Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

Abstract

Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.

Figure 1

Isolation, expansion, and differentiation of MSCs. MSCs can be isolated from various tissues of either human or mouse. This minor population of cells can be isolated, expanded, and enriched after serial passages in vitro. A combination of positive and negative markers can be used to determine the purity of MSCs. In addition to self-renewal, these multipotent MSCs can also undergo differentiation in culture. One of the gold standards for defining MSCs is their differentiation ability to cell lineages such as adipocytes and osteoblasts

Figure 2

Signaling pathways and key transcription factors in regulating the adipo-osteogenic differentiation of MSCs. The fine balance of adipogenic and osteogenic differentiation of MSCs is achieved by the actions of critical signaling pathways and key transcription factors. MSCs exist in specific microenvironments or niches, which is composed of various extracellular matrix components, growth factors, cytokines, and chemokines. Upon interaction with MSCs, these components activate or inhibit the lineage commitment of MSCs. In addition, the initiated cellular signaling pathways can also interfere each other to form a fine regulatory network. Ultimately, this signaling network maintains a delicate differentiation balance through regulating key transcription factors such as PPARγ and C/EBPs or Runx2 and Osterix for adipogenesis or osteogenesis respectively. OPN, osteopontin; FZD, Frizzled receptor; Hh, Hedgehog; Ptc, Patched; Smo, Smoothened

Figure 3

Multiple factors control MSC differentiation. The lineage commitment of MSCs can be regulated by three major cues, including chemical, physical, and biological factors. Chemical factors have been proven to be important in directing adipogenesis and osteogenesis of MSCs in vitro through regulating key transcription factors during MSC differentiation. In vivo, the differentiation of MSCs can also be altered by physical factors in the stem cell niche. Investigations into the regulation of MSC differentiation commitment by cell shape, external mechanical forces, extracellular matrix or geometric structures have provided very useful information for stem cell-based bone tissue regeneration/engineering. Meanwhile, tilted differentiation balance of MSCs is also observed during aging or other pathological processes, arguing for the roles of biological factors in lineage commitment of MSCs. Taken together, these three types of factors likely work closely and cooperate with each other to regulate MSC differentiation. IBMX, isobutylmethylxanthine; βGP, β-glycerophosphate

Figure 4

Physical factors regulating lineage commitment of MSCs. MSCs physically interact with various components in the tissue microenvironment in vivo. The physical factors including cell shape, external mechanical forces, extracellular matrix, and geometric structures are involved in stem cell fate decision. By regulating RhoA-ROCK signaling pathway, spread cells tend to differentiate into osteoblasts while round cells tend to become adipocytes (a). Different physical forces can also direct MSCs to differentiate into different lineages via controlling myosin II activity (b). Meanwhile, components of extracellular matrix, such as osteopontin and fibronectin, can regulate the adipo-osteogenic balance of MSCs through binding to integrin receptors (c). In addition, geometric cues such as nanoscale changes can also effectively dictate the differentiation of MSCs (d)