Notch signals contribute to preserve the multipotentiality of human CD34(+)CD38(-)CD45RA(-)CD90(+) hematopoietic progenitors by maintaining T cell lineage differentiation potential

Abstract

Notch signals are critical for T-cell development, limiting the differentiation potential of multipotent progenitors arriving in the thymus via the bloodstream. Notch ligands Delta-like and Jagged are expressed in the bone marrow and, consequently, a role in the regulation of early events of adult hematopoiesis has been proposed. However, mice with disruptions in the Notch pathway do not show gross defects in the hematopoietic stem cell compartment, limiting Notch effects at later stages of development. In this study, we identify cord blood CD34(+)CD38(-)CD45RA(-)CD90(+) cells, a recently described population of hematopoietic stem cells, as one of the earliest targets of Notch in human hematopoiesis. Upon Notch activation, CD34(+)CD38(-) cells are blocked in their differentiation at the CD34(+)CD38(-)CD45RA(-)CD90(+) stage. Importantly, population and clonal analysis demonstrate that Delta-like-1 exposure does not affect lymphoid vs myeloid decisions. However, Notch signaling is required before lymphoid commitment to preserve T-cell potential of CD34(+)CD38(-)CD45RA(-)CD90(+) cells. Our experiments also show that in terms of differentiation potential, CD34(+)CD38(-)CD45RA(-)CD90(+) cells cultured in the presence of Notch signals, resemble cells directly isolated from cord blood. These results could have implications for translational efforts in the design of strategies aimed to accelerate immune reconstitution after transplantation.