Impact of peripheral nerves on mesenchymal cell fate in extremity trauma

周围神经对四肢创伤间充质细胞命运的影响

• 批准号: 10904264
• 负责人: AARON W JAMES
• 金额: $ 58.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10904264
• 关键词: AVIL gene; Agonist; Amputation; Analgesics; Animal Model; Animals; Area; Axon; Biological Availability; Blood Vessels; Cell Differentiation process; Cells; Clinical; Clinical Research; Communication; Couples; Data; Data Set; Defect; Dendrites; Denervation; Disease; Disease Progression; Distal; Elements; Event; Excision; Follow-Up Studies; Gelatin; Growth; Heterotopic Ossification; Human; Hydrogels; Lesion; Link; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Nerve; Nerve Growth Factors; Neurons; Operative Surgical Procedures; Oral; Osteogenesis; Pain; Pathologic; Pathway interactions; Patients; Pericytes; Peripheral; Peripheral Nerves; Phase; Phenotype; Phosphotransferases; Pilot Projects; Postoperative Pain; Prevention; Process; Recurrence; Regimen; Regulation; Regulatory Element; Role; Sensory; Series; Signal Transduction; Site; Skeleton; Smooth Muscle Myocytes; Source; Specificity; Stimulus; Surface; TGFB1 gene; Testing; Therapeutic Intervention; Tissue Differentiation; Tissues; Trauma; Tropomyosin; Vascular Smooth Muscle; afferent nerve; bone; bone fracture repair; brief intervention; comparative efficacy; experimental study; follow-up; in vivo; insight; limb injury; nerve supply; neurotransmission; neurotrophic factor; neutralizing antibody; neutralizing monoclonal antibodies; new therapeutic target; non-opioid analgesic; novel; osteoarthritis pain; osteochondral tissue; precursor cell; prevent; programs; receptor; repaired; response; small molecule; small molecule inhibitor; stem cells; targeted treatment; therapeutic target; wound healing

Project Summary Heterotopic ossification (HO) is characterized by the aberrant osteochondral differentiation of tissue resident mesenchymal progenitor cells. HO afflicts nearly 20% of extremity trauma, amputation and large surface area burn patients and is clinically preceded by pain. Currently, no treatments exist to prevent initiation, reverse disease progression, or limit pain through efficacious, non-opioid mechanisms. In the course of analyzing our validated trauma-induced HO model, we observed nerve ingrowth as an early response to trauma. Using a unique human traumatic HO dataset of early and late HO lesions, we have confirmed this early and maladaptive nerve ingrowth precedes HO. Additionally, we discovered that surgical denervation potently inhibits early stages of HO formation. In follow up studies, we uncovered the role of nerve growth factor (NGF) as the primary stimulus of this pre-HO nerve ingrowth and, unexpectedly, that perivascular cells (pericytes and vascular smooth muscle cells) appear to be the primary source of this neurotrophin. To elucidate the role of NGF induced nerve ingrowth on HO, we performed complementary studies which suggest that nerve ingrowth may activate mesenchymal progenitor cell TGFβ1 signaling to drive aberrant chondrogenic differentiation among local mesenchymal progenitor HO precursor cells. These observations have led to our central hypothesis that perivascular derived NGF stimulates TrkA-expressing sensory dendrite ingrowth into the HO site, which in turn releases TGFβ1 to stimulate mesenchymal progenitor cell osteochondral differentiation. As such, the following aims are proposed: Aim 1: Define the role of perivascular NGF in controlling sensory nerve ingrowth at sites of HO initiation and progression. Using established animal models, we hypothesize that tissue-specific deletion of Ngf in pericytes (Pdgfrb-CreERT2;Ngffl/fl) or vascular smooth muscle cells (vSMCs; Myh11-CreERT2;Ngffl/fl) will abrogate peripheral nerve ingrowth and HO formation at sites of trauma. Aim 2: Test the role of TGFβ1 signaling in sensory nerve-mesenchymal progenitor cell cross talk in HO. Using established animal models, we hypothesize that sensory nerves positively regulate mesenchymal progenitor cell osteochondral differentiation through a TGFβ1 dependent process. Aim 3: Define a potential role for anti-NGF neutralizing antibodies as a novel HO therapeutic intervention. We hypothesize that Fasinumab (an NGF neutralizing antibody) represents a dual analgesic and negative regulator of HO disease progression, which blunts pathologic nerve ingrowth.

项目摘要 异位骨化（HO）的特征是组织驻留的异常骨软骨分化 间充质祖细胞近20％ 烧伤患者，并在临床上疼痛，目前没有治疗以防止启动，反向 疾病进展，或限制疼痛有效的非阿片机制。 经过验证的创伤诱导的HO模型，我们使用a视为早期反应。 独特的人创伤性HO病变数据集 神经向内生长，此外，我们发现外科手术会有效地抑制早期的僵局 在后续研究中，我们发现了神经生长因子（NGF）的作用 在这种前神经内生长，并且出乎意料地 细胞似乎是这种神经营养素的主要来源。 在HO上，我们进行了COMP复杂研究，该研究表明神经发育可能会激活间充质 祖细胞TGFβ1信号传导以驱动局部间充质之间的异常分化 祖细胞的祖细胞已导致我们的中心 NGF刺激表达TRKA的感觉树突向HO部位刺激，进而将TGFβ1释放到 刺激间充质祖细胞骨软骨的差异。 AIM 1：定义周围NGF在控制HO部位的感觉神经向内生长中的作用 使用已建立的动物模型的启动和进展，我们假设该组织删除 NGF（PDGFRB-CREERT2； NGFFL/FL）或血管平滑肌细胞（VSMC； MyH11-Creert2; ngffl/fl）中的NGF将 废除外周神经内生长和HO形成。 AIM 2：测试TGFβ1信号传导在感觉神经 - 间充质祖细胞横向交流中的作用 HO，使用已建立的动物模型，假设感觉神经阳性 祖细胞细胞细胞骨软骨通过TGFβ1依赖性过程。 目标3：定义抗NGF中和抗体的潜在作用 干预。我们假设Fasinumab（NGF中和抗体）压抑 HO疾病进展的负调节剂，它钝化了病神经内向。