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

这项研究将开发一种创新的疗法来促进组织再生和逆转 顽固伤口愈合的后果。这与我们的退伍军人群体特别相关 它遭受着受伤和衰老的后果。价值50亿美元的全球市场 伤口护理“预计将在未来十年增加两倍。我们有一个快速增长的老年人队列 患有糖尿病的退伍军人，新的受伤战士队列，他们的受伤包括无法愈合 脊髓损伤、多处创伤性损伤和烧伤造成的溃疡。因此，退伍军人人数 面临着数量惊人的慢性伤口的风险。我们建议使用一种分泌的纳米微囊 从脂肪来源的干细胞(人的ADSC)。脂肪组织是一种丰富的可再生的 干细胞的来源。人ADSC释放刺激内源性修复的营养因子 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。然而，hADSC的研究是有缺陷的 由于缺乏标准化和交付方式。我们的目标是利用茎的希望 细胞再生分泌因子可用于愈合伤口。我们已经确定了一种治疗伤口的方法 使用hADSC收集的条件培养液(CM)进行培养。我们认识到CM包含 HADSC分泌的外切体和外切体内的因子以旁分泌的方式起作用。在……里面 除了脂类和蛋白质外，外切体还含有各种不同种类的RNA。一种类型，长非- 编码RNA尤其令人感兴趣，因为它只由干细胞分泌。一旦细胞开始 分化为骨骼和脂肪细胞等谱系，保留为核功能。这个 我们在外体中发现的分泌的长非编码RNA是MALAT1。它在伤口中起作用 我们预测富含MALAT1的外体将能够治愈各种伤口。 我们推测，Malat很可能下调了迁移、增殖和 通过与microRNAs的相互作用促进血管生成。我们将研究外切体如何在体外发挥作用 人真皮成纤维细胞伤口愈合试验。我们将使用大鼠缺血创伤模型 研究外切体如何在体内发挥作用。这两个模型都可以让我们优化数字 以及允许伤口闭合和调节血管生成的外切体的浓度。我们 建议对hADSC进行改进，以收集更多的外切体。外切体是 在伤口应用中比干细胞更稳定。它们可以在低温下储存， 局部使用，可用于急诊室的伤口和家庭使用。这 该项目是使hADSC外切体成为伤口修复和组织临床现实的第一步。 再生。

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.