Emergency Myelopoiesis Pathways in the Control 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老化。然而，我们的理解是什么激活骨髓在这种放松管制的条件仍然非常有限。我们在NHLBI OIA应用中的目标 是（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 功能和血液生产的压力，疾病和老化;（3）确定新的目标，旨在纠正血液生产的治疗干预措施，在这些放松管制的情况下。我们最近发现，稳态时髓系细胞的输出反映了HSC产生少量髓系偏向性多能祖细胞（MPP）（称为MPP 2和MPP 3）和大量淋巴细胞偏向性多能祖细胞（MPP 2和MPP 3）的差异。 MPPs，称为MPP 4或LMPPs，它们都产生粒细胞/巨噬细胞祖细胞（GMP）和 有助于骨髓生成（Pietras等，2015年）。在血液再生过程中，我们发现造血干细胞是短暂的， 诱导过度产生MPP 2/3，MPP 4被重编程为几乎完全的骨髓输出， 这在很大程度上是由于细胞因子的刺激和特异性调节途径的触发（Eduaud等， 2011; Pietras等人，2015; 2016）。骨髓再生轴激活的一个重要后果是 是在骨髓（BM）腔中形成确定的GMP簇，其驱动局部过度生产 粒细胞（Hérault等，提交）。这种新发现的GMP簇形成过程是精细的 通过重要BM生态位信号的定时释放和诱导自我更新的瞬时激活来调节 在GMP的子集中的网络。总之，MPP隔室的重塑和GMP簇形成的诱导代表了紧急骨髓生成的新的和靶向的机制，其是短暂的。 在血液再生过程中被激活，但在骨髓恶性肿瘤中被持续触发。我们现在有兴趣探索这些机制对其他放松管制的情况，如炎症的贡献 以及回答这些研究中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谱系定型的机制及其联系 促炎BM环境，并破译BM生态位的生物物理特性的贡献 HSC和髓系祖细胞命运的决定。我们也想与人类进行相关研究， 细胞和白血病患者样品，以确定是否异常激活类似的紧急骨髓生成 导致人类血液生产失调的途径。综合起来看，这些研究是典型的 转变为理解控制血液再生的机制及其在白血病中的失调 和老化，并确定新的目标，为翻译应用和治疗的广泛的 人类的血液疾病虽然目前许多疗法通过靶向恶性肿瘤来治疗血液病， 和/或过度生产的血细胞，我们的目标是确定这些细胞上游的新的生物过程， 通过使用抗HSC分化疗法和通过恢复血液的适当调节来治疗血液疾病 生产

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.