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

Yi Ting Yeh, Josh Wei, Satenick Thorossian, Katherine Nguyen, Clarissa Hoffman, Juan C. del Álamo, Ricardo Serrano, Yi Shuan Julie Li, Kuei Chun Wang, Shu Chien

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)59-69
Number of pages11
JournalBiomaterials
Volume204
DOIs
StatePublished - Jun 2019

Keywords

  • Cell shape modulation
  • Mesenchymal stem cell
  • Smooth muscle cell
  • miR-145

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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