Natural history of mesenchymal stem cells, from vessel walls to culture vessels

Abstract

Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long-term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Mesenchymal stem cells are prime candidates in the field of regenerative medicine with considerable interest in characterising these cells as well as optimising harvesting and expansion techniques for their use in injury and tissue repair (Murray et al, 2014). While most of our understanding of MSCs is based on ex vivo cultured cells, their in vivo counterparts, along with their origin, localisation, potential and roles in disease have remained elusive (Pontikoglou et al, 2011).…”

“…However, due to the vast amount of research in this area, a standard definition was required to enable the comparison of results from different groups (Murray et al, 2014). In 2006, the International Society of Cellular Therapy (ISCT) developed a minimum criteria of characteristics required to define human MSCs (Feng et al, 2010).…”

“…and CD90 uniformly (in over 95% of the cell population), in the absence of CD45, CD34, CD14, CD11b, CD79a, CD19 and HLA-DR. Lastly, to be considered a true MSC, isolated cells must be able to undergo tri-lineage differentiation into osteoblasts, chondrocytes and adipocytes under the correct culture conditions (Murray et al, 2014). While MSCs have been shown to express other markers and to differentiate into other cell types, such as myocytes, these aspects are not considered requirements to define cells as MSCs (Dimarino et al, 2013).…”

Stromal cells–are they really useful for GVHD?

“…The fact that MSCs and MSC-like cells can be isolated from many different tissues, including BM, fat and placenta, suggests that there is a common reservoir of these cells in the body (reviewed in Murray et al 34 ). However, whether all MSCs are phenotypically and functionally equivalent and how in vitro expansion affects these features is not known.…”

“…37 Pericytes surround endothelial cells in blood microvessels and contribute to vascular development, stabilization and remodeling. 34 Pericytes have been shown to have MSC-like features, including multipotency 38,39 and immunosuppressive capacities. 40 A vascular origin of MSCs may be a positive trait in the context of blood compatibility after infusion, but in vitro expansion of the cells can still affect the phenotype and function of MSCs.…”