Heterotopic bone from stem cells in peripheral nerves released by neurogenic infl

描述(申请人提供)：异位骨化(HO)或非骨骼部位的骨形成非常罕见，但可发生在中枢神经系统(CNS)受损或截肢/髋关节置换手术中，其中骨骼被移除或替换。然而，我们自己的数据表明，周围神经可能也参与了这一过程。我们最近发现神经源性炎症介质P物质和CGRP的释放导致肥大细胞的募集和脱颗粒，并导致神经重塑。这种重建包括神经相关细胞的扩张，以及它们在软组织中的释放和迁移。观察成骨蛋白Osterix、棕色脂肪细胞蛋白UCP1、原始干细胞因子KLF4、Nanog的表达。这些数据共同引导我们假设，周围神经拥有祖细胞/干细胞，这些干细胞在BMP2的响应下扩张，为新形成的异位骨做出贡献。然而，这些干/祖细胞的确切性质和来源尚不清楚。我们自己的数据表明，p75阳性细胞可能是经历成骨的祖细胞，也可能是去分化的雪旺细胞。我们已经设计了一系列的目的来分离和表征这些细胞，并证明它们对异位骨化的直接或间接的功能贡献。 公共卫生相关性：我们的主要假设是异位骨是由周围神经中的神经前体/干细胞形成的，这些细胞是由BMP2直接引起的神经性炎症释放出来的。这些发现将为该病的诊断学和治疗学的发展提供新的机制。

DESCRIPTION (provided by applicant): Heterotopic ossification (HO) or bone formation in non-skeletal sites is very rare but can occur in cases of central nervous system (CNS) inhury or amputation/hip replacement surgery where skeletal bone is removed or replaced. However, our own data suggests that peripheral nerves may also be contributing to this process. We recently showed that release of neurogenic inflammatory mediator's substance P and CGRP, led to recruitment and degranulation of mast cells and nerve remodeling. This remodeling involved expansion of nerve associated cells, as well as their release and migration in the soft tissues. We observed the expression of osteogenic protein osterix, brown adipocyte protein UCP1, and the primitive stem cell factors, Klf4 and nanog. The data collectively have led us to hypothesize that peripheral nerves possess progenitors/stem cells, which expand in response to BMP2 for contribution to the newly forming heterotopic bone. However, the exact nature and origin of these stem/progenitors is unclear. Our own data suggests that p75 positive cells are either progenitor cells, or perhaps de-differentiating Schwann cells, that undergo osteogenesis. We have devised a series of aims to isolate and characterize these cells and demonstrate their functional contribution, either directly or indirectly to heterotopic ossification. PUBLIC HEALTH RELEVANCE: Our overarching hypothesis is that heterotopic bone is formed from nerve progenitor/stem cells that reside in peripheral nerves, which are released by neurologic inflammation caused directly by BMP2. These findings would provide a novel mechanism for the development of both diagnostics and therapuetics for the treatment of this disease.