The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine

Abstract

Mesenchymal stem cells (MSCs) are the focus of intensive efforts worldwide directed not only at elucidating their nature and unique properties but also developing cell-based therapies for a diverse range of diseases. More than three decades have passed since the original formulation of the concept, revolutionary at the time, that multiple connective tissues could emanate from a common progenitor or stem cell retained in the postnatal bone marrow. Despite the many important advances made since that time, substantial ambiguities still plague the field regarding the nature, identity, function, mode of isolation and experimental handling of MSCs. These uncertainties have a major impact on their envisioned therapeutic use.

Figure 1. The whereabouts of MSCs

In the postnatal BM, ‘MSCs’ reside around sinusoids, maintain a ‘niche’ for HSCs, support hematopoiesis, and replenish the differentiated compartment of osteoblasts and adipocytes during tissue growth and turnover; they also generate cartilage under specific conditions such as trauma). Total populations of bone marrow stromal cells (which do not coincide with cultures of ‘stem cells’ in any way) are established when total marrow cell suspensions are plated in culture at high density. Adherence to plastic separates the stromal cells from no-adherent hematopoietic cells. If cell suspensions are plated a low density, only cells capable of density-insensitive growth are selected. These cells initiate the growth of clonal colonies. Passaging a single colony, or alternatively, establishing a clonal culture from single cells isolated based on expression of phenotypic markers (which may be different in humans and mouse), results in a clonal population, which can be used to assess multipotency by in vivo transplantation. Heterotopic ossicles include multiple differentiated cell types of donor origin (osteoblasts, adipocytes, fibroblasts) and hematopoietic cells of the host. These are supported by donor stromal cells. X-ray and histology images show a heterotopic ossicle made by murine MSCs transplanted on a completely resorbable scaffold (GelfoamTM).

Figure 2. How MSCs make it to bone marrow

In development, the primitive bone marrow stroma include skeletal progenitors that originate outside of the marrow cavity (primitive periosteum-perichondrium) and invade the forming cavity along blood vessels. Similar dynamic interactions with ingrowing blood vessels are reproduced in transplants of human MSCs, and are likely the basis for the perisinusoidal position of MSCs in the intact postnatal bone marrow. Recruitment of mesenchymal cells to a mural cell fate (and a subendothelial position), a general phenomenon in development and organ growth, is mediated by endothelial cell-derived PDGF-BB, which signals through PDGF-Rβ expressed on mesenchymal cells (and on ‘MSCs’). Presumptive mural cells produce Angiopoietin-1, (also produced by human and murine bone marrow MSCs2), which is crucial for integrity, survival and remodeling of vascular lattices. Ang-1 also induces quiescence of HSCs. Both mural cells and endothelial cell are induced to mitotic quiescence by active TGF 1, which is released through proteolytic cleavage of the latent form at sites of mural cell-endothelial cell contacts (reviewed in , , –40).