Improvement of Animal Models for TMJ Stem Cell-Based Regeneration

颞下颌关节干细胞再生动物模型的改进

• 批准号: 10400088
• 负责人: Mildred Christine Embree
• 金额: $ 70.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400088
• 关键词: American; Animal Model; Animal Testing; Apoptosis; Blood Vessels; Cartilage; Cell Therapy; Cells; Clinical; Complex; Data; Degenerative polyarthritis; Dental Occlusion; Development; Disease; Disease model; Failure; Family suidae; Fatty acid glycerol esters; Fibrocartilages; Freund' s Adjuvant; Goals; Health; Homeostasis; Human; Intra-Articular Injections; Joints; Knowledge; LGR5 gene; Ligaments; Mastication; Mediating; Modeling; Mus; Muscle; National Institute of Dental and Craniofacial Research; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Palliative Care; Pathology; Pharmaceutical Preparations; Phenotype; Publishing; Quality of life; Regulation; Replacement Arthroplasty; Research Priority; Respiration; Rodent; Role; Signal Transduction; Speech; Structure of articular disc of temporomandibular joint; System; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint arthritis; Temporomandibular joint osteoarthritis; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; Work; arthropathies; base; bone; clinically relevant; cost; experimental study; inhibitor; joint injury; loss of function; minimally invasive; mouse genetics; mouse model; novel; porcine model; pre-clinical; prevent; regenerative therapy; regenerative treatment; repaired; stem cell fate; stem cell fate specification; stem cell model; stem cell population; stem cell proliferation; stem cell therapy; stem cells; tissue regeneration; treatment strategy

PROJECT SUMMARY TMJ osteoarthritis (OA) poses a major clinical problem, but there are no therapies that promote TMJ regeneration. Therapeutically exploiting resident stem cells represents a stem cell-based strategy for tissue regeneration. We have identified TMJ fibrocartilage stem cells (FCSCs) localized within the TMJ condyle superficial zone. Transplanted FCSCs engraft, self-organize and regenerate cartilage, fat and vascularized bone. FCSCs are heterogeneous, yet markers critical for studying signals regulating FCSCs are unknown. We found that Prg4+, Lgr5+ and Prg4+Lgr5+ cells represent FCSC populations in rodents and pigs. We discovered that Wnt/βCatenin signaling is critical for FCSC fate specification by inducing proliferation and inhibiting differentiation of FCSCs. However, over-active Wnt/βCatenin is associated with TMJ OA. We developed two TMJ disease models in mice and pigs and discovered that TMJ OA is correlated with increased βCatenin and apoptosis mediated FCSC depletion. These data suggest inhibition of Wnt/βCatenin may serve as a therapeutic regenerative strategy for the treatment of TMJ OA. In fact, we show that therapeutic application of a canonical Wnt inhibitor repairs TMJ in a rabbit TMJ injury model. Based on our published work and preliminary data, we hypothesize that Prg4+, Lgr5+ and Prg4+Lgr5+ are FCSCs and Wnt/βCatenin inhibition in FCSCs regenerates TMJ. We will test our hypothesis using three specific aims: 1) Define FCSC populations critical for TMJ development and homeostasis; 2) Determine the role of Wnt/βCatenin signaling in regulating FCSC fate; 3) Target resident FCSCs to regenerate cartilage in a porcine TMJ injury model. Using mouse genetics, we will characterize FCSCs and delineate the role of Wnt/βCatenin signaling in regulating FCSC fate. We will optimize a new, clinically relevant large animal model and test Wnt inhibition in FCSCs as a potential therapy for TMJ OA. Taken together, these novel studies will contribute towards the development of a non- surgical, minimally invasive stem cell-based therapy for TMJ regeneration.

项目摘要 颞下颌关节骨关节炎（OA）是一个主要的临床问题，但没有治疗，以促进颞下颌关节 再生在治疗上利用常驻干细胞代表了用于组织移植的基于干细胞的策略。 再生我们已经确定TMJ纤维软骨干细胞（FCSCs）定位于TMJ髁突 浅层移植的FCSCs移植，自我组织和再生软骨，脂肪和血管化 骨头FCSC是异质性的，但研究调控FCSC的信号的关键标志物是未知的。我们 发现Prg 4+、Lgr 5+和Prg 4 + Lgr 5+细胞代表啮齿动物和猪中的FCSC群体。我们发现 Wnt/βCatenin信号通过诱导增殖和抑制FCSC的增殖， FCSC的分化。然而，过度活跃的Wnt/βCatenin与TMJ OA相关。我们开发了两 在小鼠和猪的TMJ疾病模型中，发现TMJ OA与β连环蛋白增加相关， 凋亡介导的FCSC耗竭。这些数据表明，抑制Wnt/β连环蛋白可能是一种治疗抑郁症的方法。 治疗颞下颌关节骨性关节炎的治疗再生策略。事实上，我们发现， 典型的Wnt抑制剂在兔TMJ损伤模型中修复TMJ。基于我们已发表的工作， 根据初步数据，我们假设Prg 4+、Lgr 5+和Prg 4 + Lgr 5+是FCSCs，Wnt/β连环蛋白抑制在 FCSC再生TMJ。我们将使用三个具体目标来测试我们的假设：1）定义FCSC人群 2）确定Wnt/βCatenin信号在调节TMJ发育和稳态中的作用， FCSC命运; 3）靶向驻留FCSC以在猪TMJ损伤模型中再生软骨。使用小鼠 为了研究FCSC的遗传学特征，我们将描述FCSC的特征，并描述Wnt/β连环蛋白信号在调控FCSC命运中的作用。 我们将优化一个新的，临床相关的大型动物模型，并测试FCSC中的Wnt抑制，作为一种潜在的 治疗颞下颌关节骨性关节炎总之，这些新的研究将有助于发展一个非- 手术，微创干细胞为基础的治疗颞下颌关节再生。