Egr1 is a 3D matrix-specific mediator of mechanosensitive stem cell lineage commitment

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While extracellular matrix (ECM) mechanics strongly regulate stem cell commitment, the field's mechanistic understanding of this phenomenon largely derives from simplified two-dimensional (2D) culture substrates. Here, we found a 3D matrix-specific mechanoresponsive mechanism for neural stem cell (NSC) differentiation. NSC lineage commitment in 3D is maximally stiffness sensitive in the range of 0.1 to 1.2 kPa, a narrower and more brain-mimetic range than we had previously identified in 2D (0.75 to 75 kPa). Transcriptomics revealed stiffness-dependent up-regulation of early growth response 1 (Egr1) in 3D but not in 2D. Egr1 knockdown enhanced neurogenesis in stiff ECMs by driving beta-catenin nuclear localization and activity in 3D, but not in 2D. Mechanical modeling and experimental studies under osmotic pressure indicate that stiff 3D ECMs are likely to stimulate Egr1 via increases in confining stress during cell volumetric growth. To our knowledge, Egr1 represents the first 3D-specific stem cell mechanoregulatory factor.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Issue Date
2022-04
Language
English
Article Type
Article
Citation

SCIENCE ADVANCES, v.8, no.15

ISSN
2375-2548
DOI
10.1126/sciadv.abm4646
URI
http://hdl.handle.net/10203/296454
Appears in Collection
ME-Journal Papers(저널논문)
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