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: 10509652
• 负责人: Daisuke Nakada
• 金额: $ 61.28万
• 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/10509652
• 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 Chelation; Label; Lead; 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 differentiation; 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 cell therapy; 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。这个能力是 然而，完全释放了骨髓移植，最近的研究（包括我们的）表明HSC是 在体内平衡期间，对造血的贡献要有限得多。而来自诸如此类的压力 化学疗法或炎症增加了HSC对多个造血谱系的贡献，很少 知道HSC如何应对引起贫血的压力源。识别祖细胞群体和 促进红细胞再生的信号可能会导致新的策略，以更好地利用HSC进行治疗 贫血和再生医学总体上使用HSC谱系追踪模型，我们发现溶血性 贫血特异性增强了HSC的红细胞贡献，表明HSC对红细胞胁迫有反应 通过启动红细胞生成。溶血性贫血之后，HSC表达了更多与红细胞生成的基因，并且 暴露于体外和体内的增强红细胞分化。有趣的是，HSC增加了铁含量 溶血性贫血和铁螯合后，可以防止红斑偏分化。铁是 铁（II）/α-酮戊二酸依赖性二氧酶TET2脱甲基DNA，促红细胞生成是相关的 与DNA脱甲基化。我们发现在贫血期间，HSC中的TET2蛋白（而不是mRNA）增加了 TET2的缺失抑制了我们在溶血后观察到的HSC的增强的红系分化 贫血。因此，我们假设HSC通过增加铁的摄取，TET2表达和 DNA脱甲基化，从而增加了红细胞生成基因的表达。在AIM 1中，我们将研究 贫血期间脾脏HSC的异质性，并确定HSC的红细胞偏置部分。在AIM 2中，我们 将研究TET2在促进脾脏HSC的红系承诺中的作用。在AIM 3中，我们将调查 在贫血期间，HSC中TET2蛋白稳定的机制。这项研究的完成将提供 对骨髓和脾脏HSC之间的差异的新颖见解，对贫血有反应，以及 铁和TET2指示HSC致力于红系谱系的机制。