The senescence-linked factor Chi3L1 contributes to mesenchymal stromal cells dysfunction promoting joint aging and osteoarthritis progression

Abstract Ageing progressively disrupts joint homeostasis and increases susceptibility to osteoarthritis (OA), yet why repair fails in the altered joint remains poorly understood. Cellular senescence accumulates with age and is prominent in osteoarthritic joints, contributing to a persistent catabolic, inflammatory and tissue-remodelling microenvironment through the senescence-associated secretory phenotype (SASP). Such signals can alter the function of endogenous reparative cells including mesenchymal stromal cells (MSCs), which are important to tissue repair and immunomodulation. Nonetheless, little is known on which senescence associated stromal factors within this altered niche could compromise MSCs competence. In this study, we are interested by chitinase-3-like 1 (CHI3L1), a SASP glycoprotein whose levels are elevated in both ageing and OA. We revealed that CHI3L1 accumulates in OA joints in correlation with senescence and the disease features, where it in vitro chronic exposure converts MSC toward a dysfunctional age-like state characterized by impaired potencies, disrupted tri-lineage commitment, reduced mobility, altered metabolomic profiling, loss of immunomodulatory activity together with an acquisition of a pro-inflammatory secretome. Consequently, CHI3L1 preconditioning abolishes the homeostatic function of healthy MSCs in an inflammatory OA model. Conversely, in spontaneous age-related OA model, MSC transplantation combined to CHI3L1 transient neutralization restores joint dynamics by enhancing cartilage repair, reducing synovial inflammation, preventing bone remodeling, improving maximal speed locomotor and shifting selective circulated factors related to stromal, skeletal, and hematopoietic homeostasis toward a more youthful pattern. Collectively, our findings establish CHI3L1 as a novel senescence-associated contributor in the decline of MSC fitness and regenerative niche competence during joint ageing. Furthermore, it provides a rationale for combining microenvironment-targeted interventions with stem cell therapy to maximize their potentials for tissue regeneration in age-related diseases.