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Identification of Tendon Stem Cells May Enhance Tendon Regeneration Strategies

Review of  “A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis” from Nature Cell Biology by Stuart P. Atkinson

Fibrotic scarring during the recovery of injured tendons disrupts the tendon matrix and leads to a weakened tendon state at the end of the healing process; however, we know little regarding the underlying cellular and molecular mechanisms controlling these processes [1]. While in vitro studies have described a tentative tendon stem cell population that may play a key role [2, 3], the identifications of these cells in vivo remains a challenging task [2-4]. To fill this knowledge gap and provide new approaches to tendon regeneration, researchers led by Chen-Ming Fan (Carnegie Institution for Science, Baltimore, MD, USA) recently evaluated a regeneration-competent patellar tendon punch-injury [5-7] in an engineered mouse model to identify tendon stem cells and determine the cellular and molecular mechanisms behind tendon regeneration and fibrosis [8]. Fascinatingly, these new findings now reveal an inextricable link between regeneration and fibrosis via the shared usage of platelet-derived growth factor (PDGF) signaling.

Via single-cell RNA sequencing of cells derived from adult (~3 months old) mouse patellar tendons, Harvey et al. identified a cell population expressing tubulin polymerization promoting protein family member 3 (Tpp3) as putative tendon stem cells in vivo, with subsequent inducible lineage tracing, three-dimensional imaging, and marker/histological analyses confirming that said cells could generate new tenocytes and self-renew after injury in neonatal mice. 

However, a fraction of the Tpp3-expressing tendon stem cells also expressed platelet-derived growth factor receptor alpha (Pdgfra), a factor known to identify fibro-adipogenic progenitors found in skeletal muscle, and the team soon discovered that PDGF-AA treatment of Tpp3/Pdgfr-expressing cells induced new tenocyte production and that the loss of Pdgfra blocked tendon regeneration. 

While this data provide evidence supporting Tppp3/Pdgfra-expressing cells as bona fide in vivo tendon stem cells, these analyses also revealed the presence of a Tpp3-negative Pdgfra-expressing fibro-adipogenic progenitors that coexist within the tendon stem cell niche that give rise to fibrotic cells, thereby suggesting these cells as the origin of fibrotic scars in healing tendons

The authors hope that their findings regarding the identification of a putative tendon stem cell population will lead to the advancement of the understanding of tendon development and the construction of advanced therapeutic strategies for injured tendons. For more on the characterization of tendon stem cells and the application of these findings in optimized tendon regeneration strategies, stay tuned to the Stem Cells Portal!

References

  1. Voleti PB, Buckley MR, and Soslowsky LJ, Tendon Healing: Repair and Regeneration. Annual Review of Biomedical Engineering 2012;14:47-71.
  2. Harvey T and Fan C-M, Origin of tendon stem cells in situ. Frontiers in Biology 2018;13:263-276.
  3. Bi Y, Ehirchiou D, Kilts TM, et al., Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nature Medicine 2007;13:1219-1227.
  4. Dyment NA and Galloway JL, Regenerative Biology of Tendon: Mechanisms for Renewal and Repair. Current Molecular Biology Reports 2015;1:124-131.
  5. Lin TW, Cardenas L, Glaser DL, et al., Tendon healing in interleukin-4 and interleukin-6 knockout mice. Journal of Biomechanics 2006;39:61-69.
  6. Ansorge HL, Adams S, Birk DE, et al., Mechanical, Compositional, and Structural Properties of the Post-natal Mouse Achilles Tendon. Annals of Biomedical Engineering 2011;39:1904-1913.
  7. Beason DP, Kuntz AF, Hsu JE, et al., Development and evaluation of multiple tendon injury models in the mouse. Journal of Biomechanics 2012;45:1550-1553.
  8. Harvey T, Flamenco S, and Fan C-M, A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis. Nature Cell Biology 2019;21:1490-1503.