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

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 demonstrated 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 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.