Leveraging immune-fibroblast interactions for biomaterial induced skin regeneration

利用免疫成纤维细胞相互作用进行生物材料诱导的皮肤再生

• 批准号: 10693831
• 负责人: PHILIP SCUMPIA
• 金额: $ 52.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693831
• 关键词: Adipocytes; Adipose tissue; Adult; Animals; Antigens; Back; Biocompatible Materials; Bioinformatics; Biology; Biomedical Engineering; Cells; Cicatrix; Clinical; Data; Deposition; Development; Elements; Embryo; Engineering; Extracellular Matrix; Fibroblasts; Fibrosis; Flow Cytometry; Foreign Bodies; Foreign-Body Reaction; Formulation; Future; Gel; Gene Expression; Genetic; Grant; Growth; Growth Factor; Hair; Hair follicle structure; Histology; Human; Hydrogels; Immune; Immune signaling; Immunology; Inflammatory Response; Integrin Binding; Interleukins; Knowledge; Ligands; Lymphocyte; Macrophage; Mammals; Mesenchymal; Molecular; Mus; Natural regeneration; Outcome; Pathway interactions; Peptides; Population; Porosity; Prevention; Profibrotic signal; Property; Proteomics; Publications; Receptor Gene; Regenerative response; Research; Resolution; Role; Science; Series; Signal Pathway; Signal Transduction; Skin; Speed; Sweat Glands; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Translating; Wound models; adaptive immune response; adaptive immunity; crosslink; design; enantiomer; functional gain; gain of function; gene regulatory network; hair regeneration; healing; immunoregulation; improved; in vitro Assay; in vivo; in vivo Model; innovation; loss of function; network models; next generation; non-genetic; novel; novel strategies; overexpression; particle; phenotypic biomarker; regenerative; regenerative approach; repaired; response; single-cell RNA sequencing; skin regeneration; skin wound; small molecule inhibitor; stem cells; tissue repair; transcriptomics; wound; wound closure; wound healing; wound treatment

PROJECT SUMMARY Regeneration of native skin elements – hair follicles, sweat glands and adipose tissue, is a highly thought after outcome of wound healing. While, in principle, very large skin wounds in adult mice can spontaneously regenerate new hair follicles and new adipocytes, commonly studied small wounds in mice and clinical wounds in humans heal with a far less desirable fibrotic scarring. If and how adult skin wounds can be directed to replace the natural tendency for healing with a scar with regeneration of native skin elements remains unknown. This application is inspired by a serendipitous discovery that adding an antigen to our novel biomaterial, the Microporous Annealed Particle (MAP) hydrogel, can induce regeneration of new hair follicles when added into normally fibrotic small mouse skin wounds. This immunomodulatory MAP gel provides wound-resident immune cells with the molecular triggers that elicit an adaptive immune response to enhance macrophage responses. Further, our studies on naturally regenerating very large skin wound model show that macrophage-fibroblast interactions are essential for stimulating new hair follicle regeneration. Through an integrated bioengineering, bioinformatic and experimental approach, this application will focus on testing our new hypothesis that by engineering MAP gels to have specific immune triggers, interactions between T-cells, macrophages, and fibroblasts in the wound can transform normally profibrotic healing response into highly desirable regenerative response. The first aim of the proposed research is to mechanistically establish the lymphocyte and macrophage subsets and the molecular signaling pathways required for MAP formulations we have created to elicit hair follicle regeneration. This will be achieved using bioinformatic analyses of transcriptomics, proteomic, and functional profiling at single-cell resolution. confirmed with in vivo loss of function/ transgenic mouse studies lacking key immune pathways or cells MAP gels. The second aim is to engineer new types of immunomodulatory MAP gels designed to maximally induce T-cells and macrophage pro-regenerative signals while minimizing pro-fibrotic signals using a high-throughput in vitro assay. The third aim is to determine how MAP gel-induced immune signals enhance lineage plasticity of wound fibroblasts that is prerequisite for new hair regeneration. This will be achieved via an advanced bioinformatic analysis on single-cell transcriptomic data and functional gain- and loss-of-function studies on wound immune cells and fibroblasts. The study premise is based on newly accepted-for-publication and extensive preliminary data. The proposed studies are significant because they will establish new immune cell-driven mechanism for enhancing fibroblast plasticity and activating embryonic-like regeneration of native skin elements in adult wounds. The proposed studies are innovative because they will establish new types of immune-modulating biomaterials, and new paradigm of biomaterial-triggered regenerative response in adult tissues. In the future, the results of this study will drive the development of next-generation immune-modulating wound biomaterials for potential clinical use.

项目摘要 天然皮肤元素的再生 - 毛囊，汗腺和脂肪组织，是一个高度思考的 伤口愈合的结果后。而原则上，成年小鼠的皮肤伤口很大可以赞助 再生新的毛发和新的脂肪细胞，通常在小鼠和临床风中研究小风 在人类中，纤维化疤痕差得多。是否以及如何指示成人皮肤伤口更换 疤痕随着天然皮肤元素的再生而愈合的自然趋势仍然未知。 该应用的灵感来自偶然发现，该发现将抗原添加到我们的新型生物材料，即 微孔退火颗粒（MAP）水凝胶，将新毛囊的再生添加到 通常，纤维化小鼠皮肤伤口。这种免疫调节图凝胶可提供伤口驻留的免疫 带有分子触发的细胞会引起适应性免疫响应以增强巨噬细胞反应。 此外，我们对自然再生非常大的皮肤伤口模型的研究表明，巨噬细胞纤维细胞 相互作用对于刺激新的叶叶再生至关重要。 通过集成的生物工程，生物学和实验方法，该应用将 专注于测试我们的新假设，即通过工程地图凝胶具有特定的免疫触发器，相互作用 在伤口中的T细胞，巨噬细胞和成纤维细胞之间可以改变正常的纤维化愈合反应 进入高度理想的再生反应。拟议研究的第一个目的是机械化建立 淋巴细胞和巨噬细胞子集以及MAP公式所需的分子信号通路 我们创建的是为了引起头发再生。这将是使用生物信息学分析来实现的 单细胞分辨率下的转录组学，蛋白质组学和功能分析。通过体内功能丧失确认/ 缺乏关键免疫途径或细胞映射凝胶的转基因小鼠研究。第二个目的是设计新的 旨在最大程度诱导T细胞和巨噬细胞促进再生的免疫调节图凝胶的类型 信号同时使用高通量的体外测定最小化促纤维化信号。第三个目的是确定 地图凝胶诱导的免疫信号如何增强伤口成纤维细胞的谱系可塑性，这是先决条件的 新的头发修订。这将通过单细胞转录组的高级生物信息学分析来实现 对伤口免疫细胞和成纤维细胞的数据和功能增益和功能丧失研究。 该研究前提是基于新公认的出版物和广泛的初步数据。提议 研究很重要，因为它们将建立新的免疫细胞驱动机制来增强成纤维细胞 成人伤口中天然皮肤元素的塑性和激活的胚胎样再生。提议 研究之所以创新，是因为它们将建立新型的免疫调节生物材料和新型 成人组织中生物材料触发的再生反应的范例。将来，这项研究的结果 将推动下一代免疫调节伤口生物材料的发展，以进行潜在的临床用途。

项目成果

Improved Humoral Immunity and Protection against Influenza Virus Infection with a 3d Porous Biomaterial Vaccine.

• DOI: 10.1002/advs.202302248
• 发表时间: 2023-11
• 期刊: ADVANCED SCIENCE
• 影响因子: 15.1
• 作者: Miwa, Hiromi;Antao, Olivia Q.;Kelly-Scumpia, Kindra M.;Baghdasarian, Sevana;Mayer, Daniel P.;Shang, Lily;Sanchez, Gina M.;Archang, Maani M.;Scumpia, Philip O.;Weinstein, Jason S.;Di Carlo, Dino
• 通讯作者: Di Carlo, Dino

Injectable Microporous Annealed Crescent-Shaped (MAC) Particle Hydrogel Scaffold for Enhanced Cell Infiltration.

可注射微孔退火新月形 (MAC) 颗粒水凝胶支架，用于增强细胞浸润。

• DOI: 10.1002/adhm.202302477
• 发表时间: 2023
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Tang,Rui-Chian;Shang,Lily;Scumpia,PhilipO;DiCarlo,Dino
• 通讯作者: DiCarlo,Dino