Responders vs. non-responders to mesenchymal stromal cells in knee osteoarthritis: Mechanistic correlates of donor cell and patient features.

Mesenchymal stromal cell (MSC) injection has afforded heterogeneous outcomes in knee osteoarthritis (KOA). Herein, a framework that dually correlates KOA patient responsiveness with baseline autologous bone marrow-derived MSC(M) donor batch attributes and baseline clinical and biomarker features is provided. Using clinical trial data (NCT02351011), we demonstrated that MSC(M) with increased immunomodulatory potency are more efficacious. Multivariable MSC(M) genes correlated strongly with responder status and 12- and 24-month improvements in Knee Injury and Osteoarthritis Outcome Scores. Responder MSC(M) donor batches had unique microRNA expression and ability to polarize CD14+ monocytes in vitro. KOA responders had lower baseline physical activity and trended toward more severe baseline KOA. Baseline local but not systemic biomarkers showed trending correlations with patient responsiveness. 42% of KOA patients were responders at 24 months, emphasizing durability of single MSC(M) injections. Together, our analytical methodology defines critical quality attributes of potent MSC(M) donor batches and identifies putative KOA patient theratypes to MSC treatments.