Role of mechanical factors in fate decisions of stem cells

Abstract

Stem cells derived from adult tissues or from the inner cell mass of blastocyst-stage embryos can self-renew in culture and have the remarkable potential to undergo lineage-specific differentiation. Extensive studies have been devoted to achieving a better understanding of the soluble factors and the mechanism(s) by which they regulate the fate decisions of these cells, but it is only recently that a critical role has been revealed for physical and mechanical factors in controlling self-renewal and lineage specification. This review summarizes selected aspects of current work on stem cell mechanics with an emphasis on the influence of matrix stiffness, surface topography, cell shape and mechanical forces on the fate determination of mesenchymal stem cells and embryonic stem cells.

Figure 1. The cellular microenvironment

Soluble factors and ECM combine with cell–cell adhesion to control cell fate. ECM: Extracellular matrix.

Figure 2. Osteopontin and osteocalcin staining of mesenchymal stem cells 21 days after cultivation on various nanotopographies

The top row shows images of nanotopographies fabricated by electron beam lithography. All have 120-nm diameter pits with square array (SQ), disordered square array with dots displaced randomly by up to 50 nm on both axes from their position in a true square (DSQ20), disordered square array with dots displaced randomly by up to 50 nm on both axes from their position in a true square (DSQ50) and pits placed randomly over a 150 × 150 μm field (RAND). Mesenchymal stem cells: on the control (A & F); SQ (B & G); DSQ20 (C & H); DSQ50 (D & I); and RAND (E & J). OPN-positive cells were detected in cells on DSQ20 and DSQ50, and OCN-positive cells were detected in cells on DSQ50. Mature bone nodules containing mineral were also observed in cells on DSQ50 (arrows). Actin: red, OPN/OCN: green. OCN: Osteocalcin; OPN: Osteopontin. Adapted with permission from [51].

Figure 3. Non-muscle myosin IIA is required for colony formation and pluripotency in human embryonic stem cells

(A) Phase contrast images of human embryonic stem cells (hESCs) with or without the following treatments: blebbistatin (a highly specific inhibitor of NMMII), NT shRNA and NMMIIA-specific shRNAs. shRNA-mediated RNAi was used for depletion of NMMIIA. Depletion or inhibition of NMMII markedly impaired colony formation in hESCs. (B & C) Western blot analysis of OCT-4, SOX2 and NANOG proteins in hESCs treated with or without blebbistatin, or with or without depletion of NMMIIA. Three different shRNAs targeting NMMIIA were used. Depletion or inhibition of NMMII significantly reduced OCT-4, SOX2 and NANOG protein levels. a-tubulin was a loading control. Scale bar in (A): 100 μm. NMM: Non-muscle myosin; NT: Nontargeting. Adapted with permission from [82].