Emergency Myelopoiesis Pathways in the Control of Blood Production

项目说明 髓系分化通路的激活总是伴随着应激后的血液再生， 血液系统恶性肿瘤的发展和生理性衰老。然而，我们对什么活动的理解-- 在这种不受调控的条件下，卵细胞的骨髓生成仍然非常有限。我们在此NHLBI OIA应用程序中的目标 目的是：(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有助于解除调控的造血干细胞(HSC) 在应激、疾病和衰老中的功能和血液产生；以及(3)确定治疗间隔的新靶点。 旨在纠正这些放松管制背景下的血液生产的发明。我们最近的研究表明- 骨髓细胞系处于稳定状态的Put反映了少量My-HSCs的差异产生。 偏向于胚体的多能祖细胞(MPP)，又称MPP2和MPP3，以及大量偏向于淋巴系的 MPP，称为MPP4或LMPP，两者都能产生粒/巨噬细胞前体细胞(GMP)和 促进骨髓生成(Pietras等人，2015年)。在血液再生过程中，我们发现造血干细胞是暂时的 诱导过度产生MPP2/3，MPP4被重新编程为几乎排他的髓系输出， 在很大程度上是由于细胞因子的刺激和特定调控通路的触发(Reynaud等人， 2011年；Pietras等人，2015年；2016年)。髓系再生轴激活的一个重要后果 是在骨髓(BM)腔内形成明确的GMP簇，从而导致局部生产过剩 粒细胞(Hérault等人，提交)。这种新发现的GMP星团形成过程是微妙的 通过定时释放重要的BM利基信号和瞬时激活可诱导的自我更新进行调整 GMP子集中的网络。总之，MPP隔室的重塑和GMP的诱导- TER的形成代表了新的和有针对性的紧急骨髓生成机制，这些机制是暂时的 在血液再生过程中被激活，但在髓系恶性肿瘤中持续被触发。我们现在是国际- 致力于探索这些机制对其他放松管制的背景的贡献，如炎症 和衰老，并回答了这些研究直接出现的一系列令人兴奋的新问题。在……里面 特别是，我们想要了解功能异质性的分子和细胞基础。 在MPP和GMP隔间服务，绘制HSC血统承诺的机制及其联系 对促炎的BM环境，并破译BM生态位的生物物理特性的贡献 对HSC和髓系祖细胞命运的决定。我们也想与人类进行相关的研究 细胞和白血病患者样本是否异常激活类似的急诊骨髓生成 这些途径有助于人类血液生产的放松管制。综上所述，这些研究都是范式 转变对白血病血液再生及其调控机制的理解 和老化，并为翻译应用和治疗广泛的 人类的血液疾病。虽然目前的许多治疗方法都是通过针对恶性肿瘤来治疗血液疾病 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学过程 用抗HSC分化疗法治疗血液病，恢复血液的正常调节 制作。

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 acti- vate 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 inter- ventions aimed at correcting blood production in these deregulated contexts. We recently showed that the out- put of the myeloid lineage at steady state reflects the differential production by HSCs of a small number of my- eloid-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 clus- ter 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 inter- ested 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 ob- served 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.