Delineating the cellular and molecular pathways of hematopoietic stem cell fate decisions

理解细胞分化对于现代医学的发展至关重要，以允许有效使用基于细胞的疗法，并特异性地鉴定可以增强所需细胞类型的再生的药物靶标，并且还选择性地靶向和杀死转化的恶性细胞。血液系统的完整性取决于大量的基本血细胞类型从罕见的造血干细胞群体中不断补充，代表了如何通过替代细胞命运从共同干细胞实现多样性的范例。在过去的几十年里，骨髓移植和几种血细胞生长因子的使用已经将关于造血干细胞的基本知识转化为有效的细胞替代疗法。然而，骨髓移植仍然与大量治疗相关的死亡率相关，为了解决这个问题，需要更多的知识来识别骨髓中负责不同血细胞谱系再生的干细胞类型，以及这些干细胞是如何被调节的。此外，由于正常干细胞及其直接后代被认为经常是癌症干细胞的起源，并且由于这种转化经常通过调节正常干细胞和血细胞发育的途径中的突变发生，因此同样清楚的是，更好地理解正常血细胞发育将有助于开发更有效的治疗方法来根除白血病干细胞。在本文提出的研究中，将开发许多新的策略以在小鼠和人中鉴定和鉴定从干细胞到成熟血细胞发育的关键中间体，以及从干细胞到特定血细胞谱系的这些转变的关键调节剂。此外，我们将通过对免疫缺陷患者的新研究，将有关关键血细胞生长因子在小鼠免疫系统调节中的作用的知识转化为人类，这些患者具有导致相同生长因子途径功能丧失的突变。

The understanding of cell differentiation is of critical importance for the development of modern medicine to allow for efficient use of cell-based therapies, and to specifically identify drug targets that can enhance regeneration of required cell types, and also selectively target and kill transformed malignant cells. Integrity of the blood system depends on a large number of essential blood cell types being continuously replenished from a rare population of blood forming stem cells, representing a paradigm for how diversity can be achieved from a common stem cell through alternative cell fates. Bone marrow transplantation and the use of several blood cell growth factors have over the last decades translated basic knowledge about blood forming stem cells into efficient cell replacement therapies. However, bone marrow transplantation is still associated with substantial treatment related mortality, and to address this more knowledge is needed with regard to the identity of stem cell types in the bone marrow responsible for regeneration of different blood cell lineages, and how these are regulated. Furthermore, as normal stem cells and their immediate progeny are thought to frequently be the origin of cancer stem cells, and since such transformation frequently occurs through mutations in pathways regulating normal stem cells and blood cell development, it is equally clear that a better understanding of normal blood cell development, will facilitate development of more efficient therapies to eradicate leukaemic stem cells. In the herein proposed studies, a number of novel strategies will be developed to identify and characterise, in mouse as well as man, key intermediates in the development from stem cells to mature blood cells, as well as the key regulators of these transitions from stem cells to specific blood cell lineages. Furthermore, we will translate knowledge regarding the role of key blood cell growth factors in regulation of the immune system in mice to man, through new studies in immunodeficient patients which have mutations resulting in loss of function of the same growth factor pathways.