Mesenchymal Stem Cells: Engineering Regeneration

Adult mesenchymal stem cells are a leading candidate for application in regenerative medicine. These nonhematopoietic stem cells were discovered in the bone marrow, where they represent approximately 1 out of 10,000 nucleated cells and arise from the supporting architecture of the adult marrow.1 Comparable stem cells have also been isolated from the connective components of various postnatal tissues including adipose and synovial tissue, as well as from peripheral and cord blood.2 Mesenchymal stem cells exhibit properties of multipotency, with the capacity to contribute to the regeneration of bone, cartilage, and muscle tissues of mesodermal origin.1–3 Evidence also supports the contribution of mesenchymal stem cells to liver and pancreatic islet cell regeneration, and protection in the setting of kidney, heart, or lung injury.1–4 Mesenchymal stem cells secrete a spectrum of bioactive molecules that provide a regenerative microenvironment to limit the area of damage and to mount a self-regulated regenerative response.5 The age of the individual, the extent of tissue damage, and the local and whole body titers of mesenchymal stem cells have all been considered to play a role in the ultimate rate and extent of repair.5 Beyond the supply of differentiated mesenchymal tissues in case of cell loss, mesenchymal stem cell progeny constitute the stromal environment, which is fundamental in the regulation of parenchymal stem cell renewal and differentiation, and immune modulation.2,3 In fact, both autologous and allogeneic mesenchymal stem cells have been tested in recent clinical trials, including for treatment of osteogenesis imperfecta, Crohn's disease, and graft-versus-host disease.4,5 Identification of adult human mesenchymal stem cells as multilineage progenitors relies on their capacity to be induced to differentiate into specific phenotypes. Although the ganglioside GD2 has been proposed as a single surface marker that distinguishes mesenchymal stem cells, a panel of biomarkers has been typically employed to secure isolation.6 These include positive expression of CD44, CD73, CD90, CD105, Stro-1, and the adhesion molecules CD106 (vascular adhesion molecule VCAM-1) and the intercellular adhesion molecule ICAM-1, in the absence of expression of hematopoietic markers CD34, CD45, CD11, and CD14, and the adhesion molecule CD31 (platelet/endothelial cell adhesion molecule PECAM-1).1,3 Of note, adult human mesenchymal stem cells are characteristically devoid of human leukocyte antigen (HLA) class II antigens (MHC-II) on the cell surface, and do not express the costimulatory molecules CD80, CD86, or CD40.1 The expressed major histocompatibility complex (MHC) class I antigens may activate T cells, but, with the absence of costimulatory molecules, a secondary signal would not engage, leaving T cells anergic.1 Such a unique immune profile, that is, MHC I+, MHC II−, CD40−, CD80−, CD86−, is regarded nonimmunogenic, and accordingly transplantation into an allogeneic host may not require immunosuppression.1,3 Moreover, mesenchymal stem cells exhibit immunosuppressive properties, modulating T-cell functions including cell activation, and display immunomodulatory features impairing maturation and function of dendritic cells and inhibiting human B-cell proliferation, differentiation, and chemotaxis.1,3 However, rejection of marrow stromal cells in MHC class I and class II-mismatched recipients has been reported, underscoring the relevance of the immune response in the outcome of stem cell therapy.3 While recognizing the desirable combination of multipotent potential and tolerogenicity, Castillo and colleagues in the current issue of Clinical and Translational Science raise a cautionary note with regard to the use of the allogeneic approach, as mesenchymal stem cell interaction with the microenvironment could trigger (re)expression of MHC-II antigens compromising the fate of implanted cells.7 Additional studies are therefore needed to optimally translate mesenchymal stem cell therapy in the clinical setting. An increased understanding of how mesenchymal stem cells regulate the inflammatory response, distribute, and differentiate after delivery in humans is indeed needed.8 To maximize the safety and effectiveness of clinical transplantation, a mandate for standardization of clinical mesenchymal stem cell expansion, and the establishment of release criteria of the expanded cell population has been issued.8 At present, the consensus favors use of allogeneic mesenchymal stem cell therapy in the management of acute disorders, such as acute myocardial infarction, acute graft-versus-host disease, and acute exacerbations of inflammatory bowel disorders (Figure 1, left). This valuable strategy avoids the need for preparing autologous cells from the recipient. However, for disorders where mesenchymal stem cells are not needed on an emergency basis, it may be preferable to culture-expand autologous mesenchymal stem cells prior to implantation in an effort to personalize cell-based therapy (Figure 1, right).8,9 Because they are culture-dish adherent, mesenchymal stem cells can be expanded in culture while maintaining their multipotency.5 Culture-based expansion offers not only the opportunity to produce en masse a large pool of naïve stem cells, but also to derive progeny honed for lineage specification away from multipotency and into tissue-restricted cytopoiesis (Figure 2).7,9 In this regard, high-throughput technological platforms have been applied to decode the genomic, proteomic, and metabolomic foundation under-lying guided differentiation.10–13 Derivation and characterization of specialized mesenchymal stem cell subpopulations, and their selective application to specific disease conditions is an emerging strategy for enhanced therapeutic outcome.14 With appropriate efficacy validation and quality-control release of cellular phenotypes,8 the next generation of trials should achieve increasing intertrial consistenc