Mechanisms that regulate erythroid differentiation of hematopoietic stem cells

造血干细胞红系分化的调节机制

• 批准号: 10647781
• 负责人: Daisuke Nakada
• 金额: $ 58.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647781
• 关键词: Affect; Anemia; Biological Assay; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cell Lineage; Cues; DNA; Dioxygenases; Disease; Erythrocytes; Erythroid; Erythropoiesis; Exhibits; Gene Expression; Genes; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell heterogeneity; Hematopoietic System; Hematopoietic stem cells; Hemolytic Anemia; Hemorrhage; Heterogeneity; Homeostasis; Hypoxia; In Vitro; Inflammation; Iron; Iron Chelating Agents; Iron Chelation; Label; Mediating; Metabolic; Modeling; Mus; Natural regeneration; Phosphorylation; Phosphotransferases; Population; Proteins; Regenerative Medicine; Research; Role; Shapes; Signal Transduction; Source; Spleen; Stress; TFRC gene; Testing; Transfusion; Transplantation; alpha ketoglutarate; cell type; chemotherapy; cofactor; demethylation; design; erythroid differentiation; experimental study; hematopoietic stem cell expansion; hematopoietic stem cell fate; in vivo; injury recovery; insight; novel; novel strategies; novel therapeutic intervention; prevent; protein expression; response; self-renewal; single-cell RNA sequencing; stem cells; stressor; uptake

Hematopoietic stem cells (HSCs) are capable of regenerating the entire hematopoietic system. This capacity is fully unleashed upon bone marrow transplantation, however, recent studies including ours indicate that HSCs have a much more limited contribution to hematopoiesis during homeostasis. While stress from sources like chemotherapies or inflammation increases the contribution from HSCs to multiple hematopoietic lineages, little is known about how HSCs respond to stressors that cause anemia. Identifying the progenitor cell population and signals that promote erythroid regeneration may lead to novel strategies to better harness HSCs for the treatment of anemia and regenerative medicine overall. Using a HSC lineage tracing model, we found that hemolytic anemia specifically enhances erythroid contribution by HSCs, indicating that HSCs respond to erythroid stress by initiating erythropoiesis. After hemolytic anemia, HSCs expressed more erythropoiesis-related genes and exhibited enhanced erythroid differentiation in vitro and in vivo. Interestingly, HSCs had increased iron content after hemolytic anemia and iron chelation prevented erythroid-biased differentiation. Iron is a cofactor for the iron(II)/α-ketoglutarate-dependent dioxygenase TET2 that demethylates DNA, and erythropoiesis is associated with DNA demethylation. We found that TET2 protein, but not mRNA, is increased in HSCs during anemia and deletion of Tet2 suppressed the enhanced erythroid differentiation of HSCs we observed following hemolytic anemia. We thus hypothesized that HSCs respond to anemia by increasing iron uptake, TET2 expression, and DNA demethylation, thereby increasing the expression of erythropoiesis genes. In Aim 1, we will study the heterogeneity of splenic HSCs during anemia and identify the erythroid-biased fraction of HSCs. In Aim 2, we will examine the role of TET2 in promoting erythroid commitment of splenic HSC. In Aim 3, we will investigate the mechanism by which TET2 protein is stabilized in HSCs during anemia. Completion of this study will provide novel insights into the differences between bone marrow and splenic HSCs in responding to anemia, and the mechanism by which iron and TET2 instructs HSCs to become committed to the erythroid lineage.

造血干细胞（HSC）能够再生整个造血系统。这种能力是 然而，包括我们在内的最近的研究表明，造血干细胞在骨髓移植后完全释放， 在体内平衡过程中对造血的贡献要有限得多。当压力来自于 化疗或炎症增加了HSC对多种造血谱系的贡献， 关于造血干细胞如何对导致贫血的应激源做出反应的研究已经被人们所知。鉴定祖细胞群体， 促进红细胞再生的信号可能会导致更好地利用HSC进行治疗的新策略 贫血和再生医学的发展使用HSC谱系追踪模型，我们发现， 贫血特异性地增强HSC对红系细胞的贡献，表明HSC对红系细胞应激有反应 通过启动红细胞生成溶血性贫血后，HSC表达更多的红细胞生成相关基因， 在体外和体内表现出增强的红系分化。有趣的是，HSC铁含量增加， 在溶血性贫血和铁螯合阻止红细胞偏向分化之后。铁是一种辅助因子， 铁（II）/α-酮戊二酸依赖性双加氧酶TET 2，可使DNA去甲基化，与红细胞生成相关 DNA去甲基化我们发现，TET 2蛋白，而不是mRNA，在造血干细胞在贫血， Tet 2的缺失抑制了我们观察到的溶血性造血干细胞的红系分化增强， 贫血因此，我们假设造血干细胞通过增加铁摄取、TET 2表达和 DNA去甲基化，从而增加红细胞生成基因的表达。在目标1中，我们将研究 在贫血期间观察脾HSC的异质性，并鉴定HSC的红系偏向部分。在目标2中， 将研究TET 2在促进脾HSC红系定型中的作用。在目标3中，我们将研究 TET 2蛋白在贫血期间在HSC中稳定的机制。本研究的完成将提供 新的见解骨髓和脾造血干细胞之间的差异，在响应贫血， 铁和TET 2指导HSC定型为红系细胞的机制。