The elusive nature and function of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered.

Figure 1. Mesencymal stem cells and multipotent mesenchymal stromal cells

The plastic-adherent cellular fraction of many organs contains stromal progenitor cells that can give rise to colonies of fibroblastic morphology. This cellular subset, known as colony forming units-fibroblasts (CFU-F), totally or partially corresponds to a proposed multipotent progenitor cell population, most likely heterogeneous in nature and origin, which resides in the proximity of blood vessels in all tissues studied thus far and has been shown to express pericyte specific markers (CD146, NG2 and PDGFRβ). When cultured under the appropriate cell densities, colonies derived from single CFU-Fs can be isolated and expanded after multiple passages in vitro without losing their multipotent mesenchymal capacity. These cultured cells, classically referred to as mesenchymal stem cells, are now termed multipotent mesenchymal stromal cells. The hallmark, and unique criteria to that define mesenchymal stromal cells is their ability to differentiate into adipocytes, chondrocytes and osteoblasts when placed under inductive stimuli. Differentiation into multiple non-mesenchymal mature cell types has been reported but remains a matter of debate.

Figure 2. Proposed biological functions of BM-resident MSCs in vivo

a. Bone marrow (BM)-derived mesenchymal stem cells (MSCs) differentiate into osteoblasts, adipocytes and reticular cells, which provide the supportive environment for haematopoietic development, and are thought to be responsible for the natural turnover of these mesenchymal cell types in the bone marrow. Osteoblasts are key components of haematopoietic stem cell (HSC) niches and have been proposed to directly interact and positively regulate quiescence of some HSCs in the BM, whereas adipocytes negatively regulate HSC activity. HSCs have also been shown to lie adjacent to CXCL12-abundant reticular cells (CAR cells), which are poorly characterized cells with adipogenic and osteogenic potential and may correspond to, or originate from, BM-resident MSCs. In addition to giving rise to haemosupportive environment, BM-resident MSCs expressing the neural stem cell marker Nestin have been shown to physically associate with HSCs in perivascular BM 'dual stem cell niches` and regulate HSC homeostasis. b. BM-resident MSCs are found in perivascular areas of BM microenvironments, where they may associate with cells of the immune system, including B cells, T cells and dendritic cells (DCs). Furthermore, mesenchymal stromal cells, which are though to directly derive from MSCs in vivo, are known to regulate the function of lymphocytes (B cells and T cells), DCs and natural killer (NK) cells. It is therefore hypothesized that BM-resident MSCs may regulate immune responses occurring in the BM in vivo.