Control of cell fate decisions

Abstract

It is well established that stem cell maintenance and differentiation are governed by unique local cues found in microenvironments. The future efficacy of stem cells in regenerative medicine relies upon maintaining their properties ex vivo prior to placing them into a foreign tissue environment. This editorial preface highlights key elements controlling cell fate decisions. The subject of cell fate, also referred to as the ultimate differentiated state to which a cell has become committed, is governed by the unique local microenvironment (or niche) (Fuchs et al. 2004; Watt and Hogan 2000). The successful use of stem cells in regenerative medicine relies upon the better identification of the specific cues in these microenvironments, so that when removed from their natural habitat, expanded ex vivo and then transplanted into foreign tissues, they will retain their ability to regenerate tissue. Whilst normally quiescent in the bone marrow, human mesenchymal stem cells (hMSC) cultured ex vivo spontaneously differentiate, apparently due to the abrupt change in their microenvironment. Until recently, a combination of appropriate soluble factors and extracellular matrix molecules was thought to hold the key to ex vivo manipulation. However, a recent report published in Cell (Engler et al. 2006) has proposed that naive mesenchymal stem cells specify lineage commitment to phenotypes based on tissue-level elasticity, such that soft (brain-like) matrices confer neurogenic phenotypes, whilst stiffer (muscle-like) matrices give rise to myogenic cells, and comparatively rigid (bone-like) matrices direct to osteogenic fates. Interestingly, early on during the lineagecommitment phase, reprogramming of these lineages is possible using soluble factors; however, after several weeks in culture, cell fate decisions are specified by matrix elasticity. Thus the physical nature of a stem cell’s microenvironment appears to be equally important for determining morphological change and lineage specification. As such, more attention is now being paid to the role of actin structures and focal adhesions, as matrix sensing requires a direct pathway of force transmission from the elastic matrix into the interior of the cell (Beningo et al. 2001; Tamada et al. 2004). Indeed complex membranespanning heparan sulfate proteoglycans (HSPGs) are also known to transfer spatial information pertaining to the cellular niche to bring about cell-based adhesion or migration, behaviors crucial to cell fate decisions. Moreover, ECM proteins (via the HS side-chains on HSPGs) and cytoskeletal proteins (via cytoplasmic domains of HSPGs) interact with cell-surface receptors (such as integrins) to induce cell spreading and the formation of focal adhesions (Couchman et al. 2001) (for review see Bishop et al. 2007). Ultimately, cell fate decisions thus depend on the integration of signals mediated through HSPG-binding and integrin-based adhesive mechanisms (Bishop et al. 2007). Many excellent reviews have been written on the role HSPGs play during embryological development and their importance in mammalian physiology (Bishop et al. 2007; Bulow and Hobert 2006; Hacker et al. 2005; Haltiwanger and Lowe 2004). HS side-chains bound to core protein are known to bind not only growth factors, cytokines and chemokines, but also morphogens (such as Wnt and Sonic S. M. Cool (&) Laboratory of Stem Cells and Tissue Repair, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673 e-mail: scool@imcb.a-star.edu.sg