Emergent patterns of growth controlled by multicellular form and mechanics

Abstract

Spatial patterns of cellular growth generate mechanical stresses that help to push, fold, expand, and deform tissues into their specific forms. Genetic factors are thought to specify patterns of growth and other behaviors to drive morphogenesis. Here, we show that tissue form itself can feed back to regulate patterns of proliferation. Using microfabrication to control the organization of sheets of cells, we demonstrated the emergence of stable patterns of proliferative foci. Regions of concentrated growth corresponded to regions of high tractional stress generated within the sheet, as predicted by a finite-element model of multicellular mechanics and measured directly by using a micromechanical force sensor array. Inhibiting actomyosin-based tension or cadherin-mediated connections between cells disrupted the spatial pattern of proliferation. These findings demonstrate the existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth. Thus, tissue form is not only a consequence but also an active regulator of tissue growth. Spatial patterning of the behaviors of individual cells generates global changes in tissue architecture that drive morphogenesis (1, 2). Several morphogenic mechanisms likely collaborate to direct tissue form, including local changes in cell adhesion, cell shape, and cell proliferation. Qualitative and quantitative differences in cellular adhesiveness can lead to the segregation and layering of tissues (3); ordered changes in cell shape appear to direct gastrulation (4), epithelial folding (5), and tubulogenesis (6); and differentials in cell growth can locally alter tissue form (7,8). Although the molecular basis for these behaviors has been under intense study, the mechanical nature of morphogenesis also has been recognized since the late 19th century (9): Specific patterns of cellular growth (in which some cells proliferate but other cells do not) create mechanical stresses that help drive the buckling, budding, pinching, and branching processes of morphogenesis. Complex forms, such as the regular fractal structure of the branching organs, can thus arise from simple embryonic sheets (reviewed in refs. 10 and 11).What causes such localized patterns is one of the central puzzles of biology and has fascinated scientists from numerous disciplines for at least two millennia (12). Perhaps most well described are concentration gradients of diffusible factors, known as morphogens, which can drive spatial patterns of cellular behaviors (13-15). In addition to soluble factors, adhesion to extracellular matrix and mechanical forces also are known to modulate cell functions, including proliferation (10,16,17).Although spatial patterning of these cues can certainly explain spatial patterning of cellular behaviors, it remains unclear what initiates or maintains patterns. One theory suggests that these gradients (e.g., of morphogens) are entirely driven by prespecified genetic programs. A more tracta...

Detection of mitoses in embryonic epithelia using motion field analysis

“…A number of biological studies have suggested that the long axes of cells (Jacobson and Gordon 1976) are key determinants of mitosis orientation (O'Connell and Wang 2000). Other relevant factors may include cell signalling, biochemical factors, mechanical stresses and tissue deformation (Brodland and Veldhuis 2002;Gong et al 2004;Nelson et al 2005). In turn, regularly oriented mitosis, regardless of its origin, has been implicated as a significant driver of tissue motions (Philip et al 1992;Brodland and Veldhuis 2002;Gong et al 2004).…”

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

“…Adherent cells seem capable of both responding to applied mechanical forces (Tzima et al, 2005) and applying contractile forces to probe mechanical properties of the environment (Discher et al, 2005). The downstream responses include changes in migration (Pelham and Wang, 1997;Sheetz et al, 1998;Lo et al, 2000), cell-cell interactions (Guo et al, 2006), proliferation Nelson et al, 2005), differentiation (Engler et al, 2004(Engler et al, , 2006, and apoptosis . For cultured adherent cells, focal adhesions are thought to mediate mechanosensing through integrin-mediated anchorage to the extracellular matrix (Larsen et al, 2006).…”

Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments

“…c) Reproduced with permission. [72] Copyright 2005, National Academy of Sciences. d) Reproduced with permission.…”

“…Multicellular geometry can also feedback to regulate patterns of cell growth, with regions of high traction stress favouring growth and branching morphogenesis (Figure 5c). [72,73] Cells on a surface can sense and react to radii of curvature much larger than a single cell and regions with high local concave (convex) curvature favour (inhibit) tissue growth (Figure 5d). [74,75] On the other end of the size scale, surface nano-and microtopography influence size and shape of cell-matrix adhesion points and thus also play an important role in cell mechanotransduction, as well as in stem cell self-renewal and multipotency.…”