Investigation Of Stem Cells Ameliorate Acute Renal Failure

Renal failure is among the highest causes of mortality in hospitalized patients. Acute ischemic kidney injury is considered the leading cause of acute renal failure, which may progress and lead to onset of chronic kidney disease and renal failure. Prolonged kidney malfunction is contributed primarily by post-ischemic endothelial cell dysfunction and microvascular impairment. In the past decade, considerable research efforts have focused on the development of cell-based therapies against tissue damage, ranging from autologous transplantation of adult stem cells, bone marrow-and peripheral blood-derived endothelial progenitor cells (EPCs), to co-transplantation of human endothelial cells with smooth muscle progenitors or mesenchymal stem cells (MSCs).Endothelial cell administration, which improves revascularization, especially functional microvasculature, has therefore been proposed as a promising therapeutic solution. However, no published study has yet examined direct effects of endothelial cell treatment in kidney recovery. The first part of this paper investigated the therapeutic efficacy of endothelial cells in a mouse model with acute kidney injury (AKI). Thus, human embryonic stem cells-derived endothelial cells (hESC-ECs) labeled with a reporter system encoding a double fusion reporter gene for firefly luciferase (Fluc) and green fluorescent protein (GFP) were characterized by Flue imaging and immunofluoresence staining. Cultured hESC-ECs (1×106) were injected into ischemic kidney shortly after AKI. Survival of the transplanted hESC-ECs was monitored in vivo from day1to14after endothelial cell transplantation and potential impact of hESC-EC treatment on renal regeneration was assessed by histological analyses. We report that a substantial level of bioluminescence activity was detected24hours after hESC-EC injection followed by a gradual decline from day1to14. Human ESC-ECs markedly accelerated kidney cell proliferation in response to ischaemia-induced damage, indicated by an elevated number of BrdU+cells. Co-expression of Sca-1, a kidney stem cell proliferation marker, and BrdU further suggested that the observed stimulation in renal cell regeneration was, at least in part, due to increased proliferation of renal resident stem cells especially within the medullary cords and arteriole. Differentiation of hESC-ECs to smooth muscle cells was also observed at an early stage of kidney recovery. In summary, our results suggest that endothelial cell therapy facilitates kidney recovery by promoting vascularization, trans-differentiation and endogenous renal stem cell proliferation in AKI.Bone marrow (BM) stem cells have been reported to contribute to tissue repair after kidney injury model. However, there is no direct evidence so far that BM cells can trans-differentiate into renal stem cells. To investigate whether BM stem cells contribute to repopulate the renal stem cell pool, in the second part of this paper we transplanted BM cells from transgenic mice, expressing enhanced green fluorescent protein into wild-type irradiated recipients. Following hematological reconstitution and ischemia-reperfusion (I/R), Sca-1and c-Kit positive renal stem cells in kidney were evaluated by immunostaining and flow cytometry analysis. Moreover, granulocyte colony stimulating factor (G-CSF) was administrated to further explore if G-CSF can mobilize BM cells and enhance trans-differentiation efficiency of BM cells into renal stem cells. BM-derived cells can contribute to the Sca-1+or c-Kit+renal progenitor cells population, although most renal stem cells came from indigenous cells. Furthermore, G-CSF administration nearly doubled the frequency of Sca-1+BM-derived renal stem cells and increased capillary density of I/R injured kidneys. These findings indicate that BM derived stem cells can give rise to cells that share properties of renal resident stem cell. Moreover, G-CSF mobilization can enhance this effect.