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

造血干细胞（HSC）在整个生物体的生命周期中对健康血细胞的持续供应至关重要。对于许多血液病，干细胞移植（SCT）是唯一可用的治疗选择。尽管数十年的临床应用，控制移植的HSC从血液成功迁移和整合到其靶组织（干细胞生态位）的分子机制仍然普遍难以捉摸。造血干细胞的迁移不仅发生在SCT过程中，也发生在稳态条件下。造血干细胞生态位的细胞被认为是成功移植的关键，但迄今为止，缺乏适当的模型阻碍了对这种造血干细胞招募生态位细胞群的全面定义。本项目旨在探索造血干细胞在植入过程中与其生态位之间的相互作用。这项研究的发现可能会揭示可操作的目标，以调节植入过程。为此，我们计划：1)在SCT早期（数小时至数天）定位HSC和祖细胞的靶器官和壁龛；2)确定在HSC移植中起关键作用的壁龛细胞；3)确定HSC募集壁龛细胞群产生的相关因子和信号。为了准备这个项目，申请人已经在宿主实验室准备了新的报告小鼠模型，可以在体内跟踪hsc，并允许基于荧光的hsc -小生境细胞相互作用的可视化。更好地了解造血干细胞移植的机制将为改善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.