Force-dependent cell signaling in stem cell differentiation

Abstract

Stem cells interact with biochemical and biophysical signals in their extracellular environment. The biophysical signals are transduced to the stem cells either through the underlying extracellular matrix or externally applied forces. Increasing evidence has shown that these biophysical cues such as substrate stiffness and topography can direct stem cell differentiation and determine the cell fate. The mechanism of the biophysically induced differentiation is not understood; however, several key signaling components have been demonstrated to be involved in the force-mediated differentiation. This review will focus on focal adhesions, cytoskeletal contractility, Rho GTPase signaling and nuclear regulation in connection with biophysically induced differentiation. We will briefly introduce the important components of the mechanotransduction machinery, and the recent developments in the study of force-dependent stem cell differentiation.

Figure 1

Schematic diagrams of various methods to apply biophysical signals to cells. (A) Manipulation of substrate stiffness by (i) tuning the rigidity of the materials or (ii) using micro-post array with different height to adjust the rigidity. (B) Confinement of cell shape by patterning extracellular matrix protein such as fibronectin onto the substrate. Area outside the patterned shape will be coated with anti-fouling reagent to prevent cell adhesion. (C) Modification of surface topography. (D) Application of external forces, such as compression by compressing the substrate, tension by stretching the substrate, or shear stress by fluid flow.

Figure 2

Schematic diagram of possible key signaling components in the force-mediated stem cell differentiation. These mechanotransduction components include focal adhesion (FA), cytoskeletal contractility, Rho GTPase signaling and nuclear regulation. Simplified schematic diagram showing the components involved in (A) FAs in mechanotransduction, (B) the RhoA pathways in the regulation and differentiation of (i) embryonic stem cells and (ii) adult stem cells, and (C) nuclear regulation. (B) Pharmaceutical inhibitors are indicated in green text. Dotted lines, signaling pathway with intermediate steps not shown; dashed lines, signaling pathway with intermediate steps yet to be identified.(?), examples of questions under active research. Arrow, activation; block-ended line, inhibitions. B-Cat, beta-catenin; BMP, bone morphogenetic protein; Cad, cadherin; CCMT, continuous cyclic mechanical tension; ESC, embryonic stem cell; FAK, focal adhesion kinase; GEF, guanine exchange factor; KASH, Klarsicht, Anc-1, and Syne homology; LPA, lysophosphatidic acid; MLCK, myosin light-chain kinase; MSC, mesenchymal stem cell; NPC, neural progenitor cell; PPAR, peroxisome proliferator-activated receptor; ROCK, Rho-associated kinase; SMAD, SMA/mothers against decapentaplegic; SUN, Sad1p and UNc-84; VASP, vasodilator-stimulated phosphoprotein.