Tuned stem cell extracellular vesicles as a novel chronic wound therapeutic

调整干细胞细胞外囊泡作为新型慢性伤口治疗剂

• 批准号: 9465841
• 负责人: YOLANDA Renee LEA-CURRIE
• 金额: $ 22.32万
• 依托单位: ZEN-BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465841
• 关键词: Address; Age; Aging; Animal Model; Atrophic; Biological; Biological Assay; Bioreactors; Blood flow; Cell Count; Cell Proliferation; Cell Therapy; Cells; Chronic; Clinical; Collagen; Comorbidity; Complex; Cues; Cutaneous; Data; Decubitus ulcer; Defect; Dermal; Diabetes Mellitus; Diabetic ulcer; Effectiveness; Elderly; Endothelial Cells; Ensure; Environment; Failure; Fibroblasts; Goals; Growth Factor; Healthcare; Healthcare Systems; Heat-Shock Response; High temperature of physical object; Hypoxia; Impaired wound healing; In Vitro; Inflammation; Inflammatory; Intuition; Investigation; Keratin; Leg Ulcer; Longevity; Mediating; Modality; Modeling; Modification; Monitor; Mus; Obesity; Patients; Phase; Population; Prevalence; Process; Production; Property; Proteins; RNA; Recurrence; Reporting; Research; Resolution; Site; Stem cells; System; Testing; Therapeutic; Time; Tissues; Varicose Ulcer; Venous; Vesicle; Wound Healing; adult stem cell; age related; aged; aging population; base; biophysical properties; cell type; chronic wound; cost; db/db mouse; design; exosome; extracellular vesicles; healing; improved; in vitro testing; in vivo; individualized medicine; keratinocyte; migration; mouse model; neovascularization; non-healing wounds; novel; paracrine; programs; regenerative; regenerative therapy; repaired; response; soft tissue; stem cell biology; stem cell therapy; tissue regeneration; tissue repair; wound; wound closure

Project Summary The elderly population is rapidly increasing worldwide and those over 60 years old are expected to comprise 20% of the total population by 2050. These demographic changes will focus healthcare needs on those conditions more prevalent in the elderly. Chronic wounds, such as venous leg ulcers, pressure ulcers and diabetic ulcers are over-represented in the elderly population and even now present a significant healthcare burden. These conditions impact approximately 6.5 million patients annually with a cost to the health care system of over $25B. Rarely occurring in the young, the healing of these chronic wounds is confounded by age-related factors such as reduced blood flow, dermal atrophy, increased inflammation and reduced growth factor responses. The high recurrence rate and failure to respond to current therapies indicates the need for improved regenerative therapeutics that can overcome many of the age-associated defects in the wound healing process. Stem cell therapies represent a compelling means of tissue repair and have demonstrated wound healing and soft tissue regeneration in animal models. However, the intuitive concept that therapeutic stem cells engraft and differentiate at sites of tissue damage is not well supported given the low numbers of cells retained over time at application sites in vivo. This suggests that their mechanisms of action occur through paracrine modalities such as secretion of bioactive vesicles, including exosomes. Hence, exploiting stem cell-derived exosomes as a biologic-derived therapy, rather than delivering transient stem cells to treat chronic wounds, is an enticing approach. Secreted extracellular vesicles (EVs), such as exosomes, are packed with potent pro-repair proteins and RNA cargos that are both cell type- specific, as well as, differentially produced and secreted according to the cellular environment. Based on our compelling preliminary data, this Phase I proof-of-concept study will demonstrate that critical ex vivo environmental cues can tune stem cell-derived EVs to be pro-healing and that pro-healing EVs are a valid chronic wound therapeutic. We will achieve these goals by the following Aims: 1) manipulate the bioreactor environment to generate differential extracellular vesicle packaging, 2) in vitro testing of EV-mediated regenerative activities in fibroblasts, keratinocytes and endothelial cells, and 3) in vivo testing of pro-healing EVs in chronic wound healing models. This Phase I research program is designed to provide critical proof-of-concept data demonstrating manufacturing conditions and wound healing properties of stem cell- derived extracellular vesicles. This potential therapeutic has the unique advantage of harnessing the power of stem cells without the need for utilizing complex cell therapies in vivo.

项目概要 全球老年人口迅速增加，60岁以上老年人口预计将占总人口的20% 到 2050 年，总人口将增加。这些人口变化将使医疗保健需求集中在那些在 老年人。慢性伤口，如腿部静脉性溃疡、压力性溃疡和糖尿病性溃疡，在慢性伤口中所占比例过高。 老年人口甚至现在都构成了巨大的医疗负担。这些条件影响大约 6.5 每年 10 万名患者，医疗保健系统的费用超过 25B 美元。年轻人中很少发生，治愈 这些慢性伤口受到与年龄相关的因素的影响，例如血流量减少、真皮萎缩、皮肤老化等。 炎症和生长因子反应减少。复发率高且对当前治疗无效 表明需要改进的再生疗法来克服许多与年龄相关的缺陷 伤口愈合过程。干细胞疗法代表了一种令人信服的组织修复方法，并已证明伤口 动物模型中的愈合和软组织再生。然而，治疗性干细胞移植的直观概念 由于随着时间的推移保留的细胞数量较少，因此在组织损伤部位的分化并没有得到很好的支持。 体内应用部位。这表明它们的作用机制是通过旁分泌方式发生的，例如 分泌生物活性囊泡，包括外泌体。因此，利用干细胞衍生的外泌体作为生物衍生的外泌体 治疗，而不是提供暂时的干细胞来治疗慢性伤口，是一种诱人的方法。分泌细胞外 囊泡 (EV)，例如外泌体，充满了有效的促修复蛋白和 RNA 货物，它们都是细胞类型 特定的，以及根据细胞环境差异产生和分泌的。基于我们令人信服的 根据初步数据，这一第一阶段概念验证研究将证明关键的离体环境线索可以调节 干细胞衍生的 EV 具有促进愈合作用，并且促进愈合的 EV 是一种有效的慢性伤口治疗剂。我们将实现 这些目标通过以下目标实现：1）操纵生物反应器环境以产生差异化的细胞外囊泡 包装，2) EV 介导的成纤维细胞、角质形成细胞和内皮细胞再生活性的体外测试，以及 3）慢性伤口愈合模型中促愈合EV的体内测试。该第一阶段研究计划旨在 提供关键的概念验证数据，证明干细胞的制造条件和伤口愈合特性 衍生的细胞外囊泡。这种潜在的治疗方法具有利用干细胞力量的独特优势 无需在体内利用复杂的细胞疗法。