Functional Heterogeneity of MSC Populations Provides Clues to Their Broad Therapeutic Efficacy

Abstract

Mesenchymal stem cells (MSCs) have demonstrated therapeutic efficacy in a variety of disease models and human clinical trials. The widespread benefits of MSCs have recently been attributed to their capacity to secrete soluble factors that promote tissue repair by stimulating angiogenesis and suppressing inflammation, apoptosis, and immune cell function. However, these functional attributes are inconsistent with the designation of MSCs as stem cells, which by definition lie at the apex of a hierarchy of lineage specification and cellular differentiation. Previously, we catalogued the MSC transcriptome via serial analysis of gene expression to gain better insight into their basic biology. This analysis revealed that MSCs express a diverse range of proteins regulating angiogenesis, cell motility and communication, hematopoiesis, neural activities, immunity and defense. Furthermore, we reported that different classes of expressed regulatory proteins are restricted to distinct subpopulations of MSCs. Based on these findings we proposed that the molecular heterogeneity of the MSC transcriptome reflects the functional complexity of marrow stroma as an organ system in vivo and this complexity accounts for the broad therapeutic effects of MSCs. Examples are provided to illustrate how unique traits of MSC subpopulations from marrow may be exploited to develop more potent cellular vectors for therapy.