Regulation and function of aged hematopoietic stem cell (HSC) niche

衰老造血干细胞（HSC）生态位的调节和功能

• 批准号: 10723396
• 负责人: Xin Gao
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723396
• 关键词: Acute Myelocytic Leukemia; Affect; Age; Aging; Attenuated; Blood Cells; Blood Vessels; Bone Marrow; Bone Marrow Cells; Calcitonin Gene-Related Peptide; Capsaicin; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chili Pepper; Chimera organism; Clonal Expansion; Codon Nucleotides; Complex; Data; Dysmyelopoietic Syndromes; Endothelial Cells; Equilibrium; Fiber; Food; Frameshift Mutation; Goals; Granulocyte Colony-Stimulating Factor; Hematological Disease; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Inflammation; Ingestion; Lead; Lymphoid; Marrow; Mediating; Molecular; Mus; Mutate; Mutation; Myelogenous; Nature; Nerve; Nervous System; Neuropeptides; Nociception; Nociceptors; Peptide Signal Sequences; Pharmaceutical Preparations; Phenotype; Premature aging syndrome; Process; Proliferating; Protein Analysis; RNA analysis; Regulation; Rejuvenation; Role; Somatic Mutation; Sorting; Stromal Cells; Sympathectomy; Technology; Testing; Time; Transplant Recipients; Transplantation; age related; aged; bone aging; cell age; hematopoietic stem cell aging; hematopoietic stem cell expansion; hematopoietic stem cell niche; improved; innovation; migration; multidisciplinary; mutant; nerve supply; novel; novel strategies; novel therapeutic intervention; prevent; self-renewal; senescence; stem cell function

Project Summary The hematopoietic stem cell (HSC) microenvironment in the bone marrow, termed the niche, provides a specialized microenvironment to control the proliferation, self-renewal, differentiation and migration of HSCs. HSC aging is accompanied by an expansion of myeloid-biased HSCs with declined self-renewal functions. Aging of HSCs is associated with various age-related blood diseases, such as clonal hematopoiesis of indeterminate potential (CHIP). Whether the aged microenvironment drives the aging of HSCs and age-related hematologic diseases, however, remains unclear. I recently demonstrated that the nociceptive nervous system is an essential HSC niche component that regulates granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of neuropeptide calcitonin gene-related peptide (CGRP) in the bone marrow. Our preliminary data reveal a significant reduction of CGRP levels in the aged bone marrow microenvironment, and administration of CGRP attenuates aging-associated phenotypes of HSCs in the old mice, resulting in a reduced number of HSCs and a restored myeloid versus lymphoid balance. In addition, we find that aged bone marrow microenvironment promotes the clonal expansion of genetically mutated HSCs (Asxl1tm/+ HSCs) over wildtype HSCs. Based on these preliminary data, we propose a 5-year experimental plan to characterize the functions of nociceptive neurons in the aged bonne marrow microenvironment and to dissect the contributions of aged bone marrow microenvironment to clonal hematopoiesis. In Specific Aim 1, we will evaluate the impact of aging on nociceptive neurons in the bone marrow. We will determine whether aging induces the loss of nociceptive fibers or reduces the CGRP levels without affecting the nociceptive innervation in the bone marrow. We will explore the mechanisms by which nociceptor-derived CGRP signals in the bone marrow drive the aging of HSCs. We will investigate whether modulation of CGRP signaling via ingestion of food containing capsaicin – a natural component of chili peppers that could trigger the activation of nociceptive neurons – could rejuvenate the functional and molecular aging signatures of HSCs. In Specific Aim 2, we will determine how aged bone marrow microenvironment interacts with HSCs to promote the Asxl1tm/+ mutant clonal hematopoiesis and explore whether targeting the aged bone marrow microenvironment could prevent Asxl1tm/+ HSC expansion. These proposed studies, focusing on the interactions between bone marrow niche and HSCs, will allow us to identify new extrinsic factors regulating HSC aging and potentially provide novel approaches to rejuvenate HSCs and prevent age- related hematologic diseases.

项目摘要 骨髓中的造血干细胞（HSC）微环境称为利基，提供了一个 专门的微环境可控制HSC的增殖，自我更新，分化和迁移。 HSC衰老伴随着具有自我更新功能下降的髓样偏置HSC的扩展。老化 HSC与各种与年龄相关的血液疾病有关，例如不确定的克隆造血 潜力（芯片）。老化的微环境是否会驱动HSC的衰老和与年龄有关的血液学 但是，疾病尚不清楚。 我最近证明了伤害性神经系统是必不可少的HSC小众组成部分 调节粒细胞菌落刺激因子（G-CSF）通过分泌的HSC动员 骨髓中的神经肽降钙素基因相关肽（CGRP）。我们的初步数据显示 老化的骨髓微环境中的CGRP水平显着降低，并给予CGRP 老鼠中HSC的衰老相关表型减弱，导致HSC数量减少和A 恢复的髓样与淋巴样平衡。此外，我们发现老化的骨髓微环境 在野生型HSC上促进一般突变的HSC（ASXL1TM/+ HSC）的克隆膨胀。 基于这些初步数据，我们提出了一个为期5年的实验计划，以表征 老年Bonne Marrow微环境中的伤害性神经元，并剖析了老年Bonne的贡献 骨髓微环境到克隆造血。在特定目标1中，我们将评估衰老对 骨髓中的伤害性神经元。我们将确定衰老是否诱导伤害感受纤维的损失 或降低CGRP水平，而不会影响骨髓中的伤害感受神经。我们将探索 骨髓中伤害感受器衍生的CGRP信号驱动HSC衰老的机制。我们 将研究是否通过摄入含有辣椒素的食物来调节CGRP信号传导 - 一种天然 辣椒的成分可能会触发伤害性神经元的激活 - 可以使该活力恢复活力 HSC的功能和分子老化特征。在特定的目标2中，我们将确定老化的骨髓 微环境与HSC相互作用，以促进ASXL1TM/+突变体clonal造血并探索是否探索是否是否 靶向老化的骨髓微环境可以防止ASXL1TM/+ HSC膨胀。这些提议 研究重点是骨髓小裂和HSC之间的相互作用，将使我们能够识别新的外部外部外部 调节HSC衰老的因素，并可能提供新颖的方法来恢复HSC并防止年龄 相关的血液学疾病。