Delineation of the earliest lineage commitment steps of haematopoietic stem cells: new developments, controversies and major challenges

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Abstract
This review addresses recently reported evidence for alternative cellular pathways for haematopoietic stem cell lineage commitment. Using various approaches, several laboratories suggested the existence of adult as well as foetal multipotent progenitor cells with combined B cell, T cell and granulocyte/macrophage potential, but little or no megakaryocyte/erythroid potential. Compared with haematopoietic stem cells, these multipotent progenitor cells exhibited downregulated transcriptional expression of genes of the megakaryocyte/erythroid lineages and upregulated expression of lymphoid lineage genes. The existence of these lineage-restricted multipotent progenitor cells suggests that the first lineage commitment step of haematopoietic stem cells does not result in strict separation into myelopoiesis and lymphopoiesis, and that there might be alternative pathways for commitment toward different lineage fates. These findings have been questioned by other studies, however. To resolve this controversy and establish the complete road map for haematopoietic lineage commitment, improved tools and more stringent standards for how to identify and characterize lineage fate options of distinct stem and progenitor cells are needed. Current and future progress in establishing the complete cellular roadmap for haematopoietic lineage commitment will permit identification and characterization of key regulators of lineage fate decisions in haematopoietic stem cells.