Mechanobiology of Progenitor Cells in Heterotopic Ossification

异位骨化中祖细胞的力学生物学

基本信息

批准号：
10401824
负责人：
Robert L Mauck
金额：
$ 33.48万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401824
关键词：
ACVR1 gene Adoption Biological Biological Assay Biomechanics Bone Morphogenetic Proteins Bone Tissue Cartilage Cell Differentiation process Cell Fate Control Cell Surface Receptors Cell Transplantation Cells Cellular biology Cellularity Chondrocytes Chondrogenesis Connective Tissue Connective and Soft Tissue DNA Sequence Alteration Data Development Direct Lytic Factors Disease Environment Excision Fiber Genes Genetic Genetic Diseases Heterotopic Ossification Human Human Genetics Impairment In Vitro Inflammatory Injury Investigation Lesion Ligands Link Mechanics Mediating Medicine Mesenchymal Mesenchymal Stem Cells Molecular Biology Mus Muscle Muscle Fibers Muscle satellite cell Mutation Natural regeneration Osteoblasts Osteogenesis Outcome Pathway interactions Physiologic Ossification Population Process Production Property Receptor Mediated Signal Transduction Research Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Testing Therapeutic Intervention Tissue Differentiation Tissue Engineering Tissues Transplantation Writing base bone bone morphogenetic protein receptor type I clinical application crosslink density extracellular gain of function healing impaired capacity in vivo insight lipid biosynthesis malformation mechanical properties mechanotransduction mouse model multidisciplinary muscle regeneration mutant new therapeutic target non-genetic novel osteogenic physical property prevent progenitor programs progressive myositis ossificans rare genetic disorder receptor reconstitution repaired response restoration satellite cell skeletal stem cell biology stem cell population stem cells therapy development tissue injury tissue repair wound wound environment wound healing

项目摘要

Abstract Although rare genetic disorders directly impact relatively small segments of the population, they are caused by mutations in genes with such critical importance that perturbed function is rarely tolerated, and therefore offer unique insight into fundamental cellular mechanisms. One such disease, fibrodysplasia ossificans progressiva (FOP), is caused by misregulated control of cell fate decisions that leads to congenital skeletal malformations and disabling extra-skeletal (heterotopic) endochondral ossification (HO) that often forms in response to tissue injury. Notably, this de novo bone formation is associated with an impaired muscle repair response. We identified that all familial and sporadic cases with classic features of FOP carry the same heterozygous mutation in ACVR1/ALK2 (R206H; c.617G>A), a cell surface receptor that mediates signal transduction of bone morphogenetic proteins (BMPs). Our data showed that the ACVR1 R206H mutant receptors mildly activate the BMP signaling pathway in the presence or absence of BMP ligands. This proposal seeks to identify how the resulting gain of function in ACVR1/BMP signaling diverts the program of muscle repair from one that normally culminates in restoration of muscle tissue to one in which muscle injury leads to differentiation of endogenous mesenchymal progenitor cells (MSCs) to chondrocytes and osteoblasts and the formation of heterotopic bone tissue. Previous studies confirmed cell autonomous effects of the mutation on MSC differentiation, however, while the mutation enhances MSC chondro/osteogenesis, we have also established that mutant cells do not spontaneously differentiate, but require additional signals. Since commitment and differentiation of tissue-resident progenitor cells is regulated by signals from the tissue microenvironment, and the tissue microenvironment is itself defined by matrix production by these differentiating cells, this proposal focuses on how enhanced BMP pathway signaling in FOP changes cellular interpretation and fabrication of the biomechanical environment during muscle repair. Based on our preliminary data showing altered physical (mechanical) properties of mutant skeletal muscle tissue following injury, this proposal will first investigate and identify the mechanisms (cellularity, matrix, and stiffness) through which ACVR1 R206H mutant tissue alters the connective tissue microenvironment during the early response to muscle injury (Aim 1). Next, we will examine the mechano-sensing signaling mechanisms through which chondro/osseous mesenchymal (non-myogenic) progenitor cells (MSCs) differentially sense and interpret signals from their microenvironment (Aim 2). Finally, we will determine the effects of the mutant tissue microenvironment on endogenous myogenic muscle progenitor cells (MuSCs, Aim 3). Together, these data will identify novel mechano-regulatory mechanisms controlling cell differentiation in heterotopic ossification and muscle repair and as well as reveal new targets for therapeutic interventions to prevent genetic and non- genetic forms of HO and to engineer tissues for clinical application.

抽象的尽管罕见的遗传性疾病直接影响相对较小的人群，但它们是由基因突变的重要性如此之高，以至于功能受到干扰很少被容忍，因此提供了对基本细胞机制的独特见解。其中一种疾病是进行性骨化性纤维发育不良 (FOP)，是由细胞命运决定的失调控制引起的，导致先天性骨骼畸形并禁用通常因组织反应而形成的骨骼外（异位）软骨内骨化（HO）受伤。值得注意的是，这种从头骨形成与肌肉修复反应受损有关。我们确定所有具有 FOP 典型特征的家族性和散发性病例都携带相同的杂合子 ACVR1/ALK2（R206H；c.617G>A）突变，这是一种介导信号转导的细胞表面受体骨形态发生蛋白（BMP）。我们的数据表明 ACVR1 R206H 突变受体轻度在 BMP 配体存在或不存在的情况下激活 BMP 信号通路。该提案旨在确定 ACVR1/BMP 信号传导中所产生的功能增益如何将肌肉修复程序从通常最终导致肌肉组织恢复为肌肉损伤导致的一种内源性间充质祖细胞（MSC）向软骨细胞和成骨细胞的分化以及异位骨组织的形成。先前的研究证实了突变对细胞自主的影响然而，MSC 分化虽然突变增强了 MSC 软骨/成骨，但我们也发现确定突变细胞不会自发分化，而是需要额外的信号。自从组织驻留祖细胞的定型和分化受来自组织的信号调节微环境，组织微环境本身是由这些基质产生的分化细胞，该提案重点关注 FOP 中增强的 BMP 通路信号传导如何改变细胞肌肉修复过程中生物力学环境的解释和构建。根据我们的初步数据显示突变骨骼肌组织在受伤后物理（机械）特性发生改变，这该提案将首先调查并确定机制（细胞结构、基质和刚度） ACVR1 R206H 突变组织在早期反应期间改变结缔组织微环境肌肉损伤（目标 1）。接下来，我们将研究机械传感信号机制软骨/骨间充质（非肌源性）祖细胞（MSC）有不同的感知和解释来自微环境的信号（目标 2）。最后，我们将确定突变组织的影响内源性肌源性肌肉祖细胞（MuSC，目标 3）的微环境。这些数据一起将确定控制异位骨化中细胞分化的新机械调节机制肌肉修复，并揭示治疗干预的新目标，以预防遗传性和非遗传性疾病 HO 的遗传形式并设计用于临床应用的组织。