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

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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.