Neural crest‐derived cells migrate from nerve to participate in Achilles tendon remodeling

Abstract

During tendon injury, nerve ingrowth is one of the earliest events of tendon repair and remodeling. Since peripheral neurons and associated cells are mostly derived from neural crest (NC) cells, we sought to investigate the role of NC-derived cells in tendon regeneration. Thus, we used Sox10-Cre/ROSA26-Flox-Red Fluorescent Protein (RFP) transgenic mice to trace these cells during tendon regeneration. After 4 weeks of Achilles tendon rupture, the injured tendon tissues were harvested for immunohistological analyses, cell isolation, and phenotype identification. In addition, the tenocytes were co-cultured with RFP labeled cells to examine cellular functions. Following the injury, a significant number of RFP-labeled cells penetrated into the wound site and reached a peak (∼30% of cells) after 2 weeks, and then stabilized at a level of approximately 20%. Interestingly, 36.9% RFP labeled cells in the injured area expressed Tuj1, suggesting that most of the cells are peripheral neurons. Some RFP /Tuj1 cells were also found adjacent to newly formed blood vessels in the tendon. Importantly, the existing neuropeptide Y (NPY) and neuropeptide Y receptor (NPYr) in the invading nerve and blood vessels were directly correlated. In addition, there were also RFP cells (∼30%) negative for neuronal markers but positive for fibroblast markers, that is, FAP (34.7%) and Vimentin (Vmt) (27.2%), and approximately 10% positive for Sox10. Indeed, many RFP cells isolated from the ruptured Achilles tendon showed long spindle shapes and expressed fibroblast phenotypic markers FSP1 and FAP. Part of the Sox10 RFP-labeled cells exhibited osteogenic and adipogenic differentiation ability. It is concluded that after Achilles tendon injury, nerves sprout into the wound site. The NC-derived Vmt /FAP mesenchymal cells and peripheral nerves participate in tendon regeneration.

Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function

“… 19 Interestingly, while Sox10 is commonly studied in neural crest development, it has also been implicated in tendon progenitor migration and development, potentially supporting a more regenerative mechanism underlying C0 synthetic differentiation. 20 , 21 …”

Lysyl oxidase suppresses the inflammatory response in anterior cruciate ligament fibroblasts and promotes tissue regeneration by targeting myotrophin via the nuclear factor‐kappa B pathway

“…Immunostaining was carried out as previously described (Xu et al, 2018). In brief, the sections were blocked with 1% bovine serum albumin at 37°C for 30 min and then incubated overnight at 4°C with primary antibodies against TNF‐α and IL‐1β (Bioss, Beijing, China).…”

Psoralen Protects Chondrocytes, Exhibits Anti-Inflammatory Effects on Synoviocytes, and Attenuates Monosodium Iodoacetate-Induced Osteoarthritis

“…The cell immuno-staining was performed according to the previous protocols 17. The primary antibodies: Collagen II (Santa Cruz, sc-7763), MMP-13 (Santa Cruz, sc-30073) for chondrocytes, and IL-1β (Bioss, bs-20449R), MMP-13 (Santa Cruz, sc-30073) for synoviocytes were used.…”