Ivanovska Ana, Mancuso Patrizio, Burke Amy, Hennessy Conor, Raman Swarna, Dooley Claire, McLoughlin Steven, Shaw Georgina, Mukeria Eka, Reilly Jamie, O'Brien Aisling, Ritter Thomas, Ryan Aideen E, Kamath Raj, Levesque Marc C, Riet Deborah Van, English Karen, Hawthorne Ian, Johnstone Brian, Morris Derek W, Barry Frank, Murphy J Mary
School of Medicine, Regenerative Medicine Institute (REMEDI), University of Galway, Galway, Ireland.
Centre for Research in Medical Devices (CÚRAM), University of Galway, Galway, Ireland.
Front Cell Dev Biol. 2025 Mar 26;13:1521437. doi: 10.3389/fcell.2025.1521437. eCollection 2025.
Osteoarthritis (OA) is a widespread and debilitating joint disease characterized by synovial inflammation, cartilage degeneration, and chronic joint pain. Mesenchymal stromal cells (MSCs) have shown therapeutic efficacy for many diseases with a strong inflammatory profile, including OA. However, the disease-specific mechanisms of action underpinning the effects of post-local MSC delivery remain unaddressed. In this study, we aimed to characterize the disease-induced profile of MSCs following exposure to the osteoarthritis environment.
Murine syngeneic GFP + bone marrow-derived MSCs (BM-MSCs) were delivered intra-articular injection in a mouse collagenase-induced osteoarthritis (CIOA) model (n = 8). BM-MSCs were retrieved by cell sorting on days 14 and 56, following whole mouse knee digestions. The retrieved cells were expanded in culture and characterized based on their phenotype, immunomodulatory effects on lymphocytes and macrophages, and transcriptomic profile.
Retrieved BM-MSCs (1.33%) had minimal effects on lymphocyte proliferation but induced macrophage anti-inflammatory activity. Surviving retrieved BM-MSCs activated various pathways, with their secretome impacting immune system regulation and extracellular matrix organization, correlating with the disease stage. Data comparing the transcriptomic profiles of retrieved and licensed BM-MSCs suggested a chondroprogenitor profile and identified BRINP3 as a novel factor in MSC function for potential OA modulation.
The beneficial effects of BM-MSCs in OA post-local delivery could be attributed to a specific subset of cells able to resist the micro-inflammatory milieu and contribute to cartilage healing and suppression of associated synovial inflammation. Furthermore, data suggest a paradigm of environmentally guided plasticity associated with MSCs upon local delivery in both early and late OA.
骨关节炎（OA）是一种广泛存在且使人衰弱的关节疾病，其特征为滑膜炎症、软骨退变和慢性关节疼痛。间充质基质细胞（MSC）已显示出对包括OA在内的许多具有强烈炎症特征的疾病具有治疗效果。然而，局部注射MSC后发挥作用的疾病特异性机制仍未得到阐明。在本研究中，我们旨在描述暴露于骨关节炎环境后MSC的疾病诱导特征。
在小鼠胶原酶诱导的骨关节炎（CIOA）模型（n = 8）中，通过关节内注射递送小鼠同基因绿色荧光蛋白阳性骨髓来源的MSC（BM-MSC）。在第14天和第56天，在对整个小鼠膝关节进行消化后，通过细胞分选回收BM-MSC。回收的细胞在培养中扩增，并根据其表型、对淋巴细胞和巨噬细胞的免疫调节作用以及转录组谱进行表征。
回收的BM-MSC（1.33%）对淋巴细胞增殖的影响最小，但诱导巨噬细胞产生抗炎活性。存活的回收BM-MSC激活了各种途径，其分泌产物影响免疫系统调节和细胞外基质组织，这与疾病阶段相关。比较回收的和已鉴定的BM-MSC转录组谱的数据表明其具有软骨祖细胞特征，并确定BRINP3是MSC功能中潜在调节OA的新因子。
局部递送后BM-MSC在OA中的有益作用可能归因于能够抵抗微炎症环境并有助于软骨愈合和抑制相关滑膜炎症的特定细胞亚群。此外，数据表明在早期和晚期OA局部递送时，MSC存在与环境引导可塑性相关的模式。
