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: 9539966
• 负责人: Maksim V Plikus
• 金额: $ 33.99万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9539966
• 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; 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; progenitor; programs; promoter; public health relevance; recruit; 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恢复严重皮肤损伤后的完整性和动态平衡至关重要。虽然胚胎皮肤可以通过完全再生来愈合，但成年皮肤只能进行部分修复，改变了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差，由于疤痕缺乏脂肪组织，它们通常呈现出衰弱的肥大、瘢痕疙瘩或萎缩的特征。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)后长期发病率的主要原因。我们已经确认了以前未知的大型皮肤创面中脂肪组织新生的现象，它发生在新生毛囊的指导性信号下。这项应用将集中于识别可允许的表观遗传学变化和创面环境中新生毛囊产生的新的信号线索，以引导皮肤脂肪的从头再生。我们最近的谱系分析表明，新生毛囊并不是从伤口边缘招募已经确定的脂肪前体并简单地刺激它们向富含脂肪的脂肪细胞分化，而是通过其他非成脂伤口的肌成纤维细胞引导新生成脂细胞获得FAE。我们的研究表明，创伤肌成纤维细胞获得脂肪身份的关键依赖于Zfp423信号的重新激活，Zfp423信号是胚胎发育中的主要成脂承诺途径。我们的研究还表明，毛囊来源的BMP信号输入是伤口瘢痕组织中成脂命运承诺的关键调节因素。这项拟议研究的第一个目标是建立创面肌成纤维细胞的表观遗传学变化，使其具有成脂能力。具体地说，我们将关注Zfp423的表观遗传学变化，Zfp423是一个发育主控基因，其特征是具有异常密集的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，允许成人皮肤在伤口修复过程中扩大谱系可塑性。它们也可能适用于开发新的无疤痕伤口愈合策略。

项目成果

Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy.

• DOI: 10.1158/0008-5472.can-17-0667
• 发表时间: 2017-11-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Huang WY;Lai SF;Chiu HY;Chang M;Plikus MV;Chan CC;Chen YT;Tsao PN;Yang TL;Lee HS;Chi P;Lin SJ
• 通讯作者: Lin SJ

Principles and mechanisms of regeneration in the mouse model for wound-induced hair follicle neogenesis.

小鼠模型中的原理和机制，用于伤口诱导的毛囊新发生。

• DOI: 10.1002/reg2.38
• 发表时间: 2015-08
• 期刊: Regeneration (Oxford, England)
• 作者: Wang X;Hsi TC;Guerrero-Juarez CF;Pham K;Cho K;McCusker CD;Monuki ES;Cho KW;Gay DL;Plikus MV
• 通讯作者: Plikus MV

A Guide to Studying Human Hair Follicle Cycling In Vivo.

• DOI: 10.1038/jid.2015.354
• 发表时间: 2016-01
• 期刊: The Journal of investigative dermatology
• 作者: Oh JW;Kloepper J;Langan EA;Kim Y;Yeo J;Kim MJ;Hsi TC;Rose C;Yoon GS;Lee SJ;Seykora J;Kim JC;Sung YK;Kim M;Paus R;Plikus MV
• 通讯作者: Plikus MV

Inducing hair follicle neogenesis with secreted proteins enriched in embryonic skin.

• DOI: 10.1016/j.biomaterials.2018.03.003
• 发表时间: 2018-06
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Fan SM;Tsai CF;Yen CM;Lin MH;Wang WH;Chan CC;Chen CL;Phua KKL;Pan SH;Plikus MV;Yu SL;Chen YJ;Lin SJ
• 通讯作者: Lin SJ

MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists.

• DOI: 10.1038/s41467-017-01059-5
• 发表时间: 2017-10-19
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lv C;Li F;Li X;Tian Y;Zhang Y;Sheng X;Song Y;Meng Q;Yuan S;Luan L;Andl T;Feng X;Jiao B;Xu M;Plikus MV;Dai X;Lengner C;Cui W;Ren F;Shuai J;Millar SE;Yu Z
• 通讯作者: Yu Z