Role of substrate biomechanics in controlling (stem) cell fate: Implications in regenerative medicine

Abstract

Tissue-specific stem cells reside in a specialized environment known as niche. The niche plays a central role in the regulation of cell behaviour and, through the concerted action of soluble molecules, supportive somatic cells, and extracellular matrix components, directs stem cells to proliferate, differentiate, or remain quiescent. Great efforts have been done to decompose and separately analyse the contribution of these cues in the in vivo environment. Specifically, the mechanical properties of the extracellular matrix influence many aspects of cell behaviour, including self-renewal and differentiation. Deciphering the role of biomechanics could thereby provide important insights to control the stem cells responses in a more effective way with the aim to promote their therapeutic potential. In this review, we provide a wide overview of the effect that the microenvironment stiffness exerts on the control of cell behaviour with a particular focus on the induction of stem cells differentiation. We also describe the process of mechanotransduction and the molecular effectors involved. Finally, we critically discuss the potential involvement of tissue biomechanics in the design of novel tissue engineering strategies.

Release of pro-inflammatory cytokines from muscle and bone causes tenocyte death in a novel rotator cuff in vitro explant culture model

“…17-19 However, cell-based studies lack the native three-dimensional extracellular matrix environment that tenocytes thrive in, and a number of studies have shown that this environment is critical to cell behavior in a variety of cell lines. 20,21…”

Cells on Hydrogels with Micron-Scaled Stiffness Patterns Demonstrate Local Stiffness Sensing

“…Only the Poisson's ratio ν of the material comes in Equation (1), not the Young's modulus Y. Young's modulus comes in when imposing the surface stresses at the boundaries [43].…”

“…Cell sensitivity to the mechanical properties of an extracellular environment is presently seen as a promising route for stem cell engineering and regenerative medicine [1,2], as well as the design of organs on a chip [3]. Many technologies have arisen that build soft environments for cell cultures.…”

Unchain My Heart: Integrins at the Basis of iPSC Cardiomyocyte Differentiation

“…Substrate stiffness has been shown to be a very strong mechanotransduction stimulus, regulating physiopathological cell behaviour and cell reprogramming and subsequently guiding the development of mature cell phenotypes [164, 228–233]. In particular, regarding the in vitro application of iPSC technology in the cardiac field, matrix rigidity can guide iPSC-d-CM differentiation: the use of a substrate with compliance similar to that of native cardiac tissue [234–236] supports cardiac commitment and enhances metabolic maturity, sarcomeric protein subtype, cardiac troponin T expression, and force generation [230, 235, 237, 238]. The molecular events transferring the force from the substrate to the nuclei, through cytoskeleton engagement, have been described by Zhou et al [239], and other reviews discussed this topic at length [240, 241].…”