Abstract
We recently demonstrated the use of in vitro expanded kidney-derived mesenchymal stem cells (KMSC) protected peritubular capillary endothelial cells in acute renal ischemia-reperfusion injury. Herein, we isolated and characterized microparticles (MPs) from KMSC. We investigated their in vitro biologic effects on human endothelial cells and in vivo renoprotective effects in acute ischemia-reperfusion renal injury. MPs were isolated from the supernatants of KMSC cultured in anoxic conditions in serum-deprived media for 24 hours. KMSC-derived MPs demonstrated the presence of several adhesion molecules normally expressed on KMSC membranes, such as CD29, CD44, CD73, α4, 5, and 6 integrins. Quantitative real time PCR confirmed the presence of 3 splicing variants of VEGF-A (120, 164, 188), bFGF and IGF-1 in isolated MPs. MPs labeled with PKH26 red fluorescence dye were incorporated by cultured human umbilical vein endothelial cells (HUVEC) via surface molecules such as CD44, CD29, and α4, 5, and 6 integrins. MP dose dependently improved in vitro HUVEC proliferation and promoted endothelial tube formation on growth factor reduced Matrigel. Moreover, apoptosis of human microvascular endothelial cell was inhibited by MPs. Administration of KMSC-derived MPs into mice with acute renal ischemia was followed by selective engraftment in ischemic kidneys and significant improvement in renal function. This was achieved by improving proliferation, of peritubular capillary endothelial cell and amelioration of peritubular microvascular rarefaction. Our results support the hypothesis that KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischemic kidneys.
Highlights
Microparticles (MPs) are submicron-size vesicles that carry membrane and cytoplasmic constituents of the cells they originated from
The present study focused on characterizing the proangiogenic potential of kidney-derived mesenchymal stem cells (KMSC)-derived MPs and their contribution to peritubular capillary repair after ischemic injury via horizontal transfer of genetic materials
KMSC-derived MPs generated in this anoxic culture condition demonstrated significantly higher levels of vascular endothelial growth factor (VEGF)-A, insulin-like growth factor-1 (IGF-1) and fibroblast growth factor (FGF) mRNA compared to those released in normoxic culture condition
Summary
Microparticles (MPs) are submicron-size vesicles that carry membrane and cytoplasmic constituents of the cells they originated from They result from plasma membrane remodeling in response to various stimuli, such as oxidative stress or hypoxia. [12] Recent studies have reported that bone marrow MSC- or endothelial progenitor cell-(EPC) derived MPs exert renoprotective effects comparable to those of their origin cells in various experimental acute and chronic renal injuries by inhibiting apoptosis and stimulating proliferation of resident renal cells. MPs derived from human bone marrow MSC were found to mediate horizontal mRNA transfer that stimulated proliferation and inhibited apoptosis of tubular epithelial cells in vitro. [14] EPCderived MPs protected kidneys from acute ischemia-reperfusion (I/R) injury by delivering miRNA that contributed to reprogramming hypoxic resident tubular epithelial and peritubular capillary endothelial cells to a regenerative program. The in vitro internalization of EPC-derived MPs within hypoxic TEnCs and TEpCs was followed by reduced apoptosis and enhanced angiogenesis on Matrigel-coated surfaces. [16]
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