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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

基本信息

批准号：
10278462
负责人：
PHILIP SCUMPIA
金额：
$ 54.65万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10278462
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 Mammals Mesenchymal Molecular Mus Natural regeneration Outcome Pathway interactions Peptides Population Porosity Prevention Property Proteomics Publications Receptor Gene Regenerative response Regulator Genes 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 base crosslink design functional gain hair regeneration healing immunoregulation improved in vitro Assay in vivo in vivo Model innovation loss of function macrophage 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

项目摘要

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.

项目总结