Hair Follicle Neogenesis in Response to Wounding

受伤后的毛囊新生

• 批准号: 7777040
• 负责人: GEORGE COTSARELIS
• 金额: $ 15.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-12 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777040
• 关键词: Acute; Adipose tissue; Aging; Alopecia; Area; Back; Biology; Cells; Chronic; Cicatrix; Collaborations; Contracture; Cutaneous; Degenerative Disorder; Dermis; Development; Dissection; Epidermis; Epithelial; Event; Excision; Gene Expression; Germ; Goals; Growth Factor; Hair; Hair follicle structure; Healed; Health system; Human; Immune system; Immunologist; Immunology; Impaired wound healing; Knowledge; Laboratories; Lead; Medical; Medicine; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Pathology; Reporting; Research; Research Project Grants; Role; Sebaceous Glands; Skin; Source; Stem cells; Structure; Sweat Glands; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thick; Transgenic Mice; Wound Healing; base; fibroblast growth factor 9; healing; novel strategies; parent grant; regenerative; response; skin regeneration

DESCRIPTION (provided by applicant): Typically, skin heals with a scar without regenerating its previous normal structure that includes hair follicles and sweat glands. Scarring causes contractures and morbidity. Impaired healing without skin regeneration leads to chronic wounds. Understanding why skin does not regenerate after wounding would lead to new approaches for treating both acute and chronic wounds, which are major medical problems facing our health system. Hair follicle neogenesis (HFN) after wounding serves as a paradigm for mammalian skin regeneration. We found that following full-thickness excision of mouse skin on the back, hair follicles formed de novo in the healed wound. The skin in the area of hair follicle formation appeared normal without a scar and with the presence of new hair follicles, sebaceous glands and adipose tissue. Based on prior reports, it is possible that similar, albeit much less robust levels of regeneration also occur in humans. The goal of the parent grant is to characterize the cellular and molecular events associated with HFN following wounding. We have studied this remarkable regenerative capacity of the skin using gene expression arrays. Fibroblast growth factor 9 (Fgf9) was upregulated in the epidermis after reepithelialization, but prior to hair germ formation. Using a wounding model for hair follicle neogenesis, we showed that inhibiting Fgf9 resulted in a statistically significant decrease in new hair follicle formation. Over expression of Fgf9 in inducible K14/Fgf9 transgenic mice resulted in marked increases in hair follicle formation during wound healing. Remarkably, we discovered that gamma/delta T cells are the major source of Fgf9 in the epidermis. This finding established a potential connection between skin regeneration and the immune system, and initiated the proposed collaboration between Dr. George Cotsarelis, an expert in epithelial stem cells and PI of the parent grant, and Dr. Avinash Bhandoola, an expert in T cell immunology in the Department of Pathology and Laboratory Medicine at Penn. Epidermal gamma/delta T cells were previously implicated in wound repair in the mouse, but their possible role in hair follicle regeneration has not been studied. Intriguingly, these cells are absent in human epidermis, although they are present in the dermis. Could this explain why human skin regeneration is so severely limited compared to the mouse? We propose to: 1. Determine if hair follicle regeneration occurs in mice lacking gamma/delta T cells. 2. Delete Fgf9 in T cells using Lck-Cre/floxedFgf9 mice to test the effect of loss of Fgf9 on hair follicle neogenesis following wounding, 3. Define differences between different types of gamma/delta T cells in their ability to make Fgf9 and induce hair follicle neogenesis, 4. Determine differences between mouse and human gamma/delta T cells with respect to their wound healing response (ability to produce Fgf9 and other growth factors). These studies lend themselves to interdisciplinary efforts between cutaneous biologists and immunologists that will push research of skin regeneration into new directions. The preliminary results generated here would form a nidus for a larger interactive research project on the role of T cell subsets in skin regeneration and development. Dr. Avinash Bhandoola's expertise in T cell development combined with Dr. Cotsarelis's knowledge of epithelial stem cells and hair biology will provide a strong collaborative effort for the dissection of the role(s) of the immune system in skin regeneration. Ultimately, the findings could impact on medical problems related to wound healing, scar formation, aging and other degenerative conditions.

描述（由申请人提供）：通常情况下，皮肤愈合后会留下疤痕，而不会再生以前的正常结构，包括毛囊和汗腺。疤痕导致挛缩和发病。没有皮肤再生的愈合受损导致慢性伤口。了解为什么皮肤在受伤后不能再生，将导致治疗急性和慢性伤口的新方法，这是我们卫生系统面临的主要医疗问题。创伤后的毛囊新生（HFN）是哺乳动物皮肤再生的范例。我们发现，在小鼠背部皮肤全层切除后，毛囊在愈合的伤口中重新形成。毛囊形成区域的皮肤看起来正常，没有疤痕，并且存在新的毛囊、皮脂腺和脂肪组织。根据先前的报道，人类也可能出现类似的再生，尽管再生水平要低得多。父母补助金的目标是表征受伤后与HFN相关的细胞和分子事件。我们使用基因表达阵列研究了皮肤的这种非凡的再生能力。成纤维细胞生长因子9（Fgf 9）在表皮再上皮化后，但之前的毛胚形成上调。使用毛囊新生的创伤模型，我们表明抑制Fgf 9导致新毛囊形成的统计学显著减少。诱导型K14/Fgf 9转基因小鼠中Fgf 9的过表达导致伤口愈合期间毛囊形成的显著增加。值得注意的是，我们发现γ/δ T细胞是表皮中Fgf 9的主要来源。这一发现建立了皮肤再生和免疫系统之间的潜在联系，并启动了上皮干细胞专家和父母资助PI的乔治Cotsarelis博士与宾夕法尼亚大学病理学和实验室医学系T细胞免疫学专家Avinash Bavinola博士之间的拟议合作。表皮γ/δ T细胞先前与小鼠的伤口修复有关，但尚未研究它们在毛囊再生中的可能作用。有趣的是，这些细胞在人类表皮中不存在，尽管它们存在于真皮中。这能解释为什么人类皮肤再生与小鼠相比如此有限吗？我们建议：1.确定缺乏γ/δ T细胞的小鼠是否发生毛囊再生。2.使用Lck-Cre/EkedFgf 9小鼠在T细胞中缺失Fgf 9以测试Fgf 9的缺失对创伤后毛囊新生的影响，3.定义不同类型的γ/δ T细胞在制造Fgf 9和诱导毛囊新生的能力方面的差异，4.确定小鼠和人γ/δ T细胞在伤口愈合反应（产生Fgf 9和其他生长因子的能力）方面的差异。这些研究有助于皮肤生物学家和免疫学家之间的跨学科努力，将皮肤再生的研究推向新的方向。这里产生的初步结果将形成一个更大的互动研究项目的T细胞亚群在皮肤再生和发育中的作用的病灶。Avinash Baviola博士在T细胞发育方面的专业知识与Cotsarelis博士在上皮干细胞和毛发生物学方面的知识相结合，将为解剖免疫系统在皮肤再生中的作用提供强有力的合作。最终，这些发现可能会影响与伤口愈合，疤痕形成，衰老和其他退行性疾病有关的医疗问题。