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: 10210050
• 负责人: AARON W JAMES
• 金额: $ 62.95万
• 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/10210050
• 关键词: AVIL gene; Agonist; Amputation; Analgesics; Animal Model; Animals; Area; Axon; Bioavailable; 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; 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; 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; skeletal; 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）的特征是组织居住的异常骨软骨分化 间充质祖细胞。 Ho折磨了几乎20％的肢体创伤，截肢和大表面积 烧伤患者，并在临床上疼痛。目前，尚无治疗方法来防止启动，反向 疾病进展，或通过有效的非阿片类药物机制限制疼痛。在分析我们的过程中 经过验证的创伤引起的HO模型，我们观察到神经侵蚀是对创伤的早期反应。使用 独特的人类创伤性HO病变数据集，我们已经确认了早期和不良适应性的 神经渗透性先于ho。此外，我们发现手术神经可能会抑制早期阶段 Ho组。在后续研究中，我们发现了神经生长因子（NGF）作为主要刺激的作用 在这种神经前神经和血管周围的细胞（周周和血管平滑肌）中 细胞）似乎是该神经营养蛋白的主要来源。阐明NGF诱导神经的作用 在HO上，我们进行了完整的研究，这表明神经可能会激活间充质 祖细胞TGFβ1信号传导以驱动局部间充质之间异常软骨分化 祖细胞前体细胞。这些观察结果导致了我们的中心假设，即血管周围衍生 NGF刺激表达TRKA的感觉树状侵蚀到HO位点，进而将TGFβ1释放到 刺激间充质祖细胞骨软骨分化。因此，提出了以下目标： AIM 1：定义周围NGF在控制HO部位的感觉神经内的作用 启动和进展。使用既定的动物模型，我们假设组织特定的缺失 NGF（PDGFRB-CREERT2； NGFFL/FL）或血管平滑肌细胞（VSMC； MyH11-Creert2; ngffl/fl）中的NGF将 消除外周神经诱导和HO形成创伤部位。 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 何使用既定的动物模型，我们假设感觉神经积极调节间充质 祖细胞细胞骨软骨通过TGFβ1依赖性过程。 AIM 3：定义抗NGF中和抗体作为一种新型HO疗法的潜在作用 干涉。我们假设Fasinumab（NGF中和抗体）代表双重镇痛和 HO疾病进展的负调节剂，它钝化病神经。