Promoting regeneration in muscular dystrophy with adipose derived stem cells.

利用脂肪干细胞促进肌营养不良症的再生。

• 批准号: 8398548
• 负责人: Gretchen A Meyer
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398548
• 关键词: Adipocytes; Adipose tissue; Animals; Area; Atomic Force Microscopy; Birth; Cell Count; Cell Fate Control; Cell Lineage; Cell Therapy; Cells; Chemicals; Clinical; Complex; Connective Tissue; Contractile Proteins; Cues; Disease; Disease model; Duchenne muscular dystrophy; Dyes; Dystrophin; Engraftment; Ensure; Environment; Equilibrium; Extracellular Matrix; Family; Fatty acid glycerol esters; Focal Adhesions; Genes; Glycerol; Growth Factor; Heart Diseases; Histocytochemistry; Immunohistochemistry; In Vitro; Infiltration; Injection of therapeutic agent; Intramuscular; Intramuscular Injections; Lead; Mechanics; Mitogen-Activated Protein Kinases; Modeling; Monitor; Movement; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Dystrophies; Mutation; Myopathy; Natural regeneration; Outcome; Patients; Performance; Phenotype; Phosphorylation; Population; Predisposition; Process; Quality of life; Recovery of Function; Regulation; Severities; Signal Transduction; Source; Staining method; Stains; Stem cells; Surface; Testing; Tissues; Traction; Translations; Validation; Wit; adult stem cell; base; conditioning; early onset; exhaust; exhaustion; functional restoration; improved; in vivo; male; mdx mouse; morphometry; mortality; mouse model; muscle degeneration; muscle regeneration; myogenesis; precursor cell; progenitor; regenerative; response; restoration; stem cell differentiation; stem cell population; wasting

DESCRIPTION (provided by applicant): Restoring muscle function to patients with degenerative muscle diseases such as Duchenne Muscular Dystrophy (DMD) remains a significant clinical problem. In DMD, the increased susceptibility of muscle to damage, due to a dystrophin mutation, combined with exhaustion of the stores of resident cells capable of regenerating damaged areas cause extensive replacement of contractile material with connective tissue and fat, decreasing contractile function (1, 2). Delivery of adult stem cells wit myogenic potential could overcome both increased muscle fragility by restoring dystrophin expression and decreased regeneration by providing an exogenous source of regenerative potential. While several cell sources have been proposed, all have had significant setbacks owing either to poor engraftment and functional recovery or inability to isolate sufficient numbers of cells for clinical translation. However, adipose-derived stem cells (ASCs) can be derived in large numbers from a relatively expendable tissue and have shown some myogenic potential (26, 29). However, as ASCs are known to be highly adipogenic in-vivo and fatty replacement of muscle tissue is a hallmark of DMD, it is critical to ensure that they remain myogenic upon injection and do not contribute to the formation of intramuscular fat. Mechanical induction of myogenesis in ASCs is more robust than chemical and mechanically-induced myotubes retain their fused state when switched to nonmyogenic conditions. We therefore propose (Aim 1.a) to understand the critical differences between how ASCs and the resident source of intramuscular fat, fibro/adipogenic progenitors (FAPs), sense and respond to mechanical differentiation cues; (Aim 1.b) to exploit those differences to mechanically-condition ASCs away from the FAP phenotype to become and remain myogenic even in the face of adipogenic cues; and (Aim 2) to perform intramuscular injections of ASC-derived myotubes in dystrophic muscle with faty infiltration and ases engraftment, dystrophin expression, and restoration of degenerated muscle function. Successful validation of functional muscle restoration using ASC-derived myotubes and exploration of the mechanisms behind mechano-sensitive fusion will lead to larger animal studies and potential clinical translation. ! PUBLIC HEALTH RELEVANCE: Duchenne Muscular Dystrophy (DMD) is a debilitating disorder that afects 1 in every 3,600 male births and the early onset and severity of DMD significantly impact the quality of life both for patients and families. There is currently no curefor DMD, but cell-based therapies focused on circumventing the progressive muscle wasting at the heart of the disorder hold tremendous promise for improving patient outcomes. We will show that adipose-derived stem cells are a clinically viable cell source for promoting muscle regeneration and improving contractile performance in dystrophic muscle.

描述(由申请人提供)：恢复退行性肌肉疾病患者的肌肉功能，如Duchenne肌营养不良症(DMD)，仍然是一个重要的临床问题。在DMD中，由于dystrophin突变，肌肉对损伤的敏感性增加，再加上能够再生受损区域的驻留细胞的储存枯竭，导致收缩材料被结缔组织和脂肪广泛取代，收缩功能下降(1，2)。携带具有肌源性潜能的成体干细胞可以通过恢复dystrophin的表达来克服肌肉脆性增加的问题，也可以通过提供外源性再生潜能来减少再生。虽然已经提出了几个细胞来源，但由于植入和功能恢复不佳或无法分离足够数量的细胞，所有这些来源都遇到了重大挫折 用于临床翻译的细胞。然而，脂肪来源的干细胞(ASCs)可以从相对可消耗的组织中大量获得，并显示出一定的肌源性潜能(26，29)。然而，由于ASCs在体内是高度成脂的，肌肉组织的脂肪替代是DMD的一个标志，因此确保它们在注射后保持肌源性并且不会促进肌肉内脂肪的形成是至关重要的。在ASCs中，机械诱导的肌发生比化学诱导的更强，当切换到非肌生条件时，机械诱导的肌管保持其融合状态。因此，我们建议(目标1.a)了解ASCs和肌肉内脂肪、纤维/成脂前体细胞(FAPs)的常驻来源之间的关键差异，以及ASCs如何感知和响应机械分化线索；(目标1.b)利用这些差异来机械地调节ASCs远离FAP表型，使其成为并保持肌源性，即使面对成脂信号；以及(目标2)将ASC来源的肌管注射到有脂肪渗透和ASS植入的营养不良肌肉中，Dstrophin的表达，以及退化的肌肉功能的恢复。使用ASC衍生肌管进行功能性肌肉修复的成功验证和对机械敏感融合机制的探索将导致更大规模的动物研究和潜在的临床应用。好了！ 与公共卫生相关：杜氏肌营养不良症(DMD)是一种衰弱的疾病，每3600名男婴中就有一名受到影响，DMD的早期发病和严重程度显著影响患者和家庭的生活质量。目前还没有治疗DMD的方法，但基于细胞的疗法专注于绕过疾病中心的进行性肌肉萎缩，为改善患者预后带来了巨大的希望。我们将展示脂肪干细胞是临床上可行的细胞来源，可以促进肌肉再生和改善营养不良肌肉的收缩性能。