WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Enhancing the efficacy of mesenchymal stem cell therapy

Mesenchymal stem cell(MSC)therapy is entering a challenging phase after completion of many preclinical and clinical trials.Among the major hurdles encountered in MSC therapy are inconsistent stem cell potency,poor cell engraftment and survival,and age/disease-related host tissue impairment.The recognition that MSCs primarily mediate therapeutic benefits through paracrine mechanisms independent of cell differentiation provides a promising framework for enhancing stem cell potency and therapeutic benefits.Several MSC priming approaches are highlighted,which will likely allow us to harness the full potential of adult stem cells for their future routine clinical use.

Stem cell therapy independent of stemness

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.

Host tissue response in stem cell therapy

Preclinical and clinical trials of stem cell therapy have been carried out for treating a broad spectrum of diseases using several types of adult stem cells. While encouraging therapeutic results have been obtained, much remains to be investigated regarding the best cell type to use, cell dosage, delivery route, long-term safety, clinical feasibility, and ultimately treatment cost. Logistic aspects of stem cell therapeutics remain an area that requires urgent attention from the medical community. Recent cardiovascular trial studies have demonstrated that growth factors and cytokines derived from the injected stem cells and host tissue appear to contribute largely to the observed therapeutic benefits, indicating that trophic actions rather than the multilineage potential (or stemness) of the administered stem cells may provide the underlying tissue healing power. However, the capacity for trophic factor production can be aberrantly downregulated as seen in human heart disease. Skeletal muscle is a dynamic tissue with an impressive ability to continuously respond to environmental stimuli. Indeed, a relation exists between active skeletal muscle and low cardiovascular risk, highlighting the critical link between the skeletal muscle and cardiovascular systems. Adding to this notion are recent studies showing that stem cells injected into skeletal muscle can rescue the failing rodent heart through activation of the muscle trophic factor network and mobilization of bone marrow multilineage progenitor cells. However, aging and disease can adversely affect the host tissue into which stem cells are injected. A better understanding of the host tissue response in stem cell therapy is necessary to advance the field and bridge the gap between preclinical and clinical findings.