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的皮肤损伤后的完整性和体内平衡至关重要。尽管胚胎皮肤可以通过完全再生来愈合，但成年皮肤只能部分修复，从而改变皮肤在损伤部位的完整性。皮肤脂肪组织被认为在伤口愈合过程中会再生不良，并且由于疤痕缺乏脂肪组织，因此他们经常假设肥厚，乳突或萎缩特征会令人衰弱。在广泛的软组织创伤或手术切除（例如去除肿瘤）之后，缺乏脂肪再生也是长期发病率的主要原因。 我们已经确定了以前未知的现象在从头毛囊的启发性信号下发生的大型皮肤伤口中发生的脂肪组织新发生。该应用将着重于识别新生毛囊在伤口环境中产生的允许性表观遗传变化和新的信号提示，这些毛囊引导了皮肤脂肪的从头再生。 我们最近的谱系分析表明，新卵泡指导了从伤口的边缘招募已经从伤口的边缘订立脂肪前体，而只是刺激其分化为富含脂质的脂肪细胞的分化，而是指导了从脂肪性的细胞FAE fae Fae FAE，其他非肌纤维伤口受伤性伤口肌纤维肌瘤。我们的研究表明，通过伤口的肌纤维细胞对脂肪身份的获取至关重要取决于ZFP423信号的重新激活，ZFP423信号是胚胎发生中的铅脂肪生成承诺途径。我们的研究还暗示了毛囊来源的BMP信号输入是伤口疤痕组织中成型命运承诺的关键调节因子。 拟议的研究的第一个目标是建立允许其成脂能力的伤口肌纤维细胞的表观遗传变化。具体而言，我们将重点介绍ZFP423的表观遗传变化，ZFP423是以CPG密集的启动子为特征的发育主调控基因。第二个目标是建立在新毛囊周围伤口中生成BMP信号事件的机制，从而促进从头脂肪形成。最终，我们希望能够在无毛伤口中复制这些信号事件，以引起皮肤脂肪再生。我们预计拟议的研究将有助于发现新机制，使成人皮肤在伤口修复过程中扩大谱系可塑性。他们还可以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.

• 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

Regenerative metamorphosis in hairs and feathers: follicle as a programmable biological printer.

• DOI: 10.1111/exd.12627
• 发表时间: 2015-04
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Oh JW;Lin SJ;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