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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。

基本信息

批准号：
8607830
负责人：
Gretchen A Meyer
金额：
$ 4.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607830
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 public health relevance regenerative response restoration stem cell differentiation stem cell population wasting

项目摘要

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. !

描述（由申请人提供）：恢复退行性肌肉疾病（如杜氏肌营养不良症（DMD））患者的肌肉功能仍然是一个重要的临床问题。在DMD中，由于肌营养不良蛋白突变，肌肉对损伤的易感性增加，加上能够再生受损区域的驻留细胞的储存耗尽，导致结缔组织和脂肪广泛替代收缩材料，降低收缩功能（1，2）。具有成肌潜能的成体干细胞的递送可以通过恢复肌营养不良蛋白表达来克服增加的肌肉脆性，并且通过提供再生潜能的外源性来源来克服减少的再生。虽然已经提出了几种细胞来源，但由于移植和功能恢复差或无法分离足够数量的细胞，所有细胞来源都有重大挫折用于临床翻译。然而，脂肪源性干细胞（ASC）可以大量来源于相对消耗性组织，并显示出一些肌原性潜力（26，29）。然而，由于已知ASC在体内是高度成脂的，并且肌肉组织的脂肪替代是DMD的标志，因此确保它们在注射后保持肌原性并且不有助于肌内脂肪的形成是至关重要的。机械诱导ASCs中的肌生成比化学和机械诱导的肌管在切换到非肌生成条件时保持其融合状态更稳健。因此我们建议（目的1.a）了解ASCs和肌内脂肪的常驻来源--脂肪/成脂祖细胞（FAPs）如何感知和响应机械分化信号之间的关键差异;（目的1.b）利用这些差异以机械调节ASC远离FAP表型，从而即使面对脂肪形成线索也成为并保持肌原性;和（目的2）在具有脂肪浸润的营养不良肌肉中进行肌内注射ASC衍生的肌管，并进行ases植入、肌营养不良蛋白表达和退化肌肉功能的恢复。使用ASC衍生的肌管成功验证功能性肌肉恢复和探索机械敏感融合背后的机制将导致更大的动物研究和潜在的临床转化。!