Mesenchymal stem cell(MSC) therapy is entering a new era shifting the focus from initial feasibility study to optimization of therapeutic efficacy.However,how MSC therapy facilitates tissue regeneration remains incompletely characterized.Consistent with the emerging notion that secretion of multiple growth factors/cytokines(trophic factors) by MSC provides the underlying tissue regenerative mechanism,the recent study by Bai et al demonstrated a critical therapeutic role of MSC-derived hepatocyte growth factor(HGF) in two animal models of multiple sclerosis(MS),which is a progressive autoimmune disorder caused by damage to the myelin sheath and loss of oligodendrocytes.Although current MS therapies are directed toward attenuation of the immune response,robust repair of myelin sheath likely requires a regenerative approach focusing on long-term replacement of the lost oligodendrocytes.This approach appears feasible because adult organs contain various populations of multipotent resident stem/progenitor cells that may be activated by MSC trophic factors as demonstrated by Bai et al This commentary highlights and discusses the major findings of their studies,emphasizing the anti-inflammatory function and trophic cross-talk mechanisms mediated by HGF and other MSC-derived trophic factors in sustaining the treatment benefits.Identification of multiple functionally synergistic trophic factors,such as HGF and vascular endothelial growth factor,can eventually lead to the development of efficacious cellfree therapeutic regimens targeting a broad spectrum of degenerative conditions. Mesenchymal stem cell (MSC) therapy is entering a new era shifting the focus from initial feasibility study to optimization of therapeutic efficacy. However, the MSC therapy facilitates tissue regeneration remains incompletely characterized. Consistent with the emerging notion that secretion of multiple growth factors / cytokines (trophic factors) by MSC provides the underlying tissue regenerative mechanism, the recent study by Bai et al demonstrated a critical therapeutic role of MSC-derived hepatocyte growth factor (HGF) in two animal models of multiple sclerosis (MS), which is a progressive autoimmune disorder caused by damage to the myelin sheath and loss of oligodendrocytes. Although current MS therapies are directed toward attenuation of the immune response, robust repair of myelin sheath will require only a regenerative approach focusing on long-term replacement of the lost oligodendrocytes. This approach seem feasible because adult organs contain various populations of multipotent resident stem / progenitor cells that may be activated by MSC trophic factors as demonstrated by Bai et al This commentary highlights and discusses the major findings of their studies, emphasizing the anti-inflammatory function and trophic cross-talk mechanisms mediated by HGF and other MSC-derived trophic factors in sustaining the treatment benefits. Identification of multiple functionally synergistic trophic factors, such as HGF and vascular endothelial growth factor, can eventually lead to the development of efficacious cellfree therapeutic regimens targeting a broad spectrum of degenerative conditions.