Perruccio, A. V. | bioRxiv Science

bioRxiv2025

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

Mesenchymal stromal cell (MSC) injection has afforded heterogenous outcomes in knee osteoarthritis (KOA). Herein, a framework that dually correlates KOA patient responsiveness to baseline autologous bone marrow-derived MSC(M) donor batch attributes and baseline clinical and biomarker features is provided. Using clinical trial data, we demonstrated that MSC(M) with increased immunomodulatory potency are more efficacious. Multivariable MSC(M) genes correlated strongly with responder status and to 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 to 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/665028v4_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18bbb07org.highwire.dtl.DTLVardef@a406e8org.highwire.dtl.DTLVardef@c18c8corg.highwire.dtl.DTLVardef@f2731c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Cell and Transcriptomic Diversity of Infrapatellar Fat Pad during Knee Osteoarthritis

ObjectivesIn this study, we employ a multi-omic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex, and obesity status. MethodsSingle-nucleus RNA sequencing of 82,924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analysis were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex, and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status. ResultsWe identified multiple subclusters of fibroblasts, macrophages, adipocytes, and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles, and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs, and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of naive, profibrotic- and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFP. ConclusionsOverall, by employing a multi-omic approach, this study provides the first comprehensive map of cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as a key cell type contributing to transcriptomic and metabolic differences related to KOA disease, sex, or obesity.

cell biology↗