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: 10653033
• 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/10653033
• 关键词: Acceleration; Automobile Driving; Back; Behavior; Bioinformatics; Biological Assay; Biological Models; Biology; Cell Communication; Cell Culture Techniques; Cell Differentiation process; Cells; Chromatin; Clinical; 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; Play; Population Heterogeneity; Process; Production; Recurrence; Research; Role; Sampling; Scientist; Series; Signal Transduction; Skin; Stem cell transplant; Stereotyping; Stimulus; Stress; System; Technology; Testing; Therapeutic; Tissues; Translational Research; Transplantation; Tretinoin; Work; adult stem cell; appendage; cell behavior; cell type; chromatin immunoprecipitation; clinical center; comparative; efficacy testing; experimental study; functional outcomes; hair follicle disorder; healing; human stem cells; improved; in vivo; insight; loss of function; pre-clinical; receptor; regenerative; response; restoration; self-renewal; skills; 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.

项目概要 成体干细胞 (SC) 存在于特定的生态位中，并依赖微环境线索来指导其行为。 毛囊 (HF) 是一个出色的模型系统，可用于研究毛囊经历的一系列丰富的 SC 生态位相互作用。 这种独立的迷你器官利用了高水平的空间组织和再生循环。 然而，当毛囊干时，区室化促进 SC 命运决定于 HF 谱系。 细胞（HFSC）从它们的生态位中分离出来，它们失去了自己的身份并表现出广泛的可塑性， 可以产生皮肤的所有谱系，这种多能状态长期以来一直是恢复 HFSC 身份的障碍。 当利基市场被破坏时，尽管有大量关于控制 HFSC 信号的信息 为了克服这一挑战，我以我们实验室最近的发现为基础，即培养的 HFSC 表现出的行为。 伤口样的表观遗传特征，并追踪了针对负责驱动的途径 伤口反应将允许重新获得 HFSC 身份。在这里，我提出了一种开发方法。 恢复 HFSC 稳态特征的平台，通过我对利基的识别而成为可能 我的初步数据位于组织再生和伤口相关可塑性之间的交叉点。 证明针对这些途径解决伤口特征并恢复其敏感性的功效 在本提案中，我将根据支持获取全套差异化 HF 细胞类型的本地线索。 使用单细胞检查 HFSC 命运响应优化生态位信号所产生的异质性 我不断发展的生物信息学技能将使我能够将这些细胞的命运与它们的体内进行比较。 接下来，我将剖析视黄酸（RA）（一种重要的代谢物）所发挥的机制作用。 通过关注 RA 的转录效应子，我将在功能上进行研究。 定义 RA 可用性如何影响 HF 循环和伤口诱导的卵泡新生（目标 II）。 将该平台应用于人类患者样本，并从功能上剖析 HFSC 与其真皮生态位的相互作用 总的来说，这项工作将机械地定义最低要求。 如果成功的话，我的研究有潜力实现人类 HFSC 自我更新和分化。 快速建模和测试与人类心力衰竭疾病相关的假设，加速针对以下疾病的治疗工作 实现高频形态发生，并最终再生完整的外皮系统。