How Does a Young Extracellular Matrix Rejuvenate Old Mesenchymal Stem Cells?

年轻的细胞外基质如何​​使衰老的间充质干细胞恢复活力？

• 批准号: 9275393
• 负责人: XIAO-DONG CHEN
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275393
• 关键词: Adhesions; Adult; Age; Aging; Amino Acids; Apoptosis; Architecture; Atomic Force Microscopy; Autologous; Biological; Bone Marrow; Cell Aging; Cell Culture Techniques; Cell Lineage; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Clinical; Collagen; Data; Defect; Disease; Elderly; Environmental Risk Factor; Exposure to; Extracellular Matrix; Failure; Foundations; Goals; Growth Factor; Health; Hematopoietic; Human; Immunodeficient Mouse; In Vitro; Maintenance; Marrow; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Organ; Osteogenesis; Outcome; Patients; Play; Population; Positioning Attribute; Post-Translational Protein Processing; Property; Proteins; Proteoglycan; Proteomics; Regulation; Reporting; Role; Sampling; Scanning; Signal Transduction; Stable Isotope Labeling; Stem cells; Stromal Cells; Structure; Surveys; Target Populations; Testing; Theory of Change; Therapeutic; Time; Tissues; Transmission Electron Microscopy; Transplantation; Veterans; age effect; age related; aged; base; behavior influence; bone; cell behavior; experimental study; functional restoration; human subject; improved; in vitro Model; in vivo; innovation; juvenile animal; mechanical properties; migration; public health relevance; repaired; response; self-renewal; senescence; theories

DESCRIPTION (provided by applicant): Bone marrow-derived mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into multiple cell lineages. Because of these capabilities, MSCs play an important role in continuous maintenance and repair of most tissue types. The quantity and quality of MSCs decrease with aging, which, in turn, is associated with the progressive failure of function of tissues and organs. Recently, we reported in mice that defects in the self-renewal and bone formation capacity of aged MSCs were completely restored by exposure to extracellular matrix (ECM) made by marrow stromal cells from young animals, and such improvement was substantially diminished when cells (from either young or old mice) were cultured on ECM made by old marrow stromal cells. This led us to investigate whether this phenomenon also occurs in humans. Indeed, our preliminary studies in human subjects clearly suggest that culturing aged MSCs on ECM made by young marrow stromal cells is able to improve their number and quality. The goal of this proposal is to determine the mechanisms whereby young ECM rejuvenates old bone marrow-derived MSCs. A unique, cell-free ECM model will be used to dissect how young ECM restores the functions of old MSCs in vitro and in vivo. The hypothesis proposed in this application is that age negatively impacts the formation of an ECM that normally preserves MSC function, and the quantity and quality of aged MSCs can be improved by exposure to an ECM made by stromal cells from young donors. We are uniquely-positioned to test this hypothesis in humans since, in addition to our strong preliminary data, up to 100 human bone marrow samples have been accumulated in the past three years from elders (60 to 96 years old). To test this hypothesis, we will systematically evaluate biological activities in viro and in vivo of young vs. old MSCs maintained on young- or old-ECM (Specific aim 1), and conduct proteomic analysis of young- and old-MSCs exposed to young- or old-ECM to elucidate the underlying changes at the protein level that are associated with the restored functions of the rescued cells (Specific aim 2). To fully understand the mechanisms underlying the influence of MSC behavior, we will determine the differences in the structures of young- vs. old-ECM including the architecture, mechanical properties, and protein composition (Specific aim 3). These studies are innovative in that we will have established, for the first time, a unique in vitr human model to examine effects of age on MSCs (intrinsic theory), and changes to MSCs by the surrounding ECM (extrinsic theory). Our studies are important from a translational point of view because they will provide key information that can facilitate the use of a patient's own (autologous) stem cells for cell- based therapies. In view of the fact that the elderly are the mai target population for this type of treatment, understating age-related changes in both MSCs and host is essential for improving the clinical outcome of transplanted autologous MSCs in old veteran.

描述（由申请人提供）： 骨髓来源的间充质干细胞（MSC）能够自我更新并分化为多个细胞谱系。由于这些功能，MSC在大多数组织类型的连续维护和修复中起着重要作用。 MSC的数量和质量随老化而降低，这反过来又与组织和器官功能的进行性失败有关。最近，我们在小鼠中报道说，通过暴露于幼小动物的骨髓基质细胞使细胞外基质（ECM）暴露于幼年的自我更新和骨形成能力的缺陷完全恢复，并且当细胞（来自年轻小鼠或老小鼠）在ECM上培养在旧骨髓骨质的ECM上培养细胞时，这种改善会大大降低。这使我们研究了这种现象是否也发生在人类中。的确，我们在人类受试者中的初步研究清楚地表明，培养幼小的Marrow基质细胞对ECM的培养MSC可以提高其数量和质量。该提案的目的是确定年轻ECM恢复旧骨髓衍生的MSC的机制。独特的无细胞ECM模型将用于剖析年轻ECM在体外和体内恢复旧MSC的功能。在本应用中提出的假设是，年龄对通常保留MSC功能的ECM的形成产生负面影响，并且可以通过暴露于年轻捐助者的基质细胞中的ECM来改善老年MSC的数量和质量。我们是在人类中检验这一假设的独特位置，因为除了我们的强大初步数据外，在过去三年中，从长老（60至96岁）中积累了多达100种人体骨髓样品。 To test this hypothesis, we will systematically evaluate biological activities in viro and in vivo of young vs. old MSCs maintained on young- or old-ECM (Specific aim 1), and conduct proteomic analysis of young- and old-MSCs exposed to young- or old-ECM to elucidate the underlying changes at the protein level that are associated with the restored functions of the rescued cells (Specific aim 2).为了充分了解MSC行为影响的基础机制，我们将确定Young-ECM结构与旧ECM的差异，包括结构，机械性能和蛋白质组成（特定目标3）。这些研究具有创新性，因为我们将首次建立一个独特的VITR人类模型，以检查年龄对MSC的影响（内在理论），以及周围ECM（外部理论）对MSC的变化。从转化的角度来看，我们的研究很重要，因为它们将提供可以促进患者自己（自体）干细胞用于基于细胞疗法的关键信息。鉴于老年人是这种类型的治疗的MAI目标人群，MSC和宿主的年龄相关变化对于改善老兵移植自体MSC的临床结果至关重要。