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

• 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
• 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

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）：伤口愈合的过程对于在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，改变皮肤损伤部位的完整性。皮肤脂肪组织被认为在伤口愈合过程中很难再生，并且由于疤痕缺乏脂肪组织，它们通常呈现衰弱性肥厚、瘢痕疙瘩或萎缩特征。缺乏脂肪再生也是广泛软组织创伤或手术切除（如肿瘤切除）后长期发病的主要原因。我们已经确定了在新生毛囊的指导信号下，在大皮肤伤口中发生的脂肪组织新生的以前未知的现象。该应用将侧重于识别伤口环境中由新生毛囊产生的允许的表观遗传变化和新的信号信号，这些变化和信号信号可引导皮肤脂肪的新生再生。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，简单地刺激它们向富含脂质的脂肪细胞分化，而是引导非脂肪形成的伤口肌成纤维细胞重新获得脂肪细胞。我们的研究表明，伤口肌成纤维细胞获得脂肪身份的关键取决于Zfp423信号的再激活，Zfp423信号是胚胎发生中主要的脂肪生成承诺途径。我们的研究还表明毛囊来源的BMP信号输入是伤口疤痕组织中脂肪生成命运承诺的关键调节因子。该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，使其具有成脂能力。具体来说，我们将关注Zfp423的表观遗传变化，Zfp423是发育主调控基因，其特征是一个异常密集的cpg启动子。第二个目标是建立在新生毛囊周围的伤口中产生的BMP信号事件促进新生脂肪形成的机制。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。我们期望所提出的研究将有助于揭示在伤口修复过程中允许成人皮肤扩展谱系可塑性的新机制。它们也可能适用于开发新的无疤痕伤口愈合策略。