Spatio-temporal dynamics of hematopoietic stem cell (HSC) interaction with the HSC niche during migration and engraftment

造血干细胞(HSC)对于在生物体的整个生命周期中持续提供健康的血细胞是必不可少的。对于许多血液病，干细胞移植(SCT)是唯一可用的治疗选择。尽管已有几十年的临床应用，但移植的HSC从血流到其靶组织(干细胞巢)的成功迁移和整合的分子机制仍然很难捉摸。造血干细胞的迁移不仅发生在SCT过程中，而且在稳态条件下也会发生。造血干细胞生态位的细胞被认为是成功植入的关键，但由于缺乏合适的模型，迄今无法全面定义这种招募造血干细胞的生态位细胞群体。本项目的目的是探索移植过程中造血干细胞与其生态位之间的相互作用。这项研究的结果可能会揭示可操作的靶点，以调节植入过程。为此，我们计划：1)在SCT的早期阶段(几小时到几天)定位HSC和祖细胞的靶器官和壁龛，2)确定在HSC植入中起关键作用的壁细胞，3)确定HSC招募壁细胞群体产生的相关因素和信号。为了准备这个项目，申请人在宿主实验室准备了新的报告小鼠模型，允许跟踪体内的HSC，并允许基于荧光的HSC-NICE细胞相互作用的可视化。更好地了解HSC植入的机制将可能为改善SCT后的血液学重建开辟新的途径。

Hematopoietic stem cells (HSC) are essential for the continuous supply of healthy blood cells throughout an organism’s life span. For many hematological diseases, stem cell transplantation (SCT) represents the only available curative option. Despite decades of clinical application, the molecular mechanisms that govern successful migration and integration of transplanted HSC from the bloodstream to their target tissues (the stem cell niche) remain widely elusive. Migration of HSCs occurs not only during SCT, but also under steady state conditions. The cells of the HSC niche are thought to be crucial for successful engraftment, yet the lack of appropriate models has so far precluded a comprehensive definition of this HSC-recruiting niche cell population.The aim of this project is to explore the interplay between HSCs and their niche during engraftment. The findings of this study may uncover actionable targets for the modulation of the engraftment process. To this end, we plan to: 1) localize target organs and niches of HSCs and progenitor cells in the early stages (hours to days) of SCT, 2) define niche cells that are crucially involved in HSC engraftment, and 3) identify relevant factors and signals produced by the HSC-recruiting niche cell population. In preparation for this project, the applicant has prepared novel reporter mouse models in the host laboratory that allow for the tracking of HSCs in vivo and permit fluorescence-based visualization of HSC-niche cell interactions. A better understanding of the mechanisms orchestrating HSC engraftment will potentially open new avenues for improving hematologic reconstitution after SCT.