Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation

Abstract

Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal and regulation of lineage-specific differentiation of mesenchymal stem cells. In addition we review recent research on the concept of stem cell niche, and its relevance to adult mesenchymal stem cells.

Figure 1

Mesenchymal stem cell self-renewal and cytodifferentiation. Extracellular signaling factors, including growth factors and cytokines, demonstrated to promote and/or maintain mesenchymal stem cell (MSC) self-renewal, in vitro. Gene markers characteristic of MSC self-renewal include oct-4, sox-2, and rex-1. LIF, leukemia inhibitory factor; EGF, epidermal growth factor; HGF, hepatocyte growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; CFU-F, colony forming unit-fibroblast; c, chondroblast; o, osteoblast; a, adipoblast; m, myoblast; cm, cardio-myoblast; t, tenoblast.

Figure 2

Molecular regulation of mesenchymal stem cell cytodifferentiation programs. Extracellular molecular signaling and mechanical inducers of differentiation transduce effects through putative receptors, channels, and/or other cell-surface-associated mechanisms. Downstream crosstalk of signaling pathways, including that between distinct mitogen-activated protein kinases (MAPKs) and R-Smads, provides a level of specificity that gives rise to unique lineages, such as chondrocytes and osteoblasts. Specificity of lineage differentiation can also result from the recruitment of master transcriptional switches with binary regulation of cell fate, such as TAZ (transcriptional coactivator with PDZ-binding motif). Depending on potentially unique multiprotein complexes that it may form in response to specific upstream signaling, TAZ promotes osteogenesis and inhibits adipogenesis. Furthermore, coregulator subtypes can be invoked, such as tension-induced/-inhibited proteins (TIPs), which regulate adipogenesis and myogenesis. Specific molecular induction/regulation of cardiomyogenic and tenogenic-specific development are as yet largely unknown, with the exception of those depicted. Broken lines, unknown or putative; solid lines, as in published data; *, juxtaposing cell; GDF, growth and differentiation factor; TGF, transforming growth factor; BMP, bone morphogenetic protein; FA, fatty acid; βcat, β-catenin; PPAR, peroxisome proliferator-activated receptor; MSK, mitogen- and stress-activated protein kinase; PCAF, p300/CBP-associated factor; Ac, acetyl; c, chondroblast; o, osteoblast; a, adipoblast; m, myoblast; cm, cardiomyoblast; t, tenoblast.

Figure 3

Mesenchymal stem cell niche. Mesenchymal stem cells (MSCs) are shown in their putative perivascular niche (BV, blood vessel), interacting with (1) various other differentiated cells (DC₁, DC₂, etc.) by means of cell-adhesion molecules, such as cadherins, (2) extracellular matrix (ECM) deposited by the niche cells mediated by integrin receptors, and (3) signaling molecules, which may include autocrine, paracrine, and endocrine factors. Another variable is O₂ tension, with hypoxia associated with MSCs in the bone marrow niche.