The early stages of human lymphopoiesis are poorly characterized. Here, we compared the lymphoid potential of a novel umbilical cord blood CD34 ؉ CD45RA hi CD7 ؉ hematopoietic progenitor cell (HPC) population with that of CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs, previously proposed as candidate common lymphoid progenitors. Limitingdilution and clonal analysis, fetal thymic organ cultures, and culture onto Notch ligand Delta-like-1-expressing OP9 cells, showed that although CD34 ؉ CD45RA hi CD7 ؉ HPCs could generate cells of the 3 lymphoid lineages, their potential was skewed toward the T/natural killer (T/NK) lineages. In contrast, CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs predominantly exhibited a B-cell potential. Gene expression profiling with DNA microarrays confirmed that CD34 ؉ CD45RA hi CD7 ؉ HPCs selectively expressed T-lymphoid and NK lineage-committed genes while retaining expression of genes affiliated to the granulomonocytic lineage, whereas CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs displayed a typical pro-B-cell transcription profile and essentially lacked genes unrelated to the B lineage. In addition, both populations could be generated in vitro from CD34 ؉ CD45RA int CD7 ؊ and CD34 ؉ CD45RA hi Lin ؊ HPCs with mixed lymphomyeloid potential, from which they emerged independently with different growth/ differentiation factor requirements. These findings indicate that CD34 ؉ CD45RA hi CD7 ؉ and CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs correspond to multipotent early lymphoid progenitors polarized toward either the T/NK or B lineage, respectively. IntroductionThe immediate progeny of pluripotent hematopoietic stem cells is thought to correspond to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CMPs are assumed to give rise to granulocytes and macrophages, as well as to the erythroid and megakaryocytic lineages, whereas CLPs are committed to generate either B lymphocytes (BLs) or T lymphocytes (TLs) and natural killer (NK) cells. 1,2 Evidence for a primary segregation between CLPs and CMPs stems from in vivo transfer experiments in adult mice, where 2 populations of c-Kit lo Sca lo IL-7R ϩ and Fc␥R lo CD34 ϩ hematopoietic progenitor cells (HPCs) isolated from the postnatal bone marrow (BM) were shown to selectively reconstitute either the lymphoid 3 or erythromegakaryocytic and granulomonocytic lineages. 4 Such a dichotomous model of hematopoiesis remains however debated because there is also evidence that multilineage precursors coexpress lymphoid as well as myeloerythroid genes [5][6][7] and that populations of early lymphoid progenitors (ELPs) retain some degree of multipotency. [8][9][10][11] For example, AA4.1 ϩ Fc␥R ϩ fetal precursors with TL and BL potential retain significant macrophage potential but fail to generate erythroid or granulocytic cells. 8 In line with these findings, early GFP lo c-kit hi Sca-1 ϩ BL precursors from RAG1/GFP (recombination activating gene 1/green fluorescent protein) knock-in mice still express TL and macrophage potential when cultured under appropriate conditions...

No abstract