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

项目摘要 骨髓中的造血干细胞（HSC）微环境，称为小生境，为造血干细胞的生长提供了一个良好的环境。 造血干细胞的增殖、自我更新、分化和迁移需要特定的微环境来控制。 HSC老化伴随着骨髓偏向性HSC的扩增，其自我更新功能下降。老化 造血干细胞的增殖与各种年龄相关的血液疾病有关，如不确定的造血干细胞的克隆性造血， 电位（CHIP）。老年微环境是否驱动HSC的老化和年龄相关的血液学 然而，疾病仍然不清楚。 我最近证明，伤害性神经系统是一个重要的HSC生态位组成部分， 调节粒细胞集落刺激因子（G-CSF）诱导的HSC动员通过分泌 神经肽降钙素基因相关肽（CGRP）在骨髓中。我们的初步数据显示 老年骨髓微环境中CGRP水平的显著降低， 减弱老年小鼠中与衰老相关的HSC表型，导致HSC数量减少， 恢复了骨髓与淋巴平衡此外，我们发现，老年骨髓微环境 促进遗传突变的HSC（Asxl 1 tm/+ HSC）相对于野生型HSC的克隆扩增。 根据这些初步数据，我们提出了一个5年的实验计划，以表征的功能， 老年骨髓微环境中的伤害感受神经元，并分析老年骨的贡献 骨髓微环境对克隆性造血的影响。在具体目标1中，我们将评估衰老对 骨髓中的伤害感受神经元我们将确定衰老是否会导致伤害感受纤维的丧失 或降低CGRP水平而不影响骨髓中的伤害性神经支配。我们将探讨 骨髓中伤害感受器衍生的CGRP信号驱动HSC老化的机制。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-辣椒素是一种天然的 辣椒的一种成分，可以触发伤害感受神经元的激活，可以使 HSC的功能和分子老化特征。在具体目标2中，我们将确定衰老的骨髓 微环境与HSC相互作用以促进Asxl 1 tm/+突变体克隆造血，并探索是否 靶向衰老骨髓微环境可阻止Asx 11/+ HSC扩增。这些拟议 关注骨髓小生境和造血干细胞之间相互作用的研究，将使我们能够识别新的外源性造血干细胞。 调节HSC衰老的因子，并可能提供新的方法来恢复HSC和预防衰老。 相关血液病。

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.