hiPS cells derived skeletal muscle progenitors and their extracellular vesicles for treatment of sarcopenia

hiPS 细胞衍生的骨骼肌祖细胞及其细胞外囊泡用于治疗肌肉减少症

• 批准号: 10682558
• 负责人: Wanling Xuan
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682558
• 关键词: Acceleration; Address; Adult; Affect; Age; Aging; Biochemical; Biological; Blood Vessels; Blood capillaries; CX3CL1 gene; Cardiac; Cell Adhesion Molecules; Cell Communication; Cell Therapy; Cells; Data; Development; Direct Lytic Factors; Effectiveness; Elderly; Engineering; Engraftment; Exhibits; Experimental Animal Model; Functional disorder; Genetic Materials; HDAC4 gene; Health; Hip region structure; Histone Deacetylase Inhibitor; Homeostasis; Homing; Human; Immune response; In Vitro; Inflammation; Inflammatory; Injury; Lentivirus Vector; Life; Lipids; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Biology; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscle satellite cell; Natural regeneration; Parents; Personal Satisfaction; Physiology; Pluripotent Stem Cells; Population; Process; Proliferating; Property; Proteins; Proteomics; Quality of life; Regenerative Medicine; Rejuvenation; Research; Role; Safety; Signal Pathway; Signaling Molecule; Site; Skeletal Muscle; Somatic Cell; Source; Techniques; Testing; Time; Treatment Efficacy; Tumor Promotion; Vascular Cell Adhesion Molecule-1; Viral Vector; angiogenesis; cell type; density; design; extracellular vesicles; functional decline; induced pluripotent stem cell; injured; innovation; interdisciplinary approach; migration; muscle aging; muscle form; muscle regeneration; muscle strength; novel; novel strategies; overexpression; paracrine; pharmacologic; progenitor; regeneration potential; regenerative; repaired; sarcopenia; satellite cell; self-renewal; senescence; skeletal muscle wasting; small molecule; stem; stem cell based approach; stem cell expansion; stem cells; tumor

PROJECT SUMMARY Aging of skeletal muscle results in sarcopenia. It is believed that sarcopenia is in part due to a decreased capacity of stem cells, namely satellite cells, to repair the skeletal muscle after injury. Satellite cells are the major source of myogenic progenitors for adult muscle homeostasis and repair. A potential alternative for dysfunctional satellite cells is induced pluripotent stem cells (iPSC) which have the capacity to differentiate into skeletal muscle myocytes and blood vessels. Here, we have identified a highly efficient small molecule, givinostat (Givi), a histone deacetylase inhibitor (HDACi) which is capable of transforming human iPSC into myogenic progenitor cells (MPC) that are highly proliferative and generate large numbers of extracellular vesicles (EV). Our “pharmacological reprogramming” approach using small molecules to generate MPC in a limited period of time and without use of viral vectors is a very significant step forward in cell-based therapy. We are proposing that iPSC pharmacologically reprogrammed into MPC with Givi will be optimally effective to regenerate sarcopenic muscle. In specific aim 1, the hypothesis that induced myogenic progenitor cells (iMPC) from iPSC with novel small molecules are effective and safe for regeneration of aged muscle will be tested; In specific Aim 2, the hypothesis that accelerated mobilization and engraftment of iMPC in an aged muscle microenvironment stimulate muscle regeneration will be tested; In specific Aim 3, the hypothesis that EV derived from Givi-induced MPC rejuvenate aged muscle and augment muscle regeneration will be tested. If many of the regenerative properties of iMPC can be credited to EV, there will be a paradigm shift in regenerative medicine to enable endogenous self-repair in sarcopenia by cell to cell transfer of proteins, mRNAs, and miRNAs (miRs) by EV. EV from engineered or modified stem cells are highly enriched with bioactive molecules including myogenic miRs responsible for activation of signaling pathways important in muscle regeneration. These studies will involve multidisciplinary approaches which will employ state of the art molecular biology, biochemical, histochemical, immunohistochemical techniques and integrative physiology involving well established experimental animal model and muscle function. This proposal is conceptually innovative because it addresses the structural and molecular characterization of iMPC and their EV and tests their role as key biological messengers of iMPC action in the treatment of sarcopenia.

项目摘要 骨骼肌的老化导致肌肉减少症。据信，肌肉减少症部分是由于能力下降， 干细胞，也就是卫星细胞，修复骨骼肌损伤。卫星细胞是主要来源 用于成人肌肉的稳态和修复。一个潜在的替代功能失调 卫星细胞是诱导多能干细胞（iPSC），其具有分化成骨骼肌的能力 肌细胞和血管。在这里，我们已经确定了一种高效的小分子，givinostat（Givi）， 脱乙酰酶抑制剂（HDACi），其能够将人iPSC转化为肌源性祖细胞（MPC） 其高度增殖并产生大量细胞外囊泡（EV）。我们的“药理学 使用小分子在有限的时间段内产生MPC并且不使用“重编程”方法。 病毒载体是基于细胞的治疗中非常重要的一步。我们建议iPSC 用Givi重新编程到MPC中的BMPs将最有效地再生肌肉减少的肌肉。 在具体目标1中，从具有新的小的细胞因子的iPSC诱导肌源性祖细胞（iMPC）的假设被证实是有效的。 分子对于老化肌肉的再生是有效和安全的;在具体目标2中，假设 在老化肌肉微环境中加速iMPC的动员和植入刺激肌肉 将测试再生;在具体目标3中，假设EV来源于Givi诱导的MPC再生 老化肌肉和增强肌肉再生将被测试。如果iMPC的许多再生特性 可以归功于EV，再生医学将发生范式转变，使内源性自我修复成为可能 在通过EV的蛋白质、mRNA和miRNA（miR）的细胞间转移的肌肉减少症中。EV从工程或 修饰的干细胞高度富集生物活性分子，包括负责 激活肌肉再生中重要的信号通路。这些研究将涉及多学科 采用现有技术的分子生物学，生物化学，组织化学， 免疫组织化学技术和综合生理学，包括良好建立的实验动物 模型和肌肉功能。这一建议在概念上是创新的，因为它涉及结构和 iMPC及其EV的分子表征，并测试它们作为iMPC作用的关键生物信使的作用 用于治疗肌肉减少症