R injury. The beneficial effects of allogeneic FM-MSC administration are mediated by paracrine effects through amelioration of inflammation and apoptotic manifestation of ischemic kidney injury. We concluded that renoprotective actions of allogeneic FM-MSC provide the basis for a new therapeutic strategy for the treatment of AKI.

Disclosure: All authors have declared no conflicts of interest.