Tissue Size and Precision Control in Growing Hair Follicles

毛囊生长中的组织大小和精度控制

• 批准号: 10558684
• 负责人: Qing Nie
• 金额: $ 55.19万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558684
• 关键词: Affect; Animals; Biological; Biology; Cell Communication; Cell Compartmentation; Cell Lineage; Cell Size; Cells; Communication; Complex; Computer Models; Data; Dermal; Distant; Epithelium; Equilibrium; Experimental Models; Feedback; Fibroblast Growth Factor; Genes; Genetic; Growth; Hair; Hair Cells; Hair follicle structure; Heterogeneity; In Vitro; Injury; Knowledge; Length; Link; Mathematics; Mesenchymal; Methods; Microscopic; Modeling; Modernization; Molecular; Mus; Mutant Strains Mice; Normal tissue morphology; Organ; Output; Production; Proliferating; Regulation; Reproducibility; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stem Cell Research; Study models; Testing; Tissues; Transplantation; Work; base; cell type; computerized tools; epithelial stem cell; experimental study; gene regulatory network; in vitro Model; in vivo; innovation; mathematical model; mouse genetics; mutant; network models; novel; overexpression; predictive modeling; progenitor; single cell sequencing; single-cell RNA sequencing; stem; stem cells; tissue regeneration; tongue papilla; tool

PROJECT SUMMARY Biological tissues appear to “know” their intended final sizes and achieve them precisely and robustly. While, in principle, a simple negative signaling feedback should be sufficient to explain how a given stem cell lineage regulates its cellular outputs, in reality it cannot work because most tissues are physically large, with stem cells and their progeny spread out over centimeter-scale distances. How tissues overcome the microscopic decay limits of diffusible molecular signals to breach distances orders-of-magnitude in spatial scale remains elusive. This application is inspired by our serendipitous discovery that FGF and BMP mutant mice are able to grow super-long and highly imprecise hairs that can exceed the length of normal mouse hairs by 7-fold. Our lineage analyses suggest that hair stem cells continuously replenish short-lived transit-amplifying (TA) cells spatially located nearly 1 cm away from the stem cells. Interestingly, our single-cell RNA-sequencing analyses reveal previously unappreciated heterogeneity of the intermediate epithelial progenitor cells physically located between the stem and TA cells. Through an integrated mathematical and experimental approach, this application will focus on testing our new hypothesis that dynamic equilibrium between two or more intermediate cell states and their associated cell-cell communications enable feedback information propagation over large spatial scale from TA cells to stem cells to regulate the new progenitor cell production for hair size control. The first aim of the proposed research is to profile and quantify the heterogeneity of intermediate epithelial progenitors, and computationally and experimentally determine the functional link between specific intermediate progenitor states in the hair follicle and the hair length and its precision. The second aim is to define the cell-cell communication networks within the epithelial hair follicle lineage, and computationally and experimentally establish how multiple short-range signaling activities coordinate to form a long-range feedback mechanism that controls progenitor flux between distant stem and TA cell compartments for proper hair growth. The third aim is to determine the signaling impact of mesenchymal niche cells, which surround the hair follicle, on the epithelial lineage cells for hair size control. The study premise is based on novel and extensive preliminary experimental and computational data. The proposed studies are significant because they will establish new long-range signaling mechanisms and uncover novel roles of intermediate cell states in tissue size control. The proposed studies are innovative because they will establish new experimental models for studying tissue size regulation using super-long and extra-short hair mutant mice and will result in numerous new genetic mouse tools for epithelial stem cell research. They will also result in several novel mathematical and computational tools for analyzing single-cell RNA- sequencing data and new spatial models for complex cell lineages, such as in the hair follicle.

项目概要 生物组织似乎“知道”其预期的最终尺寸并精确而稳健地实现它们。 其中，一个简单的负信号反馈原理应该足以解释给定的干细胞谱系如何 调节其细胞输出，实际上它无法发挥作用，因为大多数组织体积很大，并且含有干细胞 以及它们的后代在厘米级距离上扩散。组织如何克服微观腐烂。 可扩散分子信号在空间尺度上突破数量级距离的限制仍然难以捉摸。 该应用的灵感来自于我们偶然发现 FGF 和 BMP 突变小鼠能够生长 超长且高度不精确的毛发，可以超过正常小鼠毛发的 7 倍。 分析表明，毛干在空间上不断补充短命的转运放大（TA）细胞 我们的单细胞 RNA 测序分析显示，它隐含地距离干细胞近 1 厘米。 以前未认识到物理上位于之间的中间上皮祖细胞的异质性 干细胞和TA细胞。 通过综合数学和实验方法，该应用程序将重点测试 我们的新假设是两个或多个中间细胞状态及其相关的动态平衡 细胞间通信使反馈信息能够在大空间范围内从 TA 细胞传播到干细胞 细胞调节新祖细胞的产生以控制头发大小是本研究的首要目标。 是描绘和量化中间上皮祖细胞的异质性，并通过计算和 通过实验确定毛囊中特定中间祖细胞状态之间的功能联系 第二个目标是定义头发长度及其精度。 上皮毛囊谱系，并通过计算和实验确定多个短程如何 信号活动协调形成远程反馈机制，控制祖细胞之间的通量 第三个目标是确定信号传导的影响。 毛囊周围的间充质微环境细胞位于上皮谱系细胞上，用于控制头发的大小。 研究前提基于新颖且初步的广泛实验和计算数据。 拟议的研究意义重大，因为它们将建立新的远程信号机制 揭示中间细胞状态在组织大小控制中的新作用。拟议的研究具有创新性。 因为他们将建立新的实验模型，利用超长和 超短毛突变小鼠，将为上皮干细胞研究带来许多新的遗传小鼠工具。 他们还将开发出几种用于分析单细胞 RNA 的新型数学和计算工具。 复杂细胞谱系（例如毛囊中的细胞谱系）的测序数据和新空间模型。