Background: Musculoskeletal tissue degeneration impairs the life quality and function of many people. Meniscus degeneration is a major origin of knee osteoarthritis and a common threat to athletic ability, but its cellular mechanism remains elusive. Methods: We built a cell atlas of healthy/degenerated human meniscus using scRNA-seq to investigate meniscal microenvironment homeostasis and its changes in the degeneration process and verified findings with immunofluorescent imaging. Results: We identified and localized cell types in inner and outer meniscus, found new chondrocyte subtypes contributing to degeneration, and revealed how cellular compositions, functions, and interactions participated in degeneration. We found that ECM disassembly, angiogenesis, and inflammation form a positive feedback loop driving the degeneration. Comparison of cellular interactions between different degenerative states identified each cell type's functions in the loop. Conclusions: The study revealed changes in the meniscal microenvironment during degeneration and discovered new cell subtypes as potential therapeutic targets. The observed mechanism could also be a general model for other joint degenerations. Funding: The National Natural Science Foundation of China (81972123, 82172508, 62050178, 61721003) and the National Key Research and Development Program of China (2021YFF1200901).

The authors have declared no competing interest.

This study was funded by the National Natural Science Foundation of China (81972123, 82172508, 62050178, 61721003) and the National Key Research and Development Program of China (2021YFF1200901).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Not Applicable

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The experiments were approved by our University Ethics Committee (Ethics Committee on Biomedical Research, West China Hospital of Sichuan University No. 2020-(921)).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Not Applicable

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Not Applicable

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Not Applicable

Data are available in a public, open access repository. The single-cell RNA-seq data, cluster annotations are available at GSA for human (https://ngdc.cncb.ac.cn/gsa-human/) with the accession number PRJCA008120

https://ngdc.cncb.ac.cn/gsa-human/