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

描述（由申请人提供）：异位骨化（HO）或非骨骼部位的骨形成非常罕见，但可能发生在中枢神经系统（CNS）损伤或截肢/髋关节置换手术中骨骼被移除或替换的情况下。然而，我们自己的数据表明，周围神经也可能在这一过程中起作用。我们最近发现，神经源性炎症介质物质P和CGRP的释放导致肥大细胞的募集和脱颗粒以及神经重塑。这种重塑涉及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、褐色脂肪蛋白UCP1、原始干细胞因子Klf4、nanog的表达。这些数据共同使我们假设周围神经具有祖细胞/干细胞，这些祖细胞/干细胞在BMP2的作用下扩增，有助于新形成的异位骨。然而，这些干细胞/祖细胞的确切性质和起源尚不清楚。我们自己的数据表明p75阳性细胞要么是祖细胞，要么可能是去分化的雪旺细胞，经历成骨。我们设计了一系列的目标来分离和表征这些细胞，并证明它们的功能贡献，直接或间接地对异位骨化。

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.