Muscle stem cell therapy in a mouse model of premature aging

描述（由申请人提供）：众所周知，在美国，老年人是一个不断扩大的人口群体，他们患许多衰弱性疾病的风险急剧增加，包括骨折、心血管疾病、认知障碍、糖尿病和癌症。尽管随着年龄的增长，体内平衡储备逐渐丧失的分子基础存在争议，但有几条证据表明，累积的DNA损伤是年龄相关病理进展的主要决定因素。特别是，大多数人类早衰症（或加速衰老综合征）是由基因组修复和维护所需基因的遗传突变引起的，包括XPF。ERCC1-XPF蛋白复合物是一种高度保守的核酸内切酶，至少需要两种DNA修复机制：核苷酸切除修复（NER）和DNA链间交联修复。我们有几种Ercc1- xpf缺乏的早衰小鼠模型，包括Ercc1-/-和Ercc1-/，它们表达Ercc1- xpf的水平分别为正常水平的0%和10%。Ercc1-/-小鼠的平均寿命为21天，Ercc1-/小鼠的平均寿命为7个月。两种小鼠都会出现与年龄相关的疾病，包括共济失调、脊柱后突、恶病质、椎间盘退变、骨质疏松、失禁、表皮萎缩、肌肉减少、骨髓变性和肝肾功能障碍。我们之前分离并表征了一群肌肉来源的干细胞（MDSCs），它们在肌肉骨骼系统的各种组织中显示出高再生能力。我们的初步结果表明，从早老性ERCC1-XPF缺陷小鼠中分离的MDSCs存在增殖和分化缺陷。此外，将野生型（wt） MDSCs注射到Ercc1-/-小鼠体内，可使其植入多种组织，显著延长寿命。因此，我们假设ERCC1-XPF缺陷小鼠的成体干细胞室缺陷参与了其显著加速衰老，干细胞治疗可能代表了预防或延缓年龄相关的衰弱变化的潜在策略。本提案的重点将是在我们独特的类早衰小鼠模型中记录和描述MDSCs的缺陷，并证明功能性MDSCs移植延缓年龄相关病理发作的能力。公共卫生相关性：衰老的特点是所有器官系统的进行性侵蚀，这使老年人面临许多衰弱性疾病和器官系统衰竭的风险增加，包括心血管疾病、痴呆、骨折、肌肉减少症和癌症。人口统计研究表明，65岁以上的个人数量将在未来25年翻一番，给美国的医疗保健系统带来前所未有的负担。这项研究计划具有重要意义，因为它不仅有可能揭示衰老的生物学机制（干细胞室缺陷），而且还可能导致干细胞疗法的发展，从而延缓或改善与衰老相关的病理；因此，确定策略，如干细胞移植，对于维持我们老龄化人口的健康至关重要。

DESCRIPTION (provided by applicant): It is well-known that aged individuals, an expanding demographic in the United States, have a dramatically increased risk of numerous debilitating diseases including bone fractures, cardiovascular disease, cognitive impairment, diabetes and cancer. Although the molecular basis of the progressive loss of homeostatic reserve with aging is controversial, there are several lines of evidence that implicate accumulated DNA damage as a major determinant in the progression of age-related pathology. In particular, the majority of human progerias (or syndromes of accelerated aging) are caused by inherited mutations in genes required for genome repair and maintenance, including XPF. ERCC1-XPF protein complex is a highly conserved endonuclease that is required for at least two DNA repair mechanisms: nucleotide excision repair (NER) and DNA interstrand crosslink repair. We have several progeroid mouse models of ERCC1-XPF deficiency including Ercc1-/- and Ercc1-/ , which express levels of ERCC1-XPF at 0% and 10% of normal, respectively. The average life span of the Ercc1-/- mice is 21 days and that of the Ercc1-/ mice is 7 months. Both mice develop age-related pathologies including ataxia, kyphosis, cachexia, disc degeneration, osteoporosis, incontinence, epidermal atrophy, sarcopenia, bone marrow degeneration and liver as well as kidney dysfunction. We previously isolated and characterized a population of muscle-derived stem cells (MDSCs) that displays a high regenerative capacity in various tissues of the musculoskeletal system. Our preliminary results suggest that MDSCs isolated from progeroid ERCC1-XPF deficient mice have proliferation and differentiation defects. Furthermore, injection of wild type (wt) MDSCs into Ercc1-/- mice results in their engraftment into multiple tissues and significantly extends lifespan. Thus we hypothesize that a defect in the adult stem cell compartment in ERCC1-XPF deficient mice is involved in their dramatically accelerated aging and that stem cell therapy may represent a potential strategy to prevent or delay age-associated debilitating changes. The focus of this proposal will be on documenting and characterizing the defect in MDSCs in our unique progeroid mouse models and on demonstrating the ability of transplantation of functional MDSCs to delay the onset of age-related pathologies. PUBLIC HEALTH RELEVANCE: Aging is characterized by the progressive erosion of all organ systems which places the elderly at an increased risk of numerous debilitating diseases and organ system failures including cardiovascular disease, dementia, bone fractures, sarcopenia, and cancer. Demographic studies indicate that the number of individuals aged greater than 65 will double in the next 25 years and impose an unprecedented burden on the U.S. health care system. This research proposal is highly significant in that it has the potential to not only reveal a biological mechanism(s) of aging (defect in stem cell compartment), but could also lead to the development of stem cell therapies which could delay or ameliorate the pathologies associated with aging; therefore, identifying strategies, such as stem cell transplantation, is essential for maintaining the health of our aging population.