Role of transcription factors in differentiation and reprogramming of hematopoietic cells

Differentiation of hematopoietic cells is a sequential process of cell fate decision originating from hematopoietic stem cells (HSCs), allowing multi- or oligopotent progenitors to commit to certain lineages. HSCs are cells that are able to self-renew and repopulate the marrow for the long term. They first differentiate into multipotent progenitors (MPPs), which give rise to common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). CMPs then differentiate into granulocyte monocyte progenitors (GMPs) and megakaryocyte erythroid progenitors (MEPs), which are the precursors of granulocytes/monocytes and erythrocytes/megakaryocytes, respectively. Lineage specification at differentiation branch points is dictated by the activation of lineage-specific transcription factors such as C/EBPα, PU.1, and GATA-1. The role of these transcription factors is generally instructive, and the expression of a single factor can often determine cell fate. Differentiation was long regarded as an irreversible process, and it was believed that somatic cells would not change their fate once they were differentiated. This paradigm was first challenged by the finding that ectopic cytokine signals could change the fate of differentiation, probably through modulating internal transcription networks. Subsequently, we and others showed that virtually all progenitors, including CLPs, CMPs, GMPs, and MEPs, still retain differentiation plasticity, and they can be converted into lineages other than their own by ectopic activation of only a single lineage-specific transcription factor. These findings established a novel paradigm for cellular differentiation and opened up an avenue for artificially manipulating cell fate for clinical use.