Induction of fat regeneration in skin wounds by hair follicle signaling

通过毛囊信号诱导皮肤伤口脂肪再生

基本信息

批准号：
9323294
负责人：
Maksim V Plikus
金额：
$ 39.99万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-18 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323294
关键词：
Acne Adipocytes Adipose tissue Adult Aging-Related Process Amphibia Appearance Architecture Atrophic Back Cells Characteristics Cicatrix Competence Coupled Cues Cutaneous DNA Methylation Development Disease Embryo Embryonic Development Environment Epidermis Epigenetic Process Event Excision Fatty acid glycerol esters Fibrinogen Genetic Goals Growth Factor Hair Hair follicle structure Homeostasis Human Inflammatory Injury Instruction Keloid Lead Lipids Lipoatrophy Lipodystrophy Mammals Mental Depression Modeling Morbidity - disease rate Mus Myofibroblast Natural regeneration Nucleic Acid Regulatory Sequences Operative Surgical Procedures Organ Pathway interactions Physiological Physiology Process Proteins Recruitment Activity Regenerative Medicine Regenerative response Regulator Genes Research Role Signal Pathway Signal Transduction Site Skin Skin injury Skin wound Stem cells Testing Time Tissues Work Wound Healing base cytokine healing histone modification in vivo innovation lipid biosynthesis mouse model novel novel therapeutics permissiveness progenitor programs promoter public health relevance regenerative repaired response skin regeneration soft tissue tissue trauma tumor wound

项目摘要

DESCRIPTION (provided by applicant): The process of wound healing is critical to restoring integrity and homeostasis after significant skin injuries. Although embryonic skin can heal by regenerating itself completely, adult skin is only capable of partial repair, altering the skin's integrity at the site of injury. Cutaneous adipose tissue is thought to poorly regenerate during wound healing, and because scars lack adipose tissue, they often assume debilitating hypertrophic, keloid, or atrophic characteristics. Lack of adipose regeneration is also a major cause of long term morbidity following extensive soft tissue trauma or surgical resection, such as tumor removal. We have identified the previously unknown phenomenon of adipose tissue neogenesis in large cutaneous wounds that occurs under the instructive signaling of de novo hair follicles. This application will focus on identifying permissive epigenetic changes and novel signaling cues generated by neogenic hair follicles in the wound environment that guide de novo regeneration of cutaneous fat. Our recent lineage analyses show that instead of recruiting already committed adipose precursors from the wound's edges and simply stimulating their differentiation to lipid-laden adipocytes, neogenic hair follicles guide de novo adipogenic cell fae acquisition by otherwise non-adipogenic wound myofibroblasts. Our studies demonstrate that acquisition of adipose identity by wound myofibroblasts critically depends on reactivation of Zfp423 signaling, the lead adipogenic commitment pathway in embryogenesis. Our studies also implicate hair follicle-derived BMP signaling inputs as the critical regulators of adipogenic fate commitment in wound scar tissue. The first goal of the proposed research is to establish the epigenetic changes in wound myofibroblasts that permit their adipogenic competence. Specifically, we will focus on epigenetic changes in Zfp423, the developmental master-regulator gene characterized by an exceptionally CpG-dense promoter. The second goal is to establish the mechanism by which BMP signaling events generated in the wound around neogenic hair follicles promote de novo fat formation. Ultimately, we want to be able to replicate these signaling events in hairless wounds for the purposes of inducing cutaneous fat regeneration. We anticipate that the proposed studies will help uncover new mechanisms that allow adult skin to expand lineage plasticity during wound repair. They could also have applicability to the development of new scarless wound healing strategies.

描述（由申请人提供）：伤口愈合过程对于严重皮肤损伤后恢复完整性和体内平衡至关重要。虽然胚胎皮肤可以通过完全再生来愈合，但成人皮肤只能部分修复，从而改变受伤部位皮肤的完整性。皮肤脂肪组织被认为在伤口愈合过程中再生能力较差，并且由于疤痕缺乏脂肪组织，它们通常呈现使人衰弱的肥厚性、疤痕疙瘩或萎缩性特征。脂肪再生缺乏也是大面积软组织创伤或手术切除（例如肿瘤切除）后长期发病的主要原因。我们已经发现了以前未知的大皮肤伤口中脂肪组织新生的现象，这种现象是在新生毛囊的指导性信号传导下发生的。该应用将重点识别伤口环境中新生毛囊产生的允许的表观遗传变化和新的信号线索，引导皮肤脂肪的从头再生。我们最近的谱系分析表明，新生毛囊不是从伤口边缘招募已经形成的脂肪前体并简单地刺激它们分化为富含脂质的脂肪细胞，而是引导非脂肪形成伤口肌成纤维细胞从头获取脂肪形成细胞。我们的研究表明，伤口肌成纤维细胞获得脂肪身份关键取决于 Zfp423 信号传导的重新激活，Zfp423 信号传导是胚胎发生中主要的脂肪形成途径。我们的研究还表明，毛囊衍生的 BMP 信号输入是伤口疤痕组织中脂肪形成命运承诺的关键调节因子。拟议研究的第一个目标是确定伤口肌成纤维细胞的表观遗传变化，从而使其具有成脂能力。具体来说，我们将重点关注 Zfp423 的表观遗传变化，Zfp423 是一种发育主调控基因，其特征是具有异常 CpG 密集的启动子。第二个目标是建立新生毛囊周围伤口中产生的 BMP 信号事件促进脂肪从头形成的机制。最终，我们希望能够在无毛伤口中复制这些信号事件，以诱导皮肤脂肪再生。我们预计拟议的研究将有助于揭示新的机制，使成人皮肤在伤口修复过程中扩大谱系可塑性。它们还可以适用于开发新的无疤痕伤口愈合策略。