Mesenchymal Stem Cells: Potential For Liver Repair

Mesenchymal stem cells (MSCs) were initially characterized as plastic adherent, fibroblastoid cells. These cells can differentiate into osteogenic, adipogenic and chondrogenic lineages under appropriate conditions. In recent years, a number of reports have also indicated that these cells possess the capacity to trans-differentiate into epithelial cells and lineages derived from the neuro-ectoderm.In this study, we mainly focus on the potential of MSCs for liver repair, which includes two parts: in vitro trans-differentiation of mouse bone marrow mesenchymal stem cell (mBM-MSCs) into hepatocytes, and in vivo recruiting and homing of mBM-MSCs towards injured liver. In the 1^st part of the project, three original protocols for directing mBM-MSCs trans-differentiate into functional hepatocyte-like cells were established by conditional medium of injured liver tissues, normal hepatocytes and fetal livers separately. Further studies by microarray analysis and antibody blocking experiments indicated that FGF4, HGF and OSM were crucial for these conditional media-induced hepatic differentiations, and mBM-MSC derived hepatocytes can also be acquired by treatment of these cytokines. Furthermore, we demonstrated that the differentiation efficacy could be considerably enhanced by pre-treatment of VPA, and regulation of FGFRs and c-Met gene expression through post translational modification of core histones might be the primary initiating event for these effects. In the 2nd part of the project, we successfully isolated and characterized circulating MSCs in the peripheral blood of liver-injured mice with expansion in culture, and provided direct evidence that mBM-MSCs were mobilized into the circulation and recruited into livers after stimulation of liver-injury. CCR9, CXCR4 and c-Met were essential for directing these cell migrate to injured liver. The recruited mBM-MSCs may play different roles, including hepatic fate specification and down-regulation of the activity hepatic satellite cells, which inhibits of over-accumulation of collagen and development of fibrosis. Our results provide new insights into liver repair involving endogenous BM-MSCs and add new information for consideration when developing clinical protocols involving the MSCs.