Lingling Hu, Jun Sun, Kyle W Morse, Seoyeon Bok, Yimin Zheng, Un In Chan, Han Choi, Eugenie Macfarlane, Alisha R Yallowitz, Michelle Cung, Ting Cong, Peyton Lee Carpen, Federico La Manna, Shawon Debnath, Haiyin Li, Tim Xu, Lipeng Wang, Yangkang Zheng, Takeshi Hirose, Ryan N Serio, Billy Lu, Ryan J Chaffee, Armin Scheben, Ling J Zheng, Jason McCormick, Daniel Shinn, Anthony Pajak, Kasra Araghi, Eric Zhao, Anna Yemelyanova, Chike Cao, Geoffrey S Pitt, Scott A Rodeo, Dawid G Nowak, Sravisht Iyer, Matthew B Greenblatt
Ligamentum flavum (LF) hypertrophy resulting in spinal cord compression is a key cause of lumbar spinal stenosis (LSS). There are no medical therapies for LSS, in part because the identity of the tendon/ligament stem cell (TLSC) mediating LSS remains unclear. Here, we identify the TLSC present in all tendons and ligaments in humans and mice as Lin-Thy1.2-Sca-1-CD73+CD140α- cells that display self-renewal and give rise to all other tenocyte lineage cells. This TLSC also sits at the apex of their differentiation hierarchy, as determined by in vivo somatic-variant-based lineage tracing. LSS induction led to druggable, calcium signaling-dependent, cell-intrinsic reprogramming of the TLSCs to increase their tenocyte output. Overall, this work identifies the TLSC and establishes dysregulated differentiation of this cell as a mechanism contributing to LSS. This TLSC is anticipated to play a central role in other disorders of tendons and ligaments.