MiR-145 mediates cell morphology-regulated mesenchymal stem cell differentiation to smooth muscle cells.

Abstract:

:The use of biochemical signaling to derive smooth muscle cells (SMCs) from mesenchymal stem cells (MSCs) has been explored, but the induction of a fully functional SMC phenotype remains to be a major challenge. Cell morphology has been shown to regulate MSC differentiation into various lineages, including SMCs. We engineered substrates with microgrooves to induce cell elongation to study the mechanism underlying the MSC shape modulation in SMC differentiation. In comparison to those on flat substrates, MSCs cultured on engineered substrates were elongated with increased aspect ratios for both cell body and nucleus, as well as augmented cytoskeletal tensions. Biochemical studies indicated that the microgroove-elongated cells expressed significantly higher levels of SMC markers. MicroRNA analyses showed that up-regulation of miR-145 and the consequent repression of KLF4 in these elongated cells promoted MSC-to-SMC differentiation. Rho/ROCK inhibitions, which impair cytoskeletal tension, attenuated cell and nuclear elongations and disrupted the miR-145/KLF4 regulation for SMC differentiation. Furthermore, cell traction force measurements showed that miR-145 is essential for the functional contractility in the microgroove-induced SMC differentiation. Collectively, our findings demonstrate that, through a Rho-ROCK/miR-145/KLF4 pathway, the elongated cell shape serves as a decisive geometric cue to direct MSC differentiation into functional SMCs.

journal_name

Biomaterials

journal_title

Biomaterials

authors

Yeh YT,Wei J,Thorossian S,Nguyen K,Hoffman C,Del Álamo JC,Serrano R,Li YJ,Wang KC,Chien S

doi

10.1016/j.biomaterials.2019.03.003

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

59-69

eissn

0142-9612

issn

1878-5905

pii

S0142-9612(19)30127-9

journal_volume

204

pub_type

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