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Using the Power of the Nuclear Piston to Drive MSC Migration!

Review of The nuclear piston activates mechanosensitive ion channels to generate cell migration paths in confining microenvironmentsfrom Science Advances by Stuart P. Atkinson

The ability of mesenchymal stem cells (MSCs) to migrate through confining and viscoelastic microenvironments represents a key factor controlling endogenous regeneration and therapeutic outcomes following stem cell therapies [1, 2]. While previous research has studied the impact of matrix viscoelasticity on MSC spreading and differentiation, we understand less regarding how MSCs create migration paths and pass through confining and viscoelastic surroundings.

A recent study by researchers led by Ovijit Chaudhuri (Stanford University, Stanford, CA, USA) explored the implication of protease-independent mechanisms in generating MSC migration paths and the role of the “stiff” nucleus [3-5] in MSC migration. Lee et al. now report that the stiff nucleus does not act as an impediment to migration through confining and viscoelastic matrices and instead powers MSC migration by generating migration paths thanks to the “nuclear piston” mechanism [6].

The authors evaluated the migration of dye-labeled MSCs in three-dimensional engineered nanoporous alginate hydrogels, which allow for cell adhesion, microenvironmental confinement, the modulation of viscoelasticity and mechanical plasticity, and the discovery of potential protease-independent mechanisms of migration. Initial analyses provided evidence that the migration of MSCs through confining viscoelastic hydrogels occurred by the mechanical expansion of initially thin protrusions through the hydrogel matrix to create migratory channels. Subsequent analysis employing small interfering RNAs and nuclear tracking then demonstrated that a “nuclear piston” – the pushing of the nucleus towards the protrusions mediated by actomyosin contractility, microtubules, vimentin, and lamin A/C - drove both the increased pressure in thin protrusions and the subsequent protrusion expansion to allow migration in confining and plastic microenvironments.

Explorations of the mechanisms connecting the nuclear piston to protrusion expansion led the authors to evaluate potential changes to osmotic pressure driven by differences in the concentrations of ions between the inside and outside of the cell membrane. Fascinatingly, the study discovered that the nuclear piston induced the flow of calcium and sodium ions through mechanosensitive ion channels (sodium hydrogen exchanger–1 (NHE-1) and transient receptor potential vanilloid–4 (TRPV4) calcium ion channel [7]) to balance and then increase the osmotic pressure inside the protrusion to reduce water efflux, which then drives protrusion expansion and allows for migration through confining cell microenvironments.

While the stiff nature of the nucleus may appear as a significant impediment to MSC migration through confining viscoelastic microenvironments, the findings of this fascinating study establish the power of the nucleus in generating migration paths. For more on this exciting advance, stay tuned to the Stem Cells Portal!

References

  1. Chaudhuri O, Gu L, Klumpers D, et al., Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nature Materials 2016;15:326-334.
  2. Chaudhuri O, Cooper-White J, Janmey PA, et al., Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 2020;584:535-546.
  3. Petrie RJ, Koo H, and Yamada KM, Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science 2014;345:1062.
  4. Renkawitz J, Kopf A, Stopp J, et al., Nuclear positioning facilitates amoeboid migration along the path of least resistance. Nature 2019;568:546-550.
  5. Petrie RJ, Harlin HM, Korsak LIT, et al., Activating the nuclear piston mechanism of 3D migration in tumor cells. Journal of Cell Biology 2016;216:93-100.
  6. Lee H-p, Alisafaei F, Adebawale K, et al., The nuclear piston activates mechanosensitive ion channels to generate cell migration paths in confining microenvironments. Science Advances 2021;7:eabd4058.
  7. Lee H-p, Stowers R, and Chaudhuri O, Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments. Nature Communications 2019;10:529.