FOETAL LIVER MULTIPOTENT PROGENITOR CELLS POSSESS ENHANCED IN VIVO RECONSTITUTING POTENTIAL

Abstract

Haematopoiesis or blood formation is an ongoing process throughout life. Discovered through their capacity to reconstitute blood lineages of lethally irradiated animals, haematopoietic stem cells (HSCs), with their unique ability to self-renew, have long been thought to sustain adult haematopoietic demands. In situ barcoding has revealed that adult multipotent progenitor cells (MPP), direct descendants of the HSCs, are capable of sustaining steady-state haematopoiesis for long periods of time. Initially thought as homogeneous, MPPs are now recognised as three discrete subpopulations (MPP2-4), each of which exhibit distinct biases in lineage output following transplantation. Analysis of foetal HSCs has shown that they have less DNA damage and strongly outcompete adult HSCs in transplantation assays. How foetal and adult MPPs compare has yet to be investigated. We assessed the short-term adult repopulating capacities of foetal MPPs. Functional analysis in transplantation models revealed similar features of adult and foetal MPP2s while the lineage outputs from foetal MPP3 and MPP4 were distinct from those of their adult counterparts. In particular, foetal MPP3s possess a strong lymphoid capacity unlike adult MPP3s. Using a combination of single-cell RNA sequencing, clonal tracking and a mouse mutant model, we have mapped the molecular mechanisms that attribute to differences observed between foetal and adult MPPs.