Repressing TGFbeta family signaling to promote hematopoietic stem cell formation in the embryo

抑制 TGFbeta 家族信号传导促进胚胎中造血干细胞的形成

• 批准号: 10589924
• 负责人: NANCY SPECK
• 金额: $ 34.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589924
• 关键词: Abbreviations; Adult; Aorta; Arteries; Bar Codes; Blood Cells; Bone Marrow; Bone Morphogenetic Proteins; Cell Differentiation process; Cell Maturation; Cell Nucleus; Cell surface; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Confocal Microscopy; Data; Data Set; Development; Dorsal; Embryo; Embryonic arterial structure; Endothelial Cells; Endothelium; Family; Generations; Genes; Goals; Gonadal structure; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Impairment; MADH2 gene; MADH7 gene; Maintenance; Measures; Mesonephric structure; Molecular; Mus; Mutation; Myelogenous; Pathway interactions; Population; Production; Protocols documentation; RUNX1 gene; Regenerative Medicine; Repression; Research; Signal Pathway; Signal Transduction; Signaling Protein; Smad Proteins; Source; Specific qualifier value; Structure of umbilical artery; Transducers; Transforming Growth Factor beta; Transplantation; bone morphogenetic protein receptors; derepression; design; differential expression; embryonic stem cell; hematopoietic stem cell differentiation; hematopoietic stem cell formation; hematopoietic stem cell self-renewal; hemogenic endothelium; human embryonic stem cell; in vivo; induced pluripotent stem cell; insight; mutant; peripheral blood; progenitor; receptor; repaired; restraint; self-renewal; single-cell RNA sequencing; stem cell engraftment; stem cell function; transcription factor; transcriptome

Summary The goal of this proposal is to understand how transforming growth factor beta (TGFb) family signaling regulates the formation of hematopoietic stem cells (HSCs) in the embryo. All HSCs in the adult bone marrow are descendants of pre-hematopoietic stem cells (pre-HSCs) that differentiate from hemogenic endothelial (HE) cells in the major caudal arteries of the embryo. However, only a subset of hematopoietic cells that differentiate from HE cells in the arteries are pre-HSCs, while many are committed lympho-myeloid biased progenitors. We generated a comprehensive single cell dataset covering the developmental trajectory of blood cell formation from HE cells and identified genes specifically expressed in pre-HSCs. We demonstrate that one of these genes, Smad7, which is a negative regulator of TGFb family signaling, is required for the formation of multi-lineage adult-repopulating HSCs in the embryo but is not required for the generation of lympho-myeloid biased progenitors. The goals of this proposal are to determine at what step of HSC formation or function the restraint of TGFb family signaling by SMAD7 is required (pre-HSC formation, pre-HSC to HSC maturation, HSC self-renewal), and which TGFb family signaling pathway SMAD7 restrains to allow HSCs to form in the embryo or function in the adult.

总结 本提案的目标是了解转化生长因子β（TGF β）家族 信号传导调节胚胎中造血干细胞（HSC）的形成。所有HSC在 成人骨髓是前造血干细胞（前HSC）后代，前HSC 从胚胎主要尾动脉中的生血内皮（HE）细胞分化而来。 然而，在动脉中只有一部分造血细胞从HE细胞分化而来， 前-HSC，而许多是定向淋巴-骨髓偏向祖细胞。我们产生了 全面的单细胞数据集，涵盖血细胞形成的发育轨迹 从HE细胞和鉴定的基因特异性表达的前HSC。我们证明， 在这些基因中，Smad 7是TGF β家族信号传导的负调节因子，是TGF β 1表达所必需的。 在胚胎中形成多谱系的成体再生HSC，但这不是胚胎发育所必需的。 产生淋巴-骨髓偏向的祖细胞。本提案的目标是确定 SMAD 7对TGF β家族信号传导的抑制是HSC形成或功能的哪一步 需要（前HSC形成，前HSC到HSC成熟，HSC自我更新），并且 家族信号通路SMAD 7抑制HSC在胚胎中形成或在胚胎中发挥功能。 成年人了