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Regulation of hematopoietic stem cell fate

Oncogene volume 21, pages 3262–3269 (2002)Cite this article

By definition, a hematopoietic stem cell (HSC) is capable both of unlimited self-renewal and differentiation into all mature peripheral blood types. Hematopoietic differentiation can be viewed as a tree with the HSC represented by the trunk (or ‘stem’) and each of the committed progenitors and their more committed progeny represented by the branches. The mechanisms that control whether a HSC self-renews or differentiates remain a mystery. However, many of the important players in this regulation have been identified. The transcriptional regulation of hematopoiesis has been studied in several different organisms and many transcription factors have been identified that specify whether hematopoietic stem cells differentiate down the myeloid, lymphoid, or erythromegakaryocytic lineages. One of the themes that has grown more apparent over years of study is that the critical pathways that control HSC and their progeny are shared by other stem and progenitor cell types throughout the body and throughout phylogeny. The transcriptional regulation of erythropoiesis, lymphopoiesis and myelopoiesis is already covered in detail in other manuscripts in this issue of Oncogene. This review focuses on components of the cellular microenvironment that regulate HSC differentiation, and on the gene expression patterns that play a role in maintaining a stem cell in its undifferentiated state. These findings are placed into context with other tissue systems and other organisms.

As cells differentiate, there is an orchestrated silencing of some genes and activation of others. Experimental data suggest that pluripotent stem/progenitor cells are ‘primed’ to differentiate down several different lineages by low level transcription of many genes that are characteristic of multiple independent discreet lineages (Billia et al., 2001; Hu et al., 1997). By single cell RT–PCR analysis, both erythroid and myeloid gene expression programs are initiated by the same progenitor cell prior to exclusive commitment toward the myeloid or erythroid lineage (Hu et al., 1997). Although many of the cells analysed shared a specific phenotype, the genes expressed in these cells varied. For example, in CD34+lin- primary bone marrow cells, approximately 50% of the cells expressed mRNA for both β-globin (consistent with RBC differentiation) and myeloperoxidase (MPO, consistent with myeloid differentiation). These data suggest that the cells were ‘primed’ to differentiate down either the erythroid or myeloid lineage. None of the cells expressed β-globin in the absence of MPO. However, 40% expressed MPO in the absence of β-globin. These latter findings suggest that some of the cells had already become committed to myeloid differentiation, or that the expression of β-globin is variable in this population of equipotent population cells. It is not yet known whether the transcripts detected at the single cell level are translated. Current methods do not allow detection of low level protein expression for a single cell.

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Acknowledgements

This work was funded by NIH grants DK53037, HL 63357, and HK 69207.

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  1. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520-8035, Connecticut, CT, USA

    Diane S Krause

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Correspondence to Diane S Krause.

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Krause, D. Regulation of hematopoietic stem cell fate. Oncogene 21, 3262–3269 (2002). https://doi.org/10.1038/sj.onc.1205316

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