Wound healing mechanisms by distinct oral fibroblast population

不同口腔成纤维细胞群的伤口愈合机制

• 批准号: 10586017
• 负责人: KANG I KO
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586017
• 关键词: Ablation; Acceleration; Anti-Inflammatory Agents; Area; Autologous Transplantation; Biological Assay; Biology; Cell Communication; Cell division; Cells; Chronic; Cicatrix; Clinical; Coculture Techniques; Connective Tissue; Data; Dermis; Development; Diphtheria; Disease; Economic Burden; Exhibits; Failure; Fibroblasts; Functional disorder; Genetic; Gingiva; Goals; Heterogeneity; Histologic; Human; Immune; Immune response; Impaired wound healing; In Situ; In Vitro; Inflammation; Inflammatory; Joints; Knowledge; Leukocytes; Link; Mediating; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Modeling; Molecular; Mouth Diseases; Mus; Natural regeneration; Nature; Oral; Oral cavity; Outcome; Pathogenesis; Pathology; Pathway interactions; Periodontal Diseases; Play; Population; Process; Proliferating; Property; Proteins; Resolution; Rheumatoid Arthritis; Role; Site; Skin; Source; Synovial Membrane; System; Testing; Tissues; Translating; Transplantation; Validation; Work; Wound models; chronic wound; cranium; cytokine; gain of function; healing; human disease; immunoregulation; improved; in vivo; insight; interest; joint inflammation; loss of function; novel; oral fibroblast; polarized cell; postnatal; progenitor; public health relevance; response; segregation; single cell sequencing; single-cell RNA sequencing; skin fibrosis; stem cell therapy; stem cells; stem-like cell; tissue regeneration; tool; transcriptomics; translational impact; tumor; wound; wound closure; wound healing

PROJECT SUMMARY Oral wound healing is characterized by rapid resolution of inflammation and minimal scarring. As it is a prime example of ideal tissue regeneration, there is a growing interdisciplinary interest in studying the mechanisms of oral wound healing. Fibroblasts play an essential role in this process and are also implicated in oral diseases responsible for the global economic burden amounting to 442 billion dollars. Recent advances in connective tissue biology have elucidated the importance of fibroblast heterogeneity in the pathogenesis of dermal fibrosis and rheumatoid arthritis. However, the in vivo heterogeneity of oral fibroblasts and thereby a functional significance of select fibroblast population during oral wound healing is poorly understood. Here, we found that postnatal Prx1+ cells are found in mouse gingiva and express common markers of fibroblasts. Preliminary data demonstrate that wounds enriched in Prx1+ cells heal faster with minimal inflammation compared to wounds that lack these cells. Therefore we will test the overall hypothesis that Prx1+ cells represent distinct oral fibroblast progenitors and are responsible for rapid tissue regeneration through a mechanism that involves resolution of inflammation. Aim 1 will utilize an auto-transplantation approach and test the hypothesis that transplanted Prx1+ cells contribute to accelerated oral wound healing by functioning as mesenchymal progenitors in vivo. Aim 2 will investigate if lineage specific ablation of Prx1+ cells delays wound healing by causing the failure to quickly resolve inflammation in vivo, and explore mechanisms of immune cell modulation by Prx1+ fibroblasts in co- culture assays. In Aim 3, we will perform single cell RNA-sequencing to compare transcriptomic profiles of mesenchymal and leukocyte cell subtypes in Prx1+ enriched oral wounds to those in Prx1-poor wounds in mice. Moreover, we will test if Prx1-equivalent cells are found in human gingiva by single cell sequencing and in situ validation. Upon completion, the proposed studies are expected to reveal Prx1+ cells as pro-healing oral fibroblast subset and provide a significant translational value by implicating the clinical utilization of connective tissues or ex vivo stem cell therapy that are enriched with Prx1+ fibroblasts.

项目摘要 口腔伤口愈合的特征在于炎症的快速消退和最小的瘢痕形成。因为它是一个质数 作为理想的组织再生的例子，在研究组织再生的机制方面有越来越多的跨学科兴趣。 口腔伤口愈合成纤维细胞在这一过程中发挥着重要作用，也与口腔疾病有关 全球经济负担高达4420亿美元。连接词研究进展 组织生物学已经阐明了成纤维细胞异质性在真皮纤维化发病机制中的重要性 和类风湿性关节炎。然而，口腔成纤维细胞的体内异质性以及由此产生的功能性 在口腔伤口愈合过程中选择成纤维细胞群意义知之甚少。在这里，我们发现， 出生后的Prx 1+细胞在小鼠牙龈中发现，并表达成纤维细胞的共同标志物。初步数据 证明与伤口相比，富含Prx 1+细胞的伤口愈合更快，炎症最小 缺乏这些细胞的人。因此，我们将检验Prx 1+细胞代表不同口腔成纤维细胞的总体假设 祖细胞，并负责通过一种机制，涉及解决快速组织再生， 炎症目的1将利用自体移植的方法和测试的假设，移植 Prx 1+细胞通过在体内充当间充质祖细胞促进口腔伤口愈合。目的 2将研究Prx 1+细胞的谱系特异性消融是否通过导致快速愈合失败而延迟伤口愈合。 解决体内炎症，并探索Prx 1+成纤维细胞在共- 培养测定。在目标3中，我们将进行单细胞RNA测序，以比较 间充质细胞和白细胞亚型在Prx 1+丰富的口腔伤口中与在Prx 1缺乏的伤口中的那些相比。 此外，我们将通过单细胞测序和原位检测Prx 1等效细胞是否存在于人类牙龈中 验证。完成后，预计拟议的研究将揭示Prx 1+细胞作为促进愈合的口腔 成纤维细胞亚群，并提供了一个显着的翻译价值，涉及临床利用结缔组织 组织或离体干细胞疗法中富集Prx 1+成纤维细胞。