0472: Detrimental Effects of Umbilical Cord Blood-derived Mesenchymal Stem Cells Intra-articular Injections on Pannus Invasiveness

Background/Purpose: Studies have shown that mesenchymal stem cell (MSC) infusion ameliorates arthritis in animal models. However, the first-pass effect in the lung has directed attention to other routes of administration for MSCs. We aimed to investigate the impact of intra-articular MSC injections in mice with arthritis and its underlying mechanism.

Methods: An indirect co-culture of umbilical cord blood-derived (UCB-) MSC and fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) was conducted to study the altered traits of proliferation, migration, and invasion of RA-FLS. We utilized proteomics to analyze the outcomes of the co-culture in both cell types. CIA was induced in DBA/1 mice, followed by a single intra-articular injection in the ankle on day 28. The mice were euthanized on day 42 for histological analyses. Recombinant transforming growth factor-beta-1-induced transcript 1 (TGFB1I1) and anti-TGFB1I1 were employed in subsequent experiments to investigate the mechanisms of the transformed milieu in the synovium.

Results: The proliferation, mobility, and invasiveness of RA-FLS were enhanced when co-cultured with UCB-MSC (Figure 1). While intravenous UCB-MSC reduced the severity of arthritis in mice, intra-articular injection of UCB-MSC resulted in significant arthritis in the injected ankle compared to the contralateral side (Figure). The proteomic analysis revealed a substantial expression of TGB1I1 in RA-FLS co-cultured with UCB-MSC and even higher levels in UCB-MSCs. Indeed, TGB1I1 was highly expressed in UCB-MSC-injected ankles of CIA mice. Furthermore, TGB1I1 not only induced cytoskeletal rearrangement in RA-FLS but also promoted the gene expression of IL-1beta, IL-8, MMP-3, and MMP-13, thereby contributing to both joint inflammation and damage. TGB1I1 knockdown resulted in significantly reduced mobility of FLS co-cultured with UCB-MSC.

Conclusion: Intra-articular injection of UCB-MSCs into inflamed joints inexplicably induces detrimental effects that may expedite joint damage and perpetuate systemic inflammation. MSC therapy may act as a double-edged sword depending on its route of administration in patients with rheumatoid arthritis.