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Prog Biophys Mol Biol. 2018 May;134:55-67. doi: 10.1016/j.pbiomolbio.2018.01.001. Epub 2018 Jan 4.

Physical constraints in cell fate specification. A case in point: Microgravity and phenotypes differentiation.

Author information

1
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy; Department of Surgery "PietroValdoni", Sapienza University of Rome, via A. Scarpa 14, 00161 Rome, Italy. Electronic address: mariagrazia.masiello@uniroma1.it.
2
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy. Electronic address: roberto.verna@uniroma1.it.
3
Department of Surgery "PietroValdoni", Sapienza University of Rome, via A. Scarpa 14, 00161 Rome, Italy; Azienda Policlinico Umberto I, viale del Policlinico 155, 00161 Rome, Italy. Electronic address: alessandra.cucina@uniroma1.it.
4
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy. Electronic address: mariano.bizzarri@uniroma1.it.

Abstract

Data obtained by studying mammalian cells in absence of gravity strongly support the notion that cell fate specification cannot be understood according to the current molecular model. A paradigmatic case in point is provided by studying cell populations growing in absence of gravity. When the physical constraint (gravity) is 'experimentally removed', cells spontaneously allocate into two morphologically different phenotypes. Such phenomenon is likely enacted by the intrinsic stochasticity, which, in turn, is successively 'canalized' by a specific gene regulatory network. Both phenotypes are thermodynamically and functionally 'compatibles' with the new, modified environment. However, when the two cell subsets are reseeded into the 1g gravity field the two phenotypes collapse into one. Gravity constraints the system in adopting only one phenotype, not by selecting a pre-existing configuration, but more precisely shaping it de-novo through the modification of the cytoskeleton three-dimensional structure. Overall, those findings highlight how macro-scale features are irreducible to lower-scale explanations. The identification of macroscale control parameters - as those depending on the field (gravity, electromagnetic fields) or emerging from the cooperativity among the field's components (tissue stiffness, cell-to-cell connectivity) - are mandatory for assessing boundary conditions for models at lower scales, thus providing a concrete instantiation of top-down effects.

KEYWORDS:

Cell-fate commitment; Constraints; Gene-regulatory networks; Microgravity; Non-equilibrium thermodynamics; Waddington landscape

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