Biochemical Heterogeneity of Mesenchymal Stem Cell Populations: Clues to their 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.

In Vitro Evidence of the Presence of Mesenchymal Stromal Cells in Cervical Cancer and Their Role in Protecting Cancer Cells from Cytotoxic T Cell Activity

“…A loss of adipogenic differentiation capacity might be caused by tumor cells through attenuation of TP53 expression that promotes osteoblast differentiation [40], thus possibly inhibiting differentiation into adipocytes. MSCs from all three sources showed osteogenic and chondrogenic potential, which demonstrates the multipontentiality of MSCs derived from NCx and CeCa; however, as in BM, these results may suggest that cultures of MSCs could represent an admixture of morphologically, phenotypically, and functionally different cells, as some authors have proposed [41,42]. Interestingly, fibrocartilage was observed in assays from NCx and CeCa, whereas hyaline cartilage was predominant in pelleted micromass from BM, which suggests distinct functional capacities between MSCs from NCx and CeCa compared with BM.…”

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

“…A major contributor to these inconsistent clinical outcomes may be the inherent variability in the immunosuppressive capacity of MSC lines due to differing tissues of origin, manufacturing processes, and donor-specific differences (10,(21)(22)(23). Although this functional heterogeneity is well known, no reliable predictors of MSC immunosuppressive capacity have been identified (3,24).…”

Rationale for Using Direct Bone Marrow Aspirate as a Proliferant for Regenerative Injection Therapy (Prolotherapy)

“…MSCs populations exhibit considerable intra-and inter-population heterogeneity. It has been suggested that heterogeneous populations reflect the complexity of the stromal system in the bone marrow and the varied functions it performs to regulate tissue homeostasis and its contribution to the demonstrated functionality of MSCs in vivo [57,59]. As of present, it is still unclear which cell(s) types are the in vivo precursor cells that expand in culture in vitro as MSCs.…”

“…Bone marrow derived MSCs display biochemical heterogeneity in phenotypes and functions -with potentially incredible biological and medical benefits and implications due to their known involvement in tissue repair, immunomodulation and inflammation [57][58][59][60][61]. MSCs populations exhibit considerable intra-and inter-population heterogeneity.…”