Mechanisms for treating ischemic wounds with human adipocyte derived stem cell exosomes

人脂肪细胞来源的干细胞外泌体治疗缺血性伤口的机制

• 批准号: 9898296
• 负责人: DENISE Ratzlaff COOPER
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898296
• 关键词: Accident and Emergency department; Address; Adipocytes; Adipose tissue; Adult; Aging; Arginine; Binding; Biological; Biological Assay; Burn injury; CRISPR/Cas technology; Cell Cycle; Cell physiology; Cells; Ceramides; Chronically Ill; Clinical; Collagen; Collection; Deposition; Dermal; Diabetes Mellitus; Endocytosis Pathway; Engineering; Environment; Face; Fibroblasts; Freezing; Gene Expression; Genes; Goals; Home environment; Homeostasis; Hospitals; Human; Hypoxia; Impaired wound healing; In Vitro; Inflammation; Inflammatory Response; Injury; Innovative Therapy; Knock-out; Lipids; Liver; MALAT1 gene; Mediating; Mediator of activation protein; Methods; MicroRNAs; Modeling; Nuclear; Ontology; Patients; Phagocytosis; Population; Populations at Risk; Porifera; Preparation; Proteins; Proteomics; RNA; Rattus; Regenerative Medicine; Research; Rodent Model; Role; Serine; Site; Soldier; Source; Spinal cord injury; Standardization; Stem Cell Factor; Stem Cell Research; Supporting Cell; Testing; Therapeutic; Time; Topical application; Traumatic injury; Untranslated RNA; Veterans; Work; Wound models; acrosome stabilizing factor; angiogenesis; bone; cell motility; chronic ulcer; chronic wound; cohort; cold temperature; derepression; diabetic patient; exosome; experience; extracellular; healing; immunoregulation; improved; in vitro Assay; in vivo; inhibitor/antagonist; injury and repair; intercellular communication; interest; migration; nanovesicle; novel therapeutics; older patient; overexpression; paracrine; pre-clinical; programs; protein expression; regenerative; relating to nervous system; repaired; skin wound; stem cells; tissue regeneration; transcriptome sequencing; uptake; wound; wound bed; wound care; wound closure; wound healing

This research will develop an innovative therapy to promote tissue regeneration and reverse the consequences of recalcitrant wound healing. It is particularly relevant to our Veteran population that suffers the consequences of injury and aging. The $5 billion global market for “advanced wound care” is anticipated to triple in the next ten years. We have a rapidly growing cohort of older veterans with diabetes, a new cohort of wounded warriors with injuries that include non-healing ulcers from spinal cord injury, multiple traumatic injuries and burns. Hence Veteran populations are at risk for a staggering number of chronic wounds. We propose to use a secreted nanovesicle from adipose derived stem cells (human ADSC). Adipose tissue is an abundant and renewable source of stem cells. Human ADSC release trophic factors that stimulate endogenous repair mechanisms in wounds, and they have immunomodulatory effects, responding to the microenvironment. They have been shown to heal wounds. However, hADSC research is flawed by the lack of standardization and delivery methods. Our goal is to harness the promise of stem cell regenerative secreted factors to heal wounds. We have identified a wound healing treatment using conditioned media (CM) collected from hADSC in culture. We recognize that CM contains exosomes secreted by hADSC, and the factors within the exosomes act in a paracrine manner. In addition to lipids and proteins, exosomes contain various species of RNA. One type, long non- coding RNA, is of particular interest in that it is only secreted by stem cells. Once cells start to differentiate to lineages such as bone and adipocytes, it is retained for a nuclear function. The secreted long non-coding RNA that we find in exosomes is MALAT1. It functions in wound healing, and we predict that exosomes rich in MALAT1 will be able to heal a variety of wounds. We hypothesize that MALAT probably derepresses genes for migration, proliferation, and angiogenesis via its interaction with microRNAs. We will examine how exosomes function in vitro in a human dermal fibroblast wound healing assay. We will use a rat ischemic wound model for examining how exosomes function in vivo. Both of these models will let us optimize the number and concentrations of exosomes that allow for wound closure and modulation of angiogenesis. We propose improvements to hADSC that will allow for collection of more exosomes. Exosomes are more stable than stem cells for wound applications. They can be stored in low temperatures, applied topically and be made available to wounds in emergency rooms and for home use. This project is the first step in making hADSC exosomes a clinical reality for wound repair and tissue regeneration.

这项研究将开发一种创新的疗法，以促进组织再生并扭转 顽固伤口愈合的后果。这与我们的资深人口特别相关 遭受了伤害和衰老的后果。 50亿美元的全球市场 预计在未来十年中，伤口护理将三倍。 患有糖尿病的退伍军人，一组新的受伤战士，包括非治疗 脊髓损伤，多发性损伤和烧伤的溃疡。因此，退伍军人人口 有大量慢性伤害的风险。我们建议使用分泌的纳米层 来自脂肪衍生的干细胞（人ADSC）。脂肪组织是丰富且可再生的 干细胞的来源。人ADSC释放刺激内源修复的营养因子 伤口中的机制，它们具有免疫调节作用，对 微环境。它们已被证明可以治愈伤口。但是，HADSC研究存在缺陷 由于缺乏标准化和交付方法。我们的目标是利用STEM的承诺 细胞再生分泌的因素治愈伤口。我们已经确定了伤口愈合治疗 使用从HADSC收集的条件介质（CM）。我们认识到CM包含 HADSC分泌的外泌体和外泌体中的因素以旁分泌方式作用。在 除脂质和蛋白质外，外泌体含有各种RNA。一种类型，长期不 编码RNA特别感兴趣，因为它仅由干细胞分泌。一旦细胞开始 与骨骼和脂肪细胞等谱系区分开，它保留在核功能中。这 我们在外泌体中发现的分泌长的非编码RNA是malat1。它在伤口中起作用 康复，我们预测富含MALAT1的外泌体能够治愈各种伤口。 我们假设Malat可能会消除基因的迁移，增殖和 血管生成通过其与microRNA的相互作用。我们将检查外泌体在体外如何在体外发挥作用 人真皮成纤维细胞伤口愈合测定法。我们将使用大鼠缺血性伤口模型 检查外泌体在体内的功能。这两种模型都将使我们优化数字 以及允许闭合和调节血管生成的外泌体的浓度。我们 对HADSC的提案改进将允许收集更多的外泌体。外泌体是 对于伤口应用，比干细胞更稳定。它们可以在低温下存储， 局部应用，可用于急诊室中的伤口和家庭用途。这 项目是使HADSC外泌体成为伤口修复和组织的临床现实的第一步 再生。