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Cell Volume modulates Mesenchymal Stem Cell Fate

Review of “Cell volume change through water efflux impacts cell stiffness and stem cell fate” from PNAS by Stuart P. Atkinson

Multiple studies have established that external osmotic pressure prompts a reduction in cell volume via the efflux of water, leading to higher cell stiffness and altered cell mechanics/behavior [1-3]. With this knowledge in hand, researchers from the laboratory of Jennifer Lippincott-Schwartz (Howard Hughes Medical Institute, Virginia, USA) and David A. Weitz (Harvard University, Massachusetts, USA) asked whether cells alter their volume to modify cell behavior in response to additional stimuli. In their new study, Guo et al. describe their new findings, and report a striking link between cell volume and mesenchymal stem cell (MSC) fate [4].

The authors discovered that cell growth on a stiff growth substrate also leads to a reduction in cell volume and an increase in cell stiffness mediated by water efflux - a similar behavior to cells cultured under external osmotic pressure. Substrate stiffness, cell spread area, and external osmotic pressure all correlated to decreased cell volume and increased stiffness mediated by water efflux. This reduction in cell volume leads to an increased concentration of intracellular material and a phenomenon known as “molecular crowding” and an overall modification of cell mechanics and cell behavior.

Interestingly, the study then established that cellular water efflux, accompanied by a decrease in cell volume and an increase in stiffness, prompted alterations to MSC differentiation propensity, specifically towards an osteogenic or adipogenic fate. This all suggests that the consequences of reduced cell volume influences stem cell fate, a hypothesis strengthened by the finding that MSCs undergoing multilineage differentiation exhibit alterations to their cell volume.

The reduction in cell volume and increase in cell stiffness can affect processes occurring both in the cytoplasm and in the nucleus that influence stem cell fate. These include protein folding and binding kinetics, cell structure, in-cell transport, protein expression, and, importantly, chromatin structure, and, therefore, transcription and gene expression patterns [3, 5]. The next quest is to understand how MSCs control this phenomenon and to discover whether this means of fate determination exists in other stem cell types.

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  1. Zhou EH, Trepat X, Park CY, et al., Universal behavior of the osmotically compressed cell and its analogy to the colloidal glass transition. Proc Natl Acad Sci U S A 2009;106:10632-7.
  2. Oh D, Zidovska A, Xu Y, et al., Development of time-integrated multipoint moment analysis for spatially resolved fluctuation spectroscopy with high time resolution. Biophys J 2011;101:1546-54.
  3. Irianto J, Swift J, Martins RP, et al., Osmotic challenge drives rapid and reversible chromatin condensation in chondrocytes. Biophys J 2013;104:759-69.
  4. Guo M, Pegoraro AF, Mao A, et al., Cell volume change through water efflux impacts cell stiffness and stem cell fate. Proceedings of the National Academy of Sciences 2017.
  5. Swift J, Ivanovska IL, Buxboim A, et al., Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 2013;341:1240104.