Five Piconewtons: The Difference between Osteogenic and Adipogenic Fate Choice in Human Mesenchymal Stem Cells

ACS Nano. 2019 Oct 22;13(10):11129-11143. doi: 10.1021/acsnano.9b03914. Epub 2019 Oct 9.

Abstract

The ability of mesenchymal stem cells to sense nanoscale variations in extracellular matrix (ECM) compositions in their local microenvironment is crucial to their survival and their fate; however, the underlying molecular mechanisms defining how such fates are temporally modulated remain poorly understood. In this work, we have utilized self-assembled block copolymer surfaces to present nanodomains of an adhesive peptide found in many ECM proteins at different lateral spacings (from 30 to 60 nm) and studied the temporal response (2 h to 14 days) of human mesenchymal stem cells (hMSCs) using a panel of real-time localization and activity biosensors. Our findings revealed that within the first 4 to 24 h postadhesion and spreading, hMSCs on smaller nanodomain spacings recruit more activated FAK and Src proteins to produce larger, longer-lived, and increased numbers of focal adhesions (FAs). The adhesions formed on smaller nanospacings rapidly recruit higher amounts of nonmuscle myosin IIA and vinculin and experience tension forces (by >5 pN/FA) significantly higher than those observed on larger nanodomain spacings. The transmission of higher levels of tension into the cytoskeleton at short times was accompanied by higher Rac1, cytosolic β-catenin, and nuclear localization of YAP/TAZ and RUNX2, which together biased the commitment of hMSCs to an osteogenic fate. This investigation provides mechanistic insights to confirm that smaller lateral spacings of adhesive nanodomains alter hMSC mechanosensing and biases mechanotransduction at short times via differential coupling of FAK/Src/Rac1/myosin IIA/YAP/TAZ signaling pathways to support longer-term changes in stem cell differentiation and state.

Keywords: focal adhesions; lateral ligand spacing; mechanosensing; mechanotransduction; stem cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adipogenesis / drug effects
  • Adipogenesis / genetics*
  • Cell Differentiation / drug effects
  • Cell Lineage / drug effects
  • Cell Lineage / genetics*
  • Cellular Microenvironment / drug effects
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Cytoskeleton / drug effects
  • Cytoskeleton / genetics
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / genetics
  • Focal Adhesions / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects*
  • Osteogenesis / drug effects
  • Osteogenesis / genetics*
  • Polymers / chemistry
  • Polymers / pharmacology
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • beta Catenin / genetics
  • rac1 GTP-Binding Protein / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Core Binding Factor Alpha 1 Subunit
  • Polymers
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • beta Catenin
  • rac1 GTP-Binding Protein