Synovial Stem Cell Biology

关节软骨不表现出内源性修复，部分原因是组织中缺乏干细胞/祖细胞，而邻近的滑膜上充满了能够在体外和体内分化成软骨的间充质干细胞（MSCs）。我们已经证明关节内的间充质干细胞对微环境的变化非常敏感，并且滑液的变化可以调节细胞的成软骨潜能。此外，我们还发现，在特定的培养条件下，来自受伤/关节炎/炎症关节的MSCs不能完全分化为软骨细胞，而来自正常关节的MSCs则具有完全的功能。我们已经深入研究了这一效应，并发现证据表明CCL2/MCP-1是由滑膜巨噬细胞分泌的，现在有初步证据表明这些巨噬细胞可能作为滑膜干细胞生态位。假设干细胞生态位提供了一个能够指导干细胞活动的微环境。该生态位被认为对随着年龄增长而下降的干细胞活性特别重要，在这种情况下，组织稳态的丧失会随着常驻干细胞群在维持和修复方面的日益不足而进展。然而，体外证据表明，当这些干细胞与生态位分离时，它们仍然具有功能，这强烈表明干细胞生态位可能在衰老和疾病过程中失效。

Articular cartilage does not exhibit endogenous repair, in part because of a lack of stem/progenitor cells in the tissue, whereas the adjacent synovial membrane is abundant with mesenchymal stem cells (MSCs) capable of differentiating into cartilage both in vitro and in vivo. We have demonstrated that the MSCs within the joint are very sensitive to changes in the micro-environment and that changes in the synovial fluid can regulate the chondrogenic potential of the cells. In addition, we have also found that MSCs from injured/arthritic/inflamed joints are incapable of fully differentiating into chondrocytes under specific culturing conditions whereas MSCs from normal joints are fully functional. We have explored this effect in great depth and found evidence that suggests CCL2/MCP-1 is being secreted from synovial macrophages and now have preliminary evidence that these macrophage cells may be acting as a synovial stem cell niche. The stem cell niche is hypothesized to provide a micro-environment that is capable of directing stem cell activity. The niche is thought to be particularly important in regards to the decline of stem cell activity with aging, in which a loss of tissue homeostasis progresses as the resident stem cell populations prove to be increasingly inadequate in terms of maintenance and repair. However, in vitro evidence demonstrates that these stem cells when separated from the niche are still functional, strongly suggesting that the stem cell niche maybe failing during aging and disease processes. The objective of my program is to elucidate the regulatory feedback mechanisms that exist between macrophages and synovial MSCs within human and mouse knee joint synovium and understand how these pathways regulate stem cell fate in vitro, ex vivo and in vivo. This will be achieved by undertaking the following aims: Aim 1 (In vitro): Determine which signaling molecules produced by macrophages regulate synovial MSCs, and assay if this ability is augmented through modification of the macrophage activation state. Aim 2 (Ex vivo): Assay for changes in synovial MSC function when macrophages are removed from the synovium using a targeted liposomal based approach. Aim 3 (In vivo): Quantify changes in synovial MSC mediated tissue repair when macrophage number or activation state is experimentally modified within the synovial stem cell niche. This program of research will result in significant advances in the field of cell biology and bioengineering by contributing to i) the understanding of the role of macrophages in the synovial stem cell niche including how these cell regulate stem cell potential; and ii) a framework for the potential development of new and improved tissue engineering / regenerative medicine approaches to restoring and/or maintaining normal joint function with aging or after injury.