Identification of the tendon/ligament stem cell in mice and humans [Amplicon]

ABSTRACT: Lumbar spinal stenosis (LSS), a narrowing of the spinal canal resulting in pain and loss of mobility, is one of the most common forms of degenerative disease. LSS is commonly caused by hypertrophy of the ligamentum flavum leading to compression of the spinal canal. LSS lacks medical therapies in part due to identity of the tendon/ligament stem cell (TLSC) generating tenocytes and its role in LF hypertrophy remaining unknown, preventing the rational development of therapies targeting the specific cell types driving LSS-associated ligament hypertrophy. Here, we identify for the first time the TLSC as a Lin-Thy1.2-Sca1-CD73+CD140a- population displaying formal evidence of stemness present in multiple tendon/ligament sites. This TLSC resides in a peri-entheseal niche and is capable of serial self-renewal and generation of tendon organoids after transplantation. The lineage of this stem cell was traced in vivo using Cas9-mediated somatic variants, identifying that this TLSC generates mature tenocytes in vivo. A mouse model of LSS was developed, finding that LSS induction led to cell intrinsic reprogramming of this TLSC to increase their output of mature tenocytes, and this pathologic expansion was dependent on calcium channel signaling. This same TLSC was identified in humans and displays conserved stemness in xenograft models. Both the numbers of this human TLSC and its tenocyte production capacity in xenograft organoid assays were enhanced in the setting of human LSS, identifying cell intrinsic contribution of this human TLSC to LSS pathology. Taken together, this work identifies the TLSC in humans and mice and establishes dysregulated differentiation of this cell as a mechanism contributing to LSS.

ORGANISM(S): Mus musculus

PROVIDER: GSE289693 | GEO | 2026/08/31

REPOSITORIES: GEO