Evolution of hematopoietic stem cell potential from preterm to term neonates

Preterm (PRET) neonates are characterized by reduced mature hematopoietic cell count and increased risk of infection, but the biological features of their Hematopoietic stem/progenitor cells (HSPC) compartment, responsible to produce immune cells, are largely unknown. Here, we exploited an optimized workflow to evaluate the immunophenotype, clonogenic potential and differentiation properties of peripheral blood (PB) HSPC from 35 PRET (< 32 weeks gestation) and 26 TERM neonates at birth. Compared to TERM, PRET displayed increased circulation of HSPC, Hematopoietic Stem Cells (HSC) and Multi-Potent Progenitors (MPP). Functionally, TERM and PRET HSPC showed a comparable clonogenic potential, although with a skew towards erythroid colonies of PRET precursors, and similar multi-lineage production. Strikingly, PRET-HSC+MPP and TERM-HSC+MPP displayed equivalent differentiation efficiency and were respectively enriched in uni-erythroid, in line with the erythroid-biased fetal hematopoiesis within the liver, and in uni-lymphoid clones, possibly reflecting the BM output. Finally, PRET with subsequent late-onset neonatal sepsis, who were even more premature, had lower counts of mature lymphoid and myeloid cells but not of HSPC subpopulations. Altogether, PRET- and TERM-HSPC showed comparable in vitro clonogenic and differentiation efficiency. In summary, the functional properties of neonatal HSPCs evolve with the gestational age, from more erythroid-biased fate at earlier stages towards a more myeloid/lymphoid-skewed composition due to distinct hematopoietic niche factors acting on HSPCs with similar differentiation properties. Moreover, our data support the hypothesis that a higher degree of immaturity of the hematopoietic system might increase the susceptibility to develop septic events in preterm newborns.