Human Mesenchymal Stem Cell-mediated Tissue Regeneration After Ischemic Injury in a Murine Hindlimb Ischemia Model
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Published on 2008 by ProQuest
Mesenchymal stem cells (MSC) are adult multipotent cells that are most commonly isolated from the bone marrow. While the MSC have been shown to improve regeneration of injured tissues in vivo, for example ischemic muscle, the mechanisms by which they contribute to this tissue recovery remain unclear. In this study, we first investigated the tissue culture conditions that would maximize the ability of MSC to contribute to the tissue recovery. We used a murine hindlimb ischemia injury model, generating a blood flow deficiency and an ischemic environment in the affected tissues, to test the ability of MSC to mediate tissue repair in vivo. Our results demonstrate that pre-conditioning of human bone marrow-derived MSC at 1 to 3% oxygen (hypoxia) prior to the transplantation improved blood flow regeneration to the ischemic limb and decreased tissue necrosis, when compared to the MSC grown at 21% oxygen (normoxia) and the saline controls. The homing studies further revealed that the MSC cultured in hypoxic conditions engrafted in the injured area to the same degree as the cells cultured in normoxic conditions. These data suggest that the pre-conditioned MSC have an increased ability to mediate tissue repair after an ischemic damage without having better homing and survival. We therefore next investigated the mechanisms that allow hypoxic MSC to respond to the signals released after an ischemic injury. The molecular analysis of MSC revealed that the cells cultured in hypoxic conditions upregulated the expression of the hepatocyte growth factor (HGF) receptor c-Met. Using the shRNA technology, we knocked down the expression of c-Met in MSC and examined the effect of this signaling pathway on their function in vitro and in vivo. Our results revealed that reducing signaling through the c-Met receptor resulted in a significant decrease of chondrogenic and osteogenic differentiation potential of MSC. Additionally, MSC that lacked 70% of the c-Met expression were unable to contribute to the blood flow regeneration in vivo, while the MSC that lacked only 60% of the c-Met expression did not recapitulate this observation. Collectively, our results contributed to the understanding of mechanisms by which MSC mediate tissue regeneration.
This Book was ranked 28 by Google Books for keyword Regenerative Medicine for Peripheral Artery Disease.
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