Abstract
Integration of soluble factors and physical properties of extracellular matrix is likely key to stem cell differentiation but the extent to which those pathways overlap remains unclear. Here motivated by the micromechanics of osteogenic niche we looked at the synergy between matrix stimuli and pharmacological perturbation of Retinoic Acid (RA) pathway on primary and iPSC-derived mesenchymal stem cells (MSCs) including iPSC- derived cells from progeria patients towards osteogenesis. Retinoic acid receptor RARG transcription factor is known to regulate nucleoskeletal protein Lamin-A. A cell-by-cell analysis showed that rigid matrix favor higher LMNA and correlates with increased nuclear-to-cytoplasmic ratio of RARG. We found that the Progerin allele of lamin-A is similarly regulated by specific RARG agonist/antagonists. A mechanochemical gene circuit in which tension on lamin-A ultimately favors RARG activity describes well the experimentally observed trend. Scatter-plots of single-cell analyses also show that some cells on stiff substrates fall within the response envelopes of cells cultured on soft substrates and that shared sub- population of non-responding cells we also found that don’t respond to RA agonist or antagonist regulation of Lamin-A. RA antagonist drove lamin-A dependent upregulation of osteogenic markers on rigid substrates and pretreated xenografts showed bone-level calcification suggesting a synergistic effect of soluble and insoluble factors on subpopulation of stem cells that are highly mechanoresponsive.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.