Emergency Myelopoiesis Pathways in the Control of Blood Production

控制血液产生的紧急骨髓生成途径

• 批准号: 10379332
• 负责人: Emmanuelle Passegue
• 金额: $ 81.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379332
• 关键词: Address; Aging; Biological Process; Blood; Blood Cells; Bone Marrow; Cell Lineage; Cells; Correlative Study; Development; Differentiation Therapy; Disease; Emergency Situation; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Cell Production; Hematopoietic stem cells; Heterogeneity; Human; Inflammation; Inflammatory; Link; Lymphoid; MPP2 gene; MPP3 gene; Malignant - descriptor; Maps; Molecular; Multipotent Stem Cells; Mus; Myelogenous; Myelopoiesis; Myeloproliferative disease; National Heart, Lung, and Blood Institute; Natural regeneration; Output; Pathway interactions; Patients; Physiological; Population; Process; Production; Regulation; Regulatory Pathway; Research Project Grants; Sampling; Signal Transduction; Stress; Therapeutic Intervention; biophysical properties; cytokine; granulocyte; hematopoietic stem cell differentiation; interest; leukemia; macrophage; new therapeutic target; novel; progenitor; self-renewal; stem; stem cell function; therapeutically effective; translational applications

PROJECT DESCRIPTION Activation of myeloid differentiation pathways always accompanies blood regeneration after stress, the development of hematological malignancies and physiological aging. However, our understanding of what activate myelopoiesis in such deregulated conditions is still very limited. Our goals in this NHLBI OIA application are to (1) decipher the cellular and molecular mechanisms controlling emergency myelopoiesis pathways; (2) understand how the hijacking of these mechanisms contributes to deregulated hematopoietic stem cell (HSC) function and blood production in stress, disease and aging; and (3) identify novel targets for therapeutic interventions aimed at correcting blood production in these deregulated contexts. We recently showed that the output of the myeloid lineage at steady state reflects the differential production by HSCs of a small number of myeloid-biased multipotent progenitors (MPP), called MPP2 and MPP3, and a large number of lymphoid-biased MPPs, known as MPP4 or LMPPs, which both give rise to granulocyte/macrophage progenitors (GMP) and contribute to myelopoiesis (Pietras et al., 2015). During blood regeneration, we found that HSCs are transiently induced to overproduce MPP2/3 and that MPP4 are reprogrammed towards almost exclusive myeloid output, in large part due to cytokine stimulation and the triggering of specific regulatory pathways (Reynaud et al., 2011; Pietras et al., 2015; 2016). An important consequence of the activation of this myeloid regeneration axis is the formation of defined GMP clusters in the bone marrow (BM) cavity, which drive the local overproduction of granulocytes (Hérault et al., submitted). This newly identified process of GMP cluster formation is finely tuned by the timed release of important BM niche signals, and transient activation of an inducible self-renewal network in a subset of GMPs. Altogether, the remodeling of the MPP compartment and induction of GMP cluster formation represent novel and targetable mechanisms of emergency myelopoiesis, which are transiently activated during blood regeneration but are continuously triggered in myeloid malignancies. We are now interested in exploring the contribution of these mechanisms to other deregulated contexts such as inflammation and aging, and in answering an exciting set of new questions that have directly emerged from these studies. In particular, we would like to understand the molecular and cellular basis for the functional heterogeneity observed in the MPP and GMP compartments, map the mechanisms of HSC lineage commitment and their links to the pro-inflammatory BM milieu, and decipher the contribution of the biophysical properties of the BM niche to HSC and myeloid progenitor fate decisions. We also would like to conduct correlative studies with human cells and leukemic patient samples to establish whether aberrant activation of similar emergency myelopoiesis pathways contribute to deregulated blood production in humans. Taken together, these studies are paradigm shifting for understanding the mechanisms controlling blood regeneration and their deregulations in leukemia and aging, and for identifying new targets for translational applications and the treatment of a broad range of blood disorders in humans. While many current therapies treat blood disorders by targeting the malignant and/or overproduced blood cells, our objective is to identify new biological process upstream of these cells to treat blood disorders by using anti-HSC differentiation therapies and by restoring proper regulation of blood production.

项目描述 骨髓分化途径的激活总是伴随着应激后的血液再生， 血液恶性肿瘤的发展和生理衰老。然而，我们对在这种放松管制的条件下激活骨髓生成的了解仍然非常有限。我们在此 NHLBI OIA 申请中的目标 (1) 破译控制紧急骨髓生成途径的细胞和分子机制； (2) 了解这些机制的劫持如何导致造血干细胞 (HSC) 失调 压力、疾病和衰老中的功能和血液生成； (3) 确定治疗干预的新目标，旨在纠正这些放松管制的情况下的血液产生。我们最近表明，稳定状态下骨髓谱系的输出反映了HSC对少数骨髓偏向的多能祖细胞（MPP）（称为MPP2和MPP3）和大量淋巴偏向的祖细胞的差异产生。 MPP，称为 MPP4 或 LMPP，两者都能产生粒细胞/巨噬细胞祖细胞 (GMP) 和 有助于骨髓生成（Pietras et al., 2015）。在血液再生过程中，我们发现 HSC 会短暂地 诱导过度产生 MPP2/3，并且 MPP4 被重新编程为几乎唯一的骨髓输出， 很大程度上是由于细胞因子刺激和特定调节途径的触发（Reynaud 等人， 2011；皮特拉斯等人，2015； 2016）。骨髓再生轴激活的一个重要结果 是在骨髓 (BM) 腔中形成明确的 GMP 簇，从而导致局部过度生产 粒细胞（Hérault 等人提交）。这个新发现的 GMP 簇形成过程非常好 通过重要 BM 生态位信号的定时释放和诱导性自我更新的瞬时激活进行调整 GMP 子集中的网络。总而言之，MPP 区室的重塑和 GMP 簇形成的诱导代表了紧急骨髓生成的新颖且可靶向的机制，这些机制是短暂的 在血液再生过程中被激活，但在骨髓恶性肿瘤中持续被触发。我们现在有兴趣探索这些机制对其他放松管制环境（例如炎症）的贡献 和衰老，并回答这些研究直接出现的一系列令人兴奋的新问题。在 特别是，我们希望了解在 MPP 和 GMP 区室中观察到的功能异质性的分子和细胞基础，绘制 HSC 谱系承诺的机制及其联系 促进炎症的 BM 环境，并破译 BM 生态位的生物物理特性的贡献 HSC 和骨髓祖细胞的命运决定。我们也想与人类进行相关研究 细胞和白血病患者样本以确定是否有类似紧急骨髓生成的异常激活 途径有助于解除人类血液生产的管制。总的来说，这些研究都是范例 转变以了解控制血液再生的机制及其在白血病中的失调 和衰老，并确定转化应用和治疗广泛的新目标 人类血液疾病。虽然目前许多疗法通过针对恶性细胞来治疗血液疾病 和/或过量产生的血细胞，我们的目标是识别这些细胞上游的新生物过程，以 通过使用抗 HSC 分化疗法和恢复血液的正常调节来治疗血液疾病 生产。