Stem Cell Mechanobiology and the Role of Biomaterials in Governing Mechanotransduction and Matrix Production for Tissue Regeneration

Abstract

Mechanobiology has underpinned many scientific advances in understanding how biophysical and biomechanical cues regulate cell behavior by identifying mechanosensitive proteins and specific signaling pathways within the cell that govern the production of proteins necessary for cell-based tissue regeneration. It is now evident that biophysical and biomechanical stimuli are as crucial for regulating stem cell behavior as biochemical stimuli. Despite this, the influence of the biophysical and biomechanical environment presented by biomaterials is less widely accounted for in stem cell-based tissue regeneration studies. This Review focuses on key studies in the field of stem cell mechanobiology, which have uncovered how matrix properties of biomaterial substrates and 3D scaffolds regulate stem cell migration, self-renewal, proliferation and differentiation, and activation of specific biological responses. First, we provide a primer of stem cell biology and mechanobiology in isolation. This is followed by a critical review of key experimental and computational studies, which have unveiled critical information regarding the importance of the biophysical and biomechanical cues for stem cell biology. This review aims to provide an informed understanding of the intrinsic role that physical and mechanical stimulation play in regulating stem cell behavior so that researchers may design strategies that recapitulate the critical cues and develop effective regenerative medicine approaches.

Keywords: 2D substrate stiffness; 3D biomaterial stiffness; biomechanical stimuli; biophysical stimuli; computational modeling; regenerative medicine; tissue engineering.

FIGURE 1

Eggs that have been fertilized in vitro give rise to embryos which give rise to embryonic stem cells (ESCs). Induced pluripotent stem cells (iPSCs) are adult cells that are genetically reprogrammed to a pluripotent stem cell–like state. Adult stem cells are undifferentiated cells, found among specialized cells in specific areas of adult tissues (called a “stem cell niche”). Pluripotent (ESCs and iPSCs) cells give rise to all cell types of the body and multipotent (adult stem cells) cells give rise to all cell types of a particular tissue or organ.

FIGURE 2

Cellular mechanosensory proteins: The internal cytoskeleton transmits mechanical stimuli from the extracellular environment to the cell nucleus. This stimulus is mediated by transmembrane proteins located at focal adhesions, which bind to ECM ligands but also intracellular proteins. Cadherins connect the cytoskeleton of adjacent cells and thus enable cells to transmit force from one to another, and also allow movement of components within the plasma membrane. Primary cilia sense fluid flow, pressure and strain and activate ion flux through channels on the ciliary axoneme, which govern intracellular signaling. Other membrane proteins can also be regulated through mechanical shear and strain.

FIGURE 3

(A) The mechanical properties of PEG hydrogels were altered by varying precursor polymer concentration. (B) Velocity of skeletal muscle stem cells cultured on soft PEG hydrogel (12 kPa) or rigid cell culture plastic (106 kPa). (C) Number of skeletal muscle stems (normalized) cultured on soft (12 kPa) or rigid substrate (106 kPa) over the course of 70 h. Adapted with permission from Gilbert et al. (2010). ***p < 0.0001.

FIGURE 4

(A) Human ASC migration and (B) speed/velocity on 2.9 kPa/mm and 8.2-kPa/mm stiffness gradient fibronectin-coated PA gels over 72 h. (C) Average speed (xy) and x and y velocity over 72 h of hASCs on low (0.5 kPa/mm), middle (1.7 kPa/mm), and high (2.9 kPa/mm) stiffness gradient hydrogels. Adapted with permission from Hadden et al. (2017). *P < 0.05, ***P < 0.001.

FIGURE 5

(A) Computational model of 3D cell with 240 fiber orientations in 3D space within a representative volume element (RVE). (B,C) High affinity and low affinity integrins involved in the formation of focal adhesions between a cell containing stress fibers and a ligand-coated substrate (Ronan et al., 2014).