Improving haematopoietic reconstitution in blood stem cell transplantation procedures through the regulation of stem cells and their niches

血液生产受到骨骼(在骨髓中)中的造血干细胞与不同的特殊微环境(称为壁龛)的相互作用的严格控制。这些利基细胞保护造血干细胞免受损害，并在一生中保持其产生血液和免疫细胞的潜力。申请团队对血液干细胞及其在血癌中的定位和功能变化做出了贡献。血液干细胞移植是血癌或遗传性代谢/免疫疾病患者的常规救命手术。异基因移植使用不同的血液干细胞来源，如骨髓、外周血和脐带血。脐带血的使用具有几个优点，如容易和非侵入性采集、降低疾病传播风险、立即获得冷冻保存的细胞和提高免疫耐受性。然而，每个脐带血中存在的血液干细胞数量有限，限制了其在低体重受者(主要是儿童)中的使用。此外，脐带血移植后血液和免疫系统的恢复以及总体存活率与移植的血液干细胞的数量有关。移植患者在以下情况下在骨髓中再生正常的血液生产需要：1)从足够数量的捐赠者那里采集血液干细胞；2)移植的血液干细胞在移植受者的骨髓壁龛中的最佳迁移和安置；3)移植的血液干细胞的扩增和产生多个血液和免疫细胞。然而，在捐赠者方面，由于每个脐带血单位可用的血液干细胞数量较少，移植需要几个脐带单位，而造血干细胞的植入延迟(与其他血液干细胞来源，如骨髓或从骨髓动员到外周血的血液干细胞相比)。b)在受者一侧(利基)，血液干细胞移植的效率在老化过程中显著降低，在许多情况下阻碍了血液干细胞移植作为一种治疗选择。主要目的是确定移植后血液干细胞植入和扩张的控制机制，以及随后骨髓再生所需的血液和免疫细胞的产生。我们的翻译目标是指导血液干细胞更有效/更快/更持久地再生血液和免疫系统。为了研究骨髓再生的过程，我们将人脐带血移植到缺乏功能免疫系统的转基因小鼠中，因此不会排斥人类细胞，从而允许植入人类血液干细胞。此外，还将创建一个人工利基，允许植入人类血液干细胞和人类利基细胞来模拟人类系统。这一联合项目将使4名申请者在人类血液干细胞的细胞和分子异质性(Laurenti)、通过炎症因子(Takizawa)、细胞新陈代谢(SUDA)和微环境线索(Mendez-Ferrer)进行调控方面的专业知识实现独特的协同作用。这四个团队的互补专业知识可以帮助克服目前造血干细胞移植程序中的限制。

Blood production is tightly controlled by the interactions of blood-forming stem cells residing inside the bones (in the bone marrow) with distinct specialised microenvironments, called niches. The niche cells protect blood forming stem cells from damage and maintain their potential to produce blood and immune cells throughout life. The applicant teams have contributed to dissect blood stem cells, their niches and their functional alterations in blood cancers.Blood stem cell transplantation is routinely performed for lifesaving procedures in patients with blood cancers or inherited metabolic/immune disorders. Different blood stem cell sources, such as bone marrow, the peripheral blood, and cord blood are used for allogeneic transplantation. The use of cord blood presents several advantages, such as easy and noninvasive harvest, reduced risk of disease transmission, immediate availability of cryopreserved units and increased immune tolerance. However, the limited number of blood stem cells present in each cord blood has restricted its use to low-body-weight recipients (mostly children). Moreover, the recovery of the blood and immune system and the overall survival after cord blood transplantation correlates with the number of blood stem cells transplanted.Regenerating normal blood production in the bone marrow of transplanted patients after requires:1) Harvest of blood stem cells from donors in sufficient numbers.2) Optimal migration and lodgement of transplanted blood stem cells in the bone marrow niches of transplanted recipients and3) Expansion of engrafted blood stem cells and production of multiple blood and immune cells.However,A) On the donor side, due to the low blood stem cell number available in each cord blood unit, several cord units are necessary for transplantation and the HSC engraftment is delayed (compared with other blood stem cell sources, such as bone marrow or blood stem cells mobilised from the bone marrow to the peripheral blood).B) On the recipient side (niche), the efficacy of blood stem cell engraftment significantly decreases during ageing, hampering the use of blood stem cell transplantation as a therapeutic option in many cases.This proposal aims at understanding and modelling the regeneration process following blood stem cell transplantation. The main goal is to identify mechanisms controlling the engraftment and the expansion of blood stem cells after transplantation, and the subsequent production of blood and immune cells necessary for bone marrow regeneration. Our translational aim is instructing blood stem cells to more efficiently/rapidly/long-lastingly regenerate the blood and immune systems.To investigate the process of bone marrow regeneration we will transplant human umbilical cord blood into genetically-modified mice which lack a functional immune system and therefore do no reject the human cells, allowing for the engraftment of human blood stem cells. Additionally, an artificial niche will be created allowing for the engraftment of human blood stem cells and human niche cells to model the human system. This joint project will enable a unique synergy between the 4 applicants with expertise in the cellular and molecular heterogeneity of human blood stem cells (Laurenti), their regulation through inflammatory factors (Takizawa), cellular metabolism (Suda) and microenvironmental cues (Mendez-Ferrer). The complementary expertise of the four teams could facilitate overcoming current limitations in HSC transplantation procedures.