(T1081) Safety and Efficacy of Mesenchymal Stromal Cells Mitochondria Transplantation as a Cell-Free Therapy for Osteoarthritis

Abstract: In osteoarthritis (OA), inflammatory responses from synovial fibroblasts and macrophages, along with mitochondrial dysfunction in chondrocytes, lead to oxidative stress and disrupt extracellular matrix homeostasis, accelerating cartilage degradation. Recent studies suggest that mesenchymal stromal cells (MSCs) can transfer functional mitochondria to damaged cells in response to stress, which may contribute to their therapeutic effects. Based on this, we hypothesize that direct mitochondrial transplantation could serve as a novel, cell-free therapy for OA, restoring both cellular and mitochondrial homeostasis to mitigate cartilage degeneration.
In this study, mitochondria were isolated from Umbilical Cord MSCs (Mito-MSC) and characterized for their morphology, functionality, and ability to be internalized by articular cells. Transcriptional changes following mitochondrial uptake were assessed in chondrocytes via Affymetrix analysis. Additionally, the therapeutic efficacy, biodistribution, and immunogenicity of Mito-MSC were evaluated in vivo using a collagenase-induced OA (CIOA) mouse model via intra-articular injection.
Our results show that Mito-MSC maintain functional integrity and are efficiently internalized by chondrocytes, synovial macrophages, and fibroblasts. Transcriptomic analysis revealed the upregulation of stress-related genes, including those involved in DNA repair and antiviral responses. Finally, Mito-MSC transplantation led to significant reductions in joint mineralization and improvements in OA-related histological signs, with the lower dose providing the most effective therapeutic response. Moreover, Mito-MSC persisted in the knee joint for up to 24 hours post-injection, without inducing an inflammatory immune response in CIOA mice.
Collectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and retained in the joint without generating an inflammatory response. This supports the potential of MSC-derived mitochondria as a novel, cell-free therapy for OA, capable of restoring mitochondrial function and reducing cartilage degradation. This approach could offer an effective strategy for mitigating OA progression, with broader implications for treating diseases with mitochondrial dysfunction.

Funding Source: ANID-Fondecyt Regular PLC N°1211353; Fondecyt Iniciación AMV N°11220549; Fondecyt Regular N° 1201420 FF; IMPACT, #FB210024, FONDEF ID21I10194 PLC, PRI-MitoMir project and the project METAB-OA (ANR-20-CE18-0014)

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