Resolving heterogeneity in liver development

解决肝脏发育的异质性

• 批准号: 10468675
• 负责人: KIMBERLY D TREMBLAY
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468675
• 关键词: ATAC-seq; Adult; Anterior; Bilateral; Cells; Cues; Data; Development; Developmental Process; Disease; Embryology; Endoderm; Epithelial; Fibroblast Growth Factor; Gene Expression; Goals; Growth; Hepatic; Hepatic Tissue; Hepatocyte; Heterogeneity; Histologic; Homeostasis; In Vitro; Invaded; Laboratories; Lateral; Lip structure; Liver; Lobe; Mesenchyme; Mesoderm; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Organ; Organogenesis; Pattern; Play; Population; Process; Publishing; Reporter; Role; Route; Signal Transduction; Structure of septum transversum; Structure of sinus venosus of fetus; Testing; Tissues; Tube; cholangiocyte; conditional knockout; experimental study; gastrulation; in vivo; insight; liver development; liver function; liver injury; mouse genetics; novel; progenitor; response; stem cells; transcriptome sequencing

Project Summary The definitive endoderm (DE) emerges during gastrulation as an epithelial sheet. This single cell sheet, which produces the entire gut tube and associated organs, is patterned and differentiates into organ domains in response to inductive cues provided by adjacent mesoderm-derived tissues. During induction, the hepatic progenitor, the hepatoblast, emerges from the DE as a group of thickened cells that express hepatic markers. The nascent hepatoblasts form a liver bud that will invade adjacent mesodermal tissue. Once invasion is complete, a single midline rostral lobe and two smaller bilaterally symmetric caudal lobes are evident. Although hepatoblasts and their associated mesoderm have each been regarded as uniform populations, we have discovered remarkable heterogeneity in both. Firstly, hepatoblast arise from two spatially distinct DE populations that each contributes uniquely to the liver bud. The ventral midline progenitors contribute mainly to the hepatoblasts that populate the anterior liver bud while the bilaterally symmetric lateral progenitors produce hepatoblasts that contribute to the posterior liver bud. Surprisingly, each progenitor has unique requirements for this process and is each associated with different supportive mesenchyme upon induction. For example, FGF signals are required to induce the sinus venosus bounded anterior hepatoblasts, while the septum transversum mesenchyme bounded posterior hepatoblasts require BMP signaling to be induced Furthermore, recent fate mapping from our group demonstrates that the anterior hepatoblasts mainly contribute to the caudal lobes while posterior hepatoblasts mainly contribute to the rostral lobe. Finally unpublished histological and molecular data suggests that the mesenchyme supporting the rostral and caudal lobes are distinct tissues. Together these observations suggest that normal development follows two routes for generating hepatoblasts. We hypothesize that the heterogeneity generated during early hepatic development is essential for normal liver function and that it aids in generating the heterogeneity recently identified in adult hepatocyte and cholangiocyte populations. Guided by the new developmental framework outlined above, the aims of our proposal use our expertise in embryology and the power of mouse genetics to further delineate this heterogeneity and to identify how it contributes to normal development. In Aim1 we propose to use conditional knock-out strategies to assess how FGF and BMP signals contribute to hepatoblast induction in vivo. In Aim2, we use an ex vivo approach and novel mouse reporters in vivo to uncover the developmental origin and adult contribution of the rostral and caudal lobe mesenchyme as well as determine the molecular signature of the rostral and caudal lobe hepatoblasts. The long-term goals are to understand how developmental heterogeneity contributes to key adult responses such as homeostasis and regeneration and to use these developmental insights to produce functional hepatic tissues in vitro.

项目概要 定形内胚层 (DE) 在原肠胚形成过程中以上皮片形式出现。这个单细胞片， 产生整个肠管和相关器官，被图案化并分化为器官域 对邻近中胚层衍生组织提供的诱导线索的反应。在诱导过程中，肝 祖细胞（肝母细胞）作为一组表达肝脏标记物的增厚细胞从 DE 中出现。 新生的成肝细胞形成肝芽，侵入邻近的中胚层组织。一旦入侵 完整的，单个中线喙叶和两个较小的双边对称尾叶是明显的。 尽管肝母细胞及其相关的中胚层均被视为统一的群体，但我们 发现两者之间存在显着的异质性。首先，肝母细胞起源于两个空间上不同的DE 每个种群对肝芽都有独特的贡献。腹侧中线祖细胞主要贡献 前肝芽中的成肝细胞，而双侧对称的侧祖细胞 产生有助于后肝芽的成肝细胞。令人惊讶的是，每个祖先都有独特的 这一过程的要求，并且在诱导时各自与不同的支持性间充质相关。 例如，需要 FGF 信号来诱导静脉窦边界的前成肝细胞，而 横隔间充质边界的后部成肝细胞需要诱导 BMP 信号传导 此外，我们小组最近的命运图谱表明，前肝母细胞主要 后成肝细胞主要贡献于尾叶，而后成肝细胞主要贡献于嘴叶。最后 未发表的组织学和分子数据表明，支持头侧和尾侧的间充质 肺叶是不同的组织。这些观察结果表明，正常发育遵循两条路线： 产生成肝细胞。我们假设早期肝脏发育过程中产生的异质性 对于正常的肝功能至关重要，并且它有助于产生最近在 成人肝细胞和胆管细胞群。以新的发展框架为指导 如上所述，我们提案的目的是利用我们在胚胎学方面的专业知识和小鼠遗传学的力量来进一步 描述这种异质性并确定它如何促进正常发育。在目标 1 中，我们建议 使用条件敲除策略来评估 FGF 和 BMP 信号如何促进肝母细胞诱导 体内。在 Aim2 中，我们使用离体方法和体内新颖的小鼠报告基因来揭示发育 头侧叶和尾侧叶间充质的起源和成体贡献，以及确定分子 头侧和尾侧肝母细胞的特征。长期目标是了解如何 发育异质性有助于关键的成人反应，例如体内平衡和再生，并有助于 利用这些发育见解在体外生产功能性肝组织。

项目成果

Deciphering the role of retinoic acid in hepatic patterning and induction in the mouse.

解读视黄酸在小鼠肝脏模式形成和诱导中的作用。

• 发表时间: 2022-11
• 影响因子: 2.7
• 作者: Guertin, Taylor M;Palaria, Amrita;Mager, Jesse;Sandell, Lisa L;Trainor, Paul A;Tremblay, Kimberly D
• 通讯作者: Tremblay, Kimberly D