Hepatocyte Growth Factor Improves the Therapeutic Efficacy of Human Bone Marrow Mesenchymal Stem Cells via RAD51

Abstract

<p class="first" id="d7496492e208">Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease. </p><div class="fig panel" id="undfig1"> <a class="named-anchor" id="undfig1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/1a8c2ed0-8e39-42b2-aa90-ef7ac46dbbfd/PubMedCentral/image/fx1"/> </div> <div class="panel-content"/> </div><p class="first" id="d7496492e216">RAD51 is the actual effector by HGF to accomplish anti-senescence. HGF induces transcription of RAD51 and activates RAD51 via sumoylation. Action mechanisms of RAD51 by HGF are telomere lengthening at nuclei and induction of mtDNA replication at mitochondria. </p>