Comparative Orthopedics Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
PLoS One. 2019 Mar 12;14(3):e0212664. doi: 10.1371/journal.pone.0212664. eCollection 2019.
Osteoarthritis (OA) is a progressive disease associated with cartilage injury and its inherently limited repair capability. Synovium-based cellular constructs (sConstructs) are proposed as possible treatments. Equine sConstructs were produced from decellularized synovium-based extracellular matrix scaffolds (sECM) seeded with synovium-derived mesenchymal stem cells (sMSC), and engineered to express green fluorescent protein (GFP), or bone morphogenetic protein-2 (BMP-2). Survival, distribution, and chondrogenic potential of the sConstructs in vitro and in vivo were assessed. sConstructs in co-culture with chondrocytes increased chondrocyte proliferation, viability, and Col II production, greatest in BMP-2-sConstructs. Chondrocyte presence increased the production of hyaluronic acid (HA), proteoglycan (PG), and BMP-2 by the sConstructs in a positive feedback loop. sECM alone, or GFP- or BMP-2-sConstructs were implanted in synovium adjacent to clinically created full-thickness rat-knee cartilage lesions. At 5 weeks, the lesion area and implants were resected. Gross anatomy, adjacent articulate cartilage growth and subchondral bone repair were scored; and peripheral, central and cartilage lesion measurements taken. For all scores and measurements, sConstruct implants were significantly greater than controls, greatest with the BMP-2-sConstructs. Immunohistochemistry demonstrated migration of endogenous cells into the sECM, with greater cellularity in the constructs with intense positive GFP staining confirming engraftment of implanted sMSC and continued gene expression. In summary, exposing cartilage to sConstructs was chondrogenic in vitro and in vivo, and resulted in substantially increased growth in vivo. This effect was mediated, in part, by soluble ECM and cell factors and upregulation of anabolic growth proteins, such as BMP-2. This work is "proof of concept" that sConstructs surgically implanted adjacent to cartilage damage can significantly improve cartilage and subchondral bone repair, and potentially prevent the progression of OA.
骨关节炎（OA）是一种与软骨损伤及其固有有限修复能力相关的进行性疾病。基于滑膜的细胞构建体（sConstructs）被提议作为可能的治疗方法。从去细胞化的基于滑膜的细胞外基质支架（sECM）中产生了马 sConstructs，该支架中播种了滑膜衍生的间充质干细胞（sMSC），并经过工程设计以表达绿色荧光蛋白（GFP）或骨形态发生蛋白-2（BMP-2）。在体外和体内评估了 sConstructs 的存活，分布和软骨生成潜力。 sConstructs 与软骨细胞共培养可增加软骨细胞的增殖，活力和 Col II 的产生，BMP-2-sConstructs 的作用最大。软骨细胞的存在增加了滑膜基质 sConstructs 中透明质酸（HA），蛋白聚糖（PG）和 BMP-2 的产生，形成正反馈回路。单独的 sECM 或 GFP 或 BMP-2-sConstructs 被植入与临床创建的全层大鼠膝关节软骨病变相邻的滑膜中。在 5 周时，切除了病变区域和植入物。对大体解剖，相邻关节软骨生长和软骨下骨修复进行评分；并进行了外围，中央和软骨病变的测量。对于所有评分和测量，sConstruct 植入物均明显大于对照物，BMP-2-sConstructs 的效果最大。免疫组织化学显示内源性细胞向 sECM 迁移，具有强烈阳性 GFP 染色的构建物中的细胞增多，证实了植入 sMSC 的移植和持续的基因表达。总的来说，sConstructs 在体外和体内使软骨具有软骨生成能力，并导致体内生长明显增加。这种作用部分是由可溶的细胞外基质和细胞因子以及合成代谢生长蛋白（例如 BMP-2）的上调介导的。这项工作是“概念验证”，表明外科植入到软骨损伤附近的 sConstructs 可以显著改善软骨和软骨下骨的修复，并有可能预防 OA 的进展。
