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

神经源性感染释放的周围神经干细胞的异位骨

• 批准号: 8383974
• 负责人: Alan ROBERT Davis
• 金额: $ 21.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383974
• 关键词: Adipocytes; Amputation; Aortic Diseases; Area; BMP2 gene; Blood Vessels; Bone Morphogenetic Proteins; Bone Tissue; Bone plates; Burn injury; Cartilage; Cells; Characteristics; Chickens; Clinical; Coin; Coronary; Cromoglicic Acid; Data; Development; Diagnostic; Disease; Embryo; Environment; Epiphysial cartilage; Foundations; Fracture; Hereditary Disease; Heterotopic Ossification; Homeostasis; Immigration; Immunofluorescence Microscopy; In Vitro; Inflammation; Inflammation Mediators; Injury; Knowledge; Laboratories; Light; Link; Maintenance; Medicine; Modeling; Molecular; Mus; Nature; Nerve; Neural Crest; Neuraxis; Neurofibromatoses; Neurologic; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteoporosis; Patients; Peripheral Nerves; Phenotype; Play; Population; Process; Proteins; Regulation; Reporter; Research; Resources; Schwann Cells; Series; Signal Transduction; Site; Skeletal bone; Skeleton; Source; Stem Cell Factor; Stem cells; Structure; Substance P; System; Tamoxifen; Testing; Time; Tissue Engineering; Tissues; Trauma; Traumatic Brain Injury; Work; afferent nerve; bone; bone morphogenetic protein 7; calcification; design; early onset; high risk; hip replacement arthroplasty; in vivo; insight; mast cell; novel; osteogenic; osteogenic protein; preference; progenitor; progressive myositis ossificans; relating to nervous system; repaired; response; rib bone structure; skeletal; soft tissue; spine bone structure; stem; transcriptional coactivator p75; tumor

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.

描述（由申请人提供）：非骨骼部位的异位骨化 (HO) 或骨形成非常罕见，但在中枢神经系统 (CNS) 损伤或截肢/髋关节置换手术（骨骼被移除或更换）的情况下可能会发生。然而，我们自己的数据表明，周围神经也可能参与这一过程。我们最近表明，神经源性炎症介质 P 物质和 CGRP 的释放会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。我们观察了成骨蛋白osterix、棕色脂肪细胞蛋白UCP1以及原始干细胞因子Klf4和nanog的表达。这些数据共同使我们推测周围神经拥有祖细胞/干细胞，这些细胞响应 BMP2 的作用而扩展，以促进新形成的异位骨。然而，这些干/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，要么是去分化的雪旺细胞，它们经历了成骨作用。我们设计了一系列目标来分离和表征这些细胞，并证明它们直接或间接对异位骨化的功能贡献。 公共健康相关性：我们的首要假设是异位骨是由周围神经中的神经祖细胞/干细胞形成的，这些神经祖细胞/干细胞是由 BMP2 直接引起的神经炎症释放的。这些发现将为该疾病的诊断和治疗方法的开发提供新的机制。