Hematopoietic stem cell heterogeneity and niche cell associations governing definitive hematopoiesis formation

造血干细胞异质性和控制最终造血形成的生态位细胞关联

• 批准号: 22K16326
• 负责人: 瀬崎 真衣子
• 金额: $ 3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22K16326/
• 关键词: HSC heterogeneity; BM niche; scRNA-seq; HSC trafficking; bone marrow niche; neonatal development; stem cell maintenance; definitive hematopoiesis

The primary goal of this project is to understand how hematopoietic stem cells (HSCs) are regulated during ontogeny by elucidating the various cell-intrinsic and cell-extrinsic factors (the BM niche) that may play a role. So far, our scRNA-seq data of neonatal P2 HSCs sampled from major hematopoietic organs has revealed three HSC groups (HSCin1, HSCin2 and HSCout) that are phenotypically and functionally (in vitro differentiation potential and in vivo reconstitution capacity) heterogenous. GO analysis of each group shows enrichment of distinct biological signatures and reinforces their specific role(s) during this temporal period. Our gene list was compared with zebrafish HSC RNA-seq data during definitive hematopoiesis formation and several genes that were significantly upregulated in both species that could potentially dictate “HSC maturation” were selected for further overexpression and downregulation studies. This is currently ongoing. We are simultaneously validating our scRNA-seq data with qPCR analysis, in vitro CFU and in vivo transplantation studies. Furthermore, we are currently devising other strategies for tracing these HSCs (barcoding) in vivo to directly investigate their contribution towards adult hematopoiesis.

该项目的主要目标是通过阐明可能发挥作用的各种细胞内在和细胞外在因素（BM小生境）来了解造血干细胞（HSC）在个体发育过程中是如何调节的。到目前为止，我们从主要造血器官中取样的新生儿P2 HSC的scRNA-seq数据已经揭示了三个HSC组（HSCin 1，HSCin 2和HSCout），它们在表型和功能（体外分化潜力和体内重建能力）上是异质的。每个组的GO分析显示了不同生物特征的富集，并加强了它们在这一时间段内的特定作用。将我们的基因列表与斑马鱼造血形成过程中的HSC RNA-seq数据进行比较，并选择在两个物种中显著上调的几个基因进行进一步的过表达和下调研究，这些基因可能决定“HSC成熟”。这项工作目前正在进行中。我们同时通过qPCR分析、体外CFU和体内移植研究验证我们的scRNA-seq数据。此外，我们目前正在设计其他策略，用于在体内追踪这些HSC（条形码），以直接研究它们对成人造血的贡献。