A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis

Nat Cell Biol. 2019 Dec;21(12):1490-1503. doi: 10.1038/s41556-019-0417-z. Epub 2019 Nov 25.

Abstract

Tendon injuries cause prolonged disability and never recover completely. Current mechanistic understanding of tendon regeneration is limited. Here, we use single-cell transcriptomics to identify a tubulin polymerization-promoting protein family member 3-expressing (Tppp3+) cell population as potential tendon stem cells. Through inducible lineage tracing, we demonstrate that these cells can generate new tenocytes and self-renew upon injury. A fraction of Tppp3+ cells expresses platelet-derived growth factor receptor alpha (Pdfgra). Ectopic platelet-derived growth factor-AA (PDGF-AA) protein induces new tenocyte production while inactivation of Pdgfra in Tppp3+ cells blocks tendon regeneration. These results support Tppp3+Pdgfra+ cells as tendon stem cells. Unexpectedly, Tppp3-Pdgfra+ fibro-adipogenic progenitors coexist in the tendon stem cell niche and give rise to fibrotic cells, revealing a clandestine origin of fibrotic scars in healing tendons. Our results explain why fibrosis occurs in injured tendons and present clinical challenges to enhance tendon regeneration without a concurrent increase in fibrosis by PDGF application.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / physiology
  • Animals
  • Cell Adhesion Molecules / metabolism*
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Disease Models, Animal
  • Fibrosis / metabolism*
  • Fibrosis / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Platelet-Derived Growth Factor / metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Regeneration / physiology*
  • Signal Transduction / physiology
  • Stem Cells / metabolism*
  • Stem Cells / physiology
  • Tendon Injuries / metabolism
  • Tendon Injuries / physiopathology
  • Tendons / metabolism*
  • Tendons / physiopathology
  • Tenocytes / metabolism
  • Tenocytes / physiology

Substances

  • Ceacam9 protein, mouse
  • Cell Adhesion Molecules
  • Platelet-Derived Growth Factor
  • Receptor, Platelet-Derived Growth Factor alpha