Stem cells interrogate numerous microenvironmental cues, including soluble factors, adhesive contexts, and mechanical signals, in order to mount physiologically relevant differentiation responses. While much is known about how soluble factors and adhesion receptors regulate differential gene expression, the molecular basis for how mechanical signaling controls gene transcription and differentiation programs is only now coming into focus. In this review, we discuss the types of mechanical forces that stem cells experience, and the evidence that applied and cell generated forces regulate stem cell differentiation in vivo and in vitro. In order to understand the mechanistic basis for mechanically-induced differentiation, we explore how mechanical forces are transduced into biochemical signals, that can in turn regulate and synergize with signaling cascades induced by other stimuli. Specifically, we emphasize how applied mechanical forces target the activity and expression or transcription factors and chromatin remodeling enzymes directly involved in gene expression. Furthermore, we highlight recent progress demonstrating that cell-generated forces (intracellular tension) can promote stem cell differentiation in the absence of or in spite of orthogonal signals from soluble factors. Together these findings define an emerging picture of how mechanical forces trigger stem cell differentiation to a specific lineage in complex microenvironments where inducers for multiple cell types are present.

Introduction

Stem cells are a driving force in functional tissue engineering due to their self-renewal capacity and pluripotency. Self-renewal enables the extensive ex-vivo (and in vivo) expansion of progenitor cells for a targeted tissue, a key feature for generating sufficient cells to meet the potential demand for tissue replacement. Pluripotency, or the ability to stem cell to differentiate into multiple cell types, allows for the possibility of generating multiple tissues from a single cell source, and even reconstituting complex multicellular interactions required for the function of a single tissue. The multilineage differentiation potential of stem cells is at once an opportunity and also a challenge as differentiation at the wrong time, place, or to an undesired cell type may lead to a pathophysiologic state or a non-functional tissue construct. To avoid such maladaptive responses, stem cells have evolved elaborate circuitry that triggers them to respond to differentiation cues only in an appropriate biological context. While biologists have long appreciated a role for soluble cues (e.g. growth factors and cytokines) in regulating stem cell differentiation, recent evidence demonstrates that the response to these stimuli are strongly modified by adhesive and mechanical cues, and that these microenvironmental factors may be used explicitly to control stem cell differentiation in their own right. Here we describe the evidence for mechanical control of stem cell differentiation and the mechanisms that transduce mechanical signals into differential gene expression.

What are mechanical signals?

Mechanical signals are cues that cells can sense as a result of the application of force. The simplest interpretation of how cells react to forces can be derived from the behavior of a classical spring. When forces are applied to springs, two potential responses can occur. First, forces can lead to a change in the spring's length, which is typically reported as a strain (change in length normalized to the original spring length). Second, applied forces can lead to the development of internal tension, often denoted as stress (force divided by the cross-sectional area of the spring). Since primary sites of mechanosensation in cells may experience both strain and stress responses, a useful distinction between types of mechanical signals is between tensile (pulling) forces and compressive forces (those that push on cells/tissues). More detailed consideration of these forces will be given in Section 3.

While the behavior of classical springs is a useful starting point for understanding the biological response to mechanical stimuli, the reality is far more complicated due to the contribution of two key factors. First, tissues and cells are not passive materials, but rather have tunable mechanical properties governed by dynamic reorganization of their cytoskeletal networks. On short time scales, the cytoskeleton can fluidize in response to mechanical stretch (Trepat et al., 2007), but cells rapidly transition to an active response in which realignment of the cytoskeleton occurs to counterbalance the applied force (Katsumi et al., 2002; Matthews et al., 2006). In parallel, the actin cytoskeleton contributes to the mechanical forces within the system due to the pulling action of myosin motors (principally non-muscle myosin II) on actin filaments, which result in the production of tensile forces against the extracellular matrix (Pelham and Wang, 1999; Balaban et al., 2001; Tan et al., 2003). Importantly, there is feedback between externally applied forces and myosin II activity such that external mechanical stimuli often activate biochemical signals responsible for increased myosin motor activity and intracellular tension (Wojciak-Stothard and Ridley, 2003; Shiu et al., 2004; Torsoni et al., 2005; Sarasa-Renedo et al., 2006; Zhao et al., 2007). As such, the biological response to exogenous force is governed not only by the initial input force, but also by subsequent alterations in cell-generated forces. In certain contexts, these cell-generated forces may be necessary or sufficient for stem cell differentiation (we will elaborate on this in further detail below).

Second, while mechanosensation begins with a mechanical response (strain, stress, and/or intracellular forces) cells transduce the mechanical stimuli into a biochemical output, otherwise known as mechanochemical signaling or mechanotransduction. Multiple activation mechanisms are simultaneously at play including release of autocrine growth factors (Resnick et al., 1993; Liu et al., 1995; Reusch et al., 1996; Robbins et al., 1997; Cillo et al., 2000; Wu et al., 2001; Zheng et al., 2001; Lindahl et al., 2002), activation of mechanically-sensitive kinases such as Src (Liu et al., 1996; Han et al., 2004; Jiang et al., 2005; Wang et al., 2005; Na et al., 2008), FAK (Li et al., 1997; Smith et al., 1998; Wang et al., 2001; Leucht et al., 2007), and ERK (Yamazaki et al., 1995; Takahashi and Berk, 1996; Jalali et al., 1998; MacKenna et al., 1998; Schmidt et al., 1998; Chen et al., 2000; Iqbal and Zaidi, 2005), and initiation of second messenger signaling (Sadoshima and Izumo, 1997; Liu et al., 1999). Thus mechanical signals have extensive potential to regulate and synergize with classical biochemical signal transduction pathways induced by soluble factors to control stem cell differentiation.

What are the sources and functional consequences of applied mechanical forces on stem cells in vivo?

Stem cell differentiation normally plays out in the context of organismal development or as part of the wound healing response. Both development and wound healing contexts are environments where extracellular forces abound, and evidence suggests that these forces instruct the subsequent behavior of stem cells. Typically, tissues may experience compressive forces or pressure, tensile forces (e.g. mechanical loading or stretch), and fluid-applied forces (shear flow). Others have enumerated these forces in thorough detail (Henderson and Carter, 2002; Estes et al., 2004); here we provide just a few illustrative examples where evidence suggests a functional link between forces and differentiation.

Compressive pressure typically arises when cells proliferate and/or deposit large amounts of extracellular matrix in regions where expansion of the tissue is resisted or prevented by rigid external boundaries. Such compressive forces can play key roles in tissue formation by controlling the balance between cell growth versus differentiation. For example, in the developing skeleton, primitive cartilage tissue is usually encapsulated by a rigid perichondrial membrane. Relaxation of this mechanical constraint by transection or removal of the perichondrium results in unregulated growth of the remaining tissue (Rooney and Archer, 1992; Long and Linsenmayer, 1998), likely by allowing chondroprogenitors cells to continue to grow rather than differentiate into cartilage. Furthermore, inappropriate development of compressive pressure can lead to ectopic cartilage formation. In classic tissue explants studies, Glucksmann demonstrated ectopic cartilage formation in developing bones when bone explants were trapped between artificial barriers (Glucksmann, 1939). Similarly, in models of the developing jaw, applied compression to the mandible joint led to ectopic cartilage formation on the jaw bones (Hall, 1967; Hall, 1968) and mechanical compression of the midplatal suture reprogrammed mesenchymal stem cell (MSC)-like cells from an osteogenic to a chondrogenic fate (Saitoh et al., 2000).

Tensional forces are prominent in the skeletal system and arise in response to movement of articulated tissues, such as the flexion of tendons or muscle contractions pulling on bones. It has also been suggested that tensional forces evolve also from the highly directional and asymmetric growth of two articulated tissues, for example the stretching of periosteal tissue anchored to both the bone shaft and the tips of tangentially expanding bone epiphyses (Glucksmann, 1942), or the stretching of musculoskeletal units that bridge rapidly growing skeletal elements (Stewart 1972; Taber 1998). Experimental manipulation of tension can profoundly alter development of the skeletal system. Severe osteogenic defects occur when tension in the periosteal tissue is alleviated by resection of bone epiphyses (Glucksmann, 1942); conversely ectopically applied tensional forces appear to transform cartilaginous tissue into bone (Glucksmann, 1942; Takahashi et al., 1996, 2003). In contrast, loss of muscle-induced tension via experimentally-induced paralysis or limb-tissue transplantation surgeries has more limited effects. These manipulations alter the formation of specific sesamoid bones, such as the plantar tarsal sesamoid and the patella (Drachman and Sokoloff, 1966; Hosseini and Hogg, 1991), and reduce the formation of bony ridges at tendon attachment sites (Murray and Huxley, 1925; Hamburger, 1938; Hamburger and Waugh, 1940).

Another important source of mechanical forces are fluid shear stresses, typically experienced by the developing myocardium (Hove et al., 2003), fetal lung epithelium (Liu and Post, 2000), or kidney (Serluca et al., 2002). In addition to these developmental contexts, fluid shear stress is also experienced in bone, where interstitial fluid flow governs the physiological responses to mechanical loading (Burger and Klein-Nulend, 1999). Shear stress is perhaps best known for its effects on the vascular endothelium (Davies, 1995; Orr et al., 2006). Disruption of hydrodynamic forces by the introduction of beads that block cardiac inflow or outflow produces dramatic cardiac defects in zebrafish, including failure of valve formation, and absence of heart looping and formation of a third chamber (Hove et al., 2003). Although Hove et al. did not establish a direct role for shear flow in regulating endothelial cell differentiation, other studies have demonstrated that changes in shear flow is associated with widescale reprogramming of gene expression in endothelial cells (Dai et al., 2004; Garcia-Cardena et al., 2001), and has inductive roles in determining arterial-venous specification (Le Noble et al., 2004). Moreover, shear flow has been reported to promote endothelial differentiation of mesenchymal stem cells or endothelial progenitors (Wang et al., 2005; Yamamoto et al., 2003, 2005), and cardiac differentiation of embryonic stem cells (Illi et al., 2005).

Collectively, these studies highlight two themes in mechanical regulation of tissue development and cell differentiation by external forces. First, while mechanical stimuli are relevant to a wide variety of tissues/cell types, distinct classes of mechanical forces trigger divergent programs of cell differentiation (c.f. the effects of compressive versus tensional forces on skeletogenesis (Glucksmann, 1939; Glucksmann, 1942)). Second, early differentiation persists even in the absence of external forces; that is, paralytic agents do not prevent the appearance of muscle fibers, although morphology and growth is perturbed (Hall and Herring, 1990); osteoblasts and chondrocytes persist even when limbs are mechanically unloaded by transplantation (Murray and Huxley, 1925, Fell and Robison, 1929; Hamburger, 1938; Bradley, 1970; Hall, 1972), and endothelial cells form when flow is disrupted (Hove et al., 2003). This is not particularly surprising given the fact that in embryogenesis, differentiated cell types typically appear and segregate prior to coordinated tissue function (such as muscle contraction or blood flow) that might contribute to the generation of substantial forces. Thus the likely mechanism by which applied mechanical forces control stem cells is not through the direct and spontaneous triggering of differentiation per se, but rather, by specification of a particular fate under environmental conditions that can induce several possible cell types. Put another way, mechanical signals act as a molecular switch to bias stem cells towards one lineage over another.

How do mechanical forces lead to lineage switching?

Despite the importance of the aforementioned in vivo studies in establishing a link between tissue formation, differentiation, and mechanical stimuli, it is important to acknowledge certain inherent limitations in these experiments, including the inability to measure the change in applied forces or stresses in these experiments, and the likelihood that the mechanical manipulations employed also perturb paracrine signaling and/or adhesive cues. Our understanding of how mechanical signals regulate stem cell differentiation and lineage switching is greatly informed by several elegant studies that directly examine the link between mechanical force, gene expression, and cell differentiation.

Mechanosensors

While cell shape, RhoA signaling, and cytoskeletal tension appear to have major roles in governing the response of stem cells to mechanical forces, it is not yet clear whether these players converge on a single mechanosensitive cellular compartment or molecule, and a mechanotransduction pathway connecting tension to mechanoresponsive transcriptional machinery (see section 4.1) remains elusive. Focal adhesions, cellular footholds that anchor matrix-bound integrins to the actin cytoskeleton, are likely to factor into tension-dependent mechanotransduction. Cell-generated traction forces are transmitted to the extracellular matrix at focal adhesions (Balaban et al., 2001; Beningo et al., 2001; Tan et al., 2003), which implies the development of stress within these structures, and these stresses regulate the assembly/disassembly of focal adhesions (Chrzanowska-Wodnicka and Burridge, 1996; Helfman et al., 1999; Balaban et al., 2001; Riveline et al., 2001; Sniadecki et al., 2007). Second, focal adhesions are molecular signaling hubs implicated in the recruitment and activation of key mechanosensitive kinases such as FAK, Src, and ERK (Miyamoto et al., 1995; Fincham et al., 2000; Wang et al., 2005; Cai et al., 2008), and also in the regulation of nuclear-cytoplasmic shuttling of some transcription factors (Nix and Beckerle, 1997; Petit et al., 2000; Aoto et al., 2002; Shibanuma et al., 2003; Silver et al., 2004). In spite of the potential importance of focal adhesions in mechanotransduction, they are but one of several mechanosensors identified in cells (Ingber, 2006); these include changes in membrane curvature or lipid microdomains (Rizzo et al., 1998; Hamill and Martinac, 2001;), GPCRs (Chachiscilis et al., 2006), mechanosensitive ion channels (Sukharev and Corey, 2004),conformational change of cytoskeletal proteins (Sawada et al., 2006; Johnson et al., 2007), the nuclear lamina or nuclear deformations (Lammerding et al., 2004; Lammerding et al., 2005), and primary cilia (Resnick and Hopfer, 2007). Importantly, no stem-cell specific mechanosensory mechanisms have been proposed, and any number of aforementioned mechanisms may contribute to mechanical control of stem cell differentiation. Nonetheless, in addition to the RhoA/tension/focal adhesion pathway, MAPK signaling and primary cilia probably warrant special mention. MAPK signaling, and ERK in particular, is distinctive in that it can be activated in response to numerous types of applied forces (Iqbal and Zaidi, 2005), sits at a cross-roads between soluble factor and adhesion signaling (like RhoA; Estes et al., 2004; Ross, 2004), and regulates differentiation of stem cells (Jaiswal et al., 2000; Binétruy et al., 2007). Primary cilia are receiving increasing attention following the discovery that these structures play key roles in controlling the Hedgehog signaling pathway (Huangfu and Anderson, 2005; Corbit et al., 2005), one of the major determinants of embryonic patterning (Ingham and McMahon, 2001; Hirokawa et al., 2006). Given the recent identification of primary cilia in cultured embryonic stem cells (Kiprilov et al., 2008), exploring the role of primary cilia in mechanical regulation of differentiation, perhaps by altered Hedgehog signaling, represents an exciting future direction for stem cell research.

Conclusions and perspectives

Both externally-applied and cell-generated mechanical forces are pivotal to the differentiation response of stem cells. Largely, the evidence for these effects are focused around mesenchymal stem cells, tensile or compressive strains, and the musculoskeletal system, but compelling evidence exists also in tissues subject to fluid flow, such as the endothelium and the lung. As such, we anticipate that mechanical forces will play an extensive, if not ubiquitous, role in stem cell differentiation. Notably absent from the literature, however, are any studies of how mechanical signals might promote the undifferentiated state or “stemness.” Preliminary findings indicate that RhoA/ROCK signaling controls differentiation of embryonic stem cells (Peerani et al., 2007; Watanbe et al., 2007), although a specific role of tension/mechanical force remains wholly unexplored. Given the poor efficiency of forming induced pluripotent cells in vitro (Meissner et al., 2007; Takahashi et al., 2007) and the apparent importance of microenvironmental cues in forming “stem cell niches” (Lensch et al., 2006; Moore and Lemischka, 2006), it is tempting to speculate that the mechanical environment may hold the keys to engineering stemness, and represents an important opportunity and direction for future research.

Also critical to our understanding of stem cells is a better picture of the mechanisms by which mechanical signals are transduced into changes in gene expression. Currently much remains to be addressed, but it is clear that RhoA/ROCK (Sordella et al., 2003; McBeath et al., 2004) and ERK signaling (Iqbal and Zaidi, 2005) are key players in mechanosensation, and these molecules may serve as hubs to mediate cross-talk between mechanical stimuli and soluble factors. Indeed, mechanical forces appear to either enhance or antagonize differentiation signals induced by growth factors and cytokines. Nonetheless, it is also important to acknowledge that in some cases mechanical signals appear to completely bypass the influence of soluble factors by directly altering gene expression (Farge, 2003; McBeath et al., 2004; Jakkaraju et al., 2005; Engler et al., 2006). Moreover, unlike soluble cues, mechanical forces are distinct in their potential for propagating across large distances, and thus may provide an instantaneous conduit for coordinating differentiation events at both the single cell and tissue-wide scales. Given the prominent role of scaffolds in regenerative medicine, scaffold-derived mechanical signals, such as matrix stiffness, must be given careful consideration by tissue engineers for potential effects on stem cell differentiation. Functional tissue engineering, particularly in cases where stem cells must form multiple cell types in situ, will likely hinge on our ability to understand and manipulate the propagation of tissue-scale mechanical signaling.

Acknowledgements

Work in C.S.C's lab is supported by grants from the NIH (EB00262, EB001046, HL73305, GM74048), the Army Research Office Multidisciplinary University Research Initiative, and the Penn Center for Musculoskeletal Disorders. D.M.C has also received support from by a Kirschstein National Research Service Award (HL084966).

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Edited by Sangeeta Bhatia and Julia Polak. Last revised June 13, 2008. Published October 31, 2008. This chapter should be cited as: Cohen, D.M. and Chen, C.S., Mechanical control of stem cell differentiation (October 31, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.26.1, http://www.stembook.org.