Understanding immune-epithelial interactions during wound repair in live mammals

了解活体哺乳动物伤口修复过程中免疫上皮相互作用

• 批准号: 10718332
• 负责人: Sangbum Park
• 金额: $ 51.16万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718332
• 关键词: Address; Affect; Aging; Antigens; Area; Behavior; Behavioral; Cell Communication; Cells; Cellular biology; Communication; Data; Defect; Development; Diabetic Foot Ulcer; Disease; Disease Progression; Epidermis; Epithelial Cells; Epithelium; Foundations; Goals; Hair follicle structure; Healthcare; Homeostasis; Immune; Immune system; Immunity; Immunologics; Infection; Injury; Knowledge; Langerhans cell; Macrophage; Malignant Neoplasms; Mammals; Mus; Natural regeneration; Nature; Persons; Play; Population; Process; Recovery; Regenerative Medicine; Research; Role; Sentinel; Signal Transduction; Site; Skin; Skin injury; Skin repair; Stratified Epithelium; Surface; Testing; Therapeutic; Tissues; Work; acute wound; burden of illness; care burden; cell behavior; cell motility; cell type; chemokine; chronic wound; diabetic; diabetic ulcer; effective therapy; epithelial repair; epithelial wound; genetic approach; imaging system; immune function; in vivo; in vivo imaging system; injured; innovation; insight; intravital imaging; lymphatic vessel; migration; monocyte; neutrophil; novel; novel therapeutic intervention; obese person; prevent; recruit; repaired; single cell analysis; single-cell RNA sequencing; skin barrier; skin regeneration; skin wound; stem cells; surveillance network; therapeutic development; therapeutic target; tissue repair; transcriptomics; uptake; wound; wound healing

SUMMARY Treatments for chronic wounds incur a substantial healthcare burden, but are largely ineffective. In addition, prolonged skin barrier defects in chronic wounds can cause infection or develop into even more severe diseases such as cancer. Therefore, there is a critical need to understand the mechanisms involved in the recovery of the skin barrier during wound repair to develop effective treatments and prevent progression of disease. The skin epidermis (i.e., outermost layers of skin) serves as a barrier to our body and is composed of different types of cells: epithelial cells in the stratified epithelium of the epidermis act as a physical barrier, and a network of skin- resident immune cells, Langerhans cells (LCs), act as an immunological barrier. LCs surveil the skin surface as immune sentinels and can induce both immunity and tolerance. Although immunological functions of LCs have been thoroughly investigated, and other immune cells (e.g., macrophages and neutrophils) are known to play a role in skin regeneration, little is known about the role of LCs in skin regeneration. Our long-term goal is to understand the fundamental mechanisms that regulate skin regeneration and repair. The objective of this proposal is to gain a deeper understanding of LC-epithelial cell interactions that restore an intact skin barrier in live mammals. This will inform and advance new therapeutic strategies for acute and chronic wound repair. We will test how LCs behave with epithelial cells during re-epithelization and rebuild a damaged network de novo in live mice using our intravital imaging system. Upon completion of this project, we will understand how LCs, in conjunction with neighboring epithelial cells, contribute to skin regeneration during wound repair. Our work suggests that LC and epithelial cells communicate with each other to maintain epidermal homeostasis. Remarkably, activated LCs near the wound show distinct transcriptomic signatures that can regulate the behaviors of epithelial cells. We recently observed that activated LCs near the wound migrate with epithelial cells during re-epithelization. These LCs eventually migrate to the wounded area and contribute to the recovery of the LC network with monocyte-derived LCs. This finding led us to hypothesize that communication between activated LCs and epithelial cells in the injured epidermis is essential for re-epithelization and recovery of the LC network. To address this hypothesis, we will determine how LCs regulate epithelial behaviors that impact re-epithelization. Next, we will test how the interactions between LCs and epithelial cells affect the mobility and surveillance of LCs during re-epithelization. Finally, we will elucidate how LCs of different origins cooperatively reestablish new LC networks within the wounded area to restore an intact immune barrier of the skin. The insights from our proposed work will provide the foundations to harness the power of LCs in regenerative medicine for treating chronic wounds.

总结 慢性伤口的治疗会带来很大的医疗负担，但在很大程度上是无效的。此外，本发明还提供了一种方法， 慢性伤口中皮肤屏障的长期缺陷会导致感染或发展成更严重的疾病 例如癌症。因此，迫切需要了解恢复中涉及的机制， 在伤口修复过程中的皮肤屏障，以开发有效的治疗和防止疾病的进展。皮肤 表皮（即，皮肤的最外层）作为我们身体的屏障，由不同类型的 细胞：表皮的复层上皮中的上皮细胞充当物理屏障，并且皮肤- 常驻免疫细胞，朗格汉斯细胞（LC），充当免疫屏障。LC监测皮肤表面， 免疫哨兵，可诱导免疫和耐受。虽然LC的免疫功能 已经被彻底研究，而其他免疫细胞（例如，巨噬细胞和嗜中性粒细胞）已知发挥 尽管LCs在皮肤再生中的作用是已知的，但关于LCs在皮肤再生中的作用知之甚少。我们的长期目标是 了解调节皮肤再生和修复的基本机制。的目的 一个建议是获得更深入的了解LC-上皮细胞的相互作用，恢复一个完整的皮肤屏障， 活的哺乳动物这将为急性和慢性伤口修复提供信息并推进新的治疗策略。我们 将测试LC在再上皮化过程中如何与上皮细胞一起表现，并在2015年重新重建受损的网络。 用我们的活体成像系统对小鼠进行活体成像。在这个项目完成后，我们将了解如何LC，在 与邻近的上皮细胞结合，有助于伤口修复期间的皮肤再生。我们的工作 表明LC和上皮细胞相互沟通以维持表皮的稳态。 值得注意的是，伤口附近激活的LC显示出不同的转录组学特征，可以调节伤口周围的细胞。 上皮细胞的行为。我们最近观察到伤口附近激活的LC随上皮细胞迁移 在上皮再生过程中。这些LC最终迁移到受伤区域，并有助于恢复 具有单核细胞衍生LC的LC网络。这一发现使我们假设， 损伤表皮中的LC和上皮细胞对于LC网络的再上皮化和恢复至关重要。 为了解决这一假设，我们将确定LC如何调节上皮细胞的行为，影响再上皮化。 接下来，我们将测试LC和上皮细胞之间的相互作用如何影响细胞的流动性和监视。 上皮再生过程中的LC。最后，我们将阐明不同起源的LC如何合作重建新的 LC网络在受伤区域内恢复皮肤的完整免疫屏障。我们的洞察力 拟议的工作将为利用LC在再生医学中的力量治疗 慢性创伤