Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Endothelial cell therapy has been implicated to enhance tissue regeneration and vascularization in ischemic kidney. However, no published study has yet examined direct effects of endothelial cell treatment in kidney recovery. This study 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 Fluc 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 day 1 to 14 after 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 detected 24 h after hESC-EC injection followed by a gradual decline from 1 to 14 d. 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.