Restoring hair follicle stem cell fate and heterogeneity outside their native niche

在其天然生态位之外恢复毛囊干细胞的命运和异质性

• 批准号: 10449490
• 负责人: Matthew Tierney
• 金额: $ 11.17万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449490
• 关键词: Automobile Driving; Back; Behavior; Bioinformatics; Biological Assay; Biological Models; Biology; Cell Communication; Cell Culture Techniques; Cell Differentiation process; Cells; Chromatin; Clinical; Clinical Sciences; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Collaborations; Cues; Data; Data Set; Dermal; Development; Diagnosis; Effectiveness; Elements; Engineered skin; Engineering; Epigenetic Process; Exhibits; Family; Foundations; Generations; Genetic Enhancer Element; Genetic Transcription; Hair follicle structure; Hair shaft structure; Heterogeneity; Human; Integumentary system; Maintenance; Maps; Modeling; Molecular; Morphogenesis; Natural regeneration; Organ; Pathway interactions; Patients; Physiology; Plant Roots; Play; Population Heterogeneity; Process; Production; Recurrence; Research; Role; Sampling; Scientist; Series; Signal Transduction; Skin; Stem cell transplant; Stimulus; Stress; System; Technology; Testing; Therapeutic; Tissues; Translational Research; Transplantation; Tretinoin; Work; adult stem cell; appendage; base; cell behavior; cell type; chromatin immunoprecipitation; clinical center; comparative; efficacy testing; experimental study; functional outcomes; hair follicle disorder; human stem cells; improved; in vivo; insight; loss of function; pre-clinical; receptor; regenerative; response; restoration; self-renewal; skin regeneration; stem cell biology; stem cell fate; stem cell niche; stem cell self renewal; stem cells; therapy design/development; three dimensional structure; tissue regeneration; tongue papilla; transcriptomics; wound; wound healing; wound response

PROJECT SUMMARY Adult stem cells (SCs) reside in defined niches and depend on microenvironmental cues to instruct their behavior. The hair follicle (HF) is an excellent model system to study a rich set of SC-niche interactions as it undergoes stereotypic regenerative cycles. This self-contained mini-organ utilizes high levels of spatial organization and compartmentalization to promote SC fate determination along HF lineages. However, when hair follicle stem cells (HFSCs) become isolated from their niche, they lose their identity and display a wide-ranging plasticity that can produce all lineages of the skin. This multipotent state has long acted as a barrier to restoring HFSC identity when the niche becomes disrupted, despite a wealth of information regarding the signals that control HFSC behavior. To overcome this challenge, I have built upon our lab’s recent discovery that cultured HFSCs exhibit a wound-like epigenetic signature and hypothesized that targeting the pathways responsible for driving the wound response would permit the re-acquisition of HFSC identity. Here, I present here the development of a platform that reinstates the homeostatic identify of HFSCs, made possible through my identification of niche signals that lie at the intersection between tissue regeneration and wound-related plasticity. My preliminary data demonstrate the efficacy of targeting these pathways to resolve the wound signature and restore their sensitivity to local cues that support the acquisition of a full suite of differentiated HF cell types. In this proposal, I will examine the resulting heterogeneity of HFSC fates in response to optimized niche signals using single cell transcriptomics. My developing bioinformatic skillset will allow me to compare these cell fates with their in vivo counterparts (Aim I). Next, I will dissect the mechanistic role played by retinoic acid (RA), an essential metabolite required for HFSC identity and self-renewal. By focusing on the transcriptional effectors of RA, I will functionally define how RA availability impacts HF cycling and wound-induced follicular neogenesis (Aim II). Lastly, I will apply this platform to human patient samples and functionally dissect HFSC interactions with their dermal niche in newly engineered skin (Aim III). In total, this work will mechanistically define the minimal requirements necessary for human HFSC self-renewal and differentiation. If successful, my research has the potential to rapidly model and test hypotheses related to human HF disorders, accelerate therapeutic efforts aimed at achieving HF morphogenesis, and ultimately regenerate the complete integumentary system.

项目摘要 成年干细胞（SC）居住在定义的壁ni中，并依靠微环境提示来指导其行为。 毛囊（HF）是研究丰富的SC-niche相互作用的出色模型系统 刻板印象再生周期。这种独立的迷你器官利用了高水平的空间组织和 隔间化以促进沿HF谱系的SC命运确定。但是，当毛囊茎 细胞（HFSC）与他们的利基市场孤立，它们失去身份并显示出广泛的可塑性 可以产生所有皮肤。长期以来，这种多元状态一直是恢复HFSC身份的障碍 当利基市场被破坏时，请进行大量有关控制HFSC的信号的信息 行为。为了克服这一挑战，我建立了我们最近发现的，即文化的HFSC展览 一种类似伤口的表观遗传学签名，并假设针对负责驱动该途径的途径 伤口反应将允许重新获得HFSC身份。在这里，我在这里介绍了 恢复HFSC的体内稳态识别的平台，通过我对利基的识别而成为可能 位于组织再生和与伤口相关的可塑性之间的交点处的信号。我的初步数据 证明针对这些途径以解决伤口签名并恢复其灵敏度的效率 局部提示，这些提示支持获得一套分化的HF细胞类型的完整套件。在这个建议中，我将 使用单个单元格检查HFSC命运的结果异质性，以响应优化的小众信号 转录组学。我正在发展的生物信息学技能集将使我能够将这些细胞命运与它们的体内进行比较 同行（AIM I）。接下来，我将剖析视黄酸（RA）扮演的机械作用，这是一种必不可少的代谢物 HFSC身份和自我更新所必需的。通过关注RA的转录效应，我将在功能上 定义RA的可用性如何影响HF循环和伤口诱导的卵泡新发生（AIM II）。最后，我会的 将此平台应用于人类患者样品，并在功能上剖析了HFSC与其皮肤小境相互作用 在新设计的皮肤（AIM III）中。总的来说，这项工作将机械地定义最小要求 人类HFSC自我更新和分化所必需的。如果成功，我的研究有可能 快速模型和检验与人类HF疾病有关的假设，旨在加速的治疗工作 实现HF形态发生，并最终再生完整的整体系统。