Oral Presentation 36th Lorne Cancer Conference 2024

Understanding how the tissue microenvironment directs cell fate in haematopoietic stem and progenitor cells (#5)

Elanor N Wainwright 1 , Ali Motazedian 1 , Enid Lam 1 , Liyang Fei 1 , Jovana Maksimovic 1 , Alicia Oshlack 1 , Mark Dawson 1
  1. Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia

Transplantation of haematopoietic stem and progenitor cells (HSPCs) remains the corner stone of management for a broad range of haematological diseases. The influence of the tissue microenvironment and cell-intrinsic transcriptional properties in determining cell fate decisions and clonal output remains unclear. To address this issue we have taken a “clone-splitting” approach to serially monitor the cell-fate and contribution of clonal siblings in different tissue microenvironments within multiple mice. Using single-cell profiling and lineage tracing (SPLINTR) barcoding and ex vivo expansion of HSPCs, multiple representation of identical HSPC clones were transplanted across several mice to assess if clones have the same cell fate in different environments. Direct transplantation of sister clones into blood, bone marrow or thymic tissue revealed that specific cell-intrinsic transcriptional properties result in identical cell fate decisions of sister clones across multiple mice. Notably, single-cell RNA sequencing identified several clones where the microenvironment determined engraftment or clone fate highlighting that distinct microenvironments impose unique restrictions in cell fate potential. Moreover, transplantation of sister clones into different immune microenvironments in the bone marrow or thymus suggested that niche composition and inflammatory environment do not have a strong influence on the engraftment capacity or fate of clones. Rather, the immune microenvironment dramatically influenced the clonal output of transplanted HSPCs. These data support a strong cell-intrinsic basis for engraftment and lineage bias, which can be restricted by the microenvironment in particular sub-populations of HSPCs.  All together, we provide a detailed resolution of stem cell niche engraftment and the role of the host microenvironment in clonal expansion of donor cells.