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Stem Cell Res Ther
2015 Apr 11;6:52. doi: 10.1186/s13287-015-0051-z.
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Hematopoiesis: from start to immune reconstitution potential.
Liang HC
,
Zúñiga-Pflücker JC
.
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The study of hematopoiesis has been a focus for developmental biologists for over 100 years. What started as a series of microscopic observations in different animal model systems has since evolved into studies of gene expression and regulation, and subsequent protein-protein interactions, cell surface protein expression profiling, and functional mapping of cell fates. In this review, we will discuss the milestone discoveries that have been achieved in the field of hematopoietic development, as well as the techniques that have been employed. Finally, we look toward the future and consider unresolved questions. We also reflect on one of the earliest realizations made in this area of study: that hematopoiesis is evolutionarily conserved, and as a consequence we reflect on the impacts of early and current discoveries and their clinical implications. The future direction of the study of hematopoietic stem cells will probably make use of pluripotent stem cells to yield specific immune cell lineages and eventual clinical applications.
Figure 1.
Primitive and definitive hematopoietic development. (A) Distinct anatomical regions of primitive and definitive hematopoietic development in both the mouse and human. (B) Subset of cell surface markers used in the characterization of this developmental process. CD309, vascular endothelial growth factor receptor 2; CD202b, Tie2 or angiopoietin receptor 2; CD41, integrin 2 alpha; CD45, leukocyte common antigen.
Figure 2.
Transcriptional regulators in the definitive hematopoietic development program. Lim-domain-binding 1 (Ldb1) stabilizes a complex of transcription factors involving Lim-motif 2 (Lmo2), stem cell leukemia (Scl), and GATA box binding protein 2 (GATA2) [29]. During hematopoietic differentiation, this complex induces the expression of runt related protein 1 (Runx1), which is required for definitive hematopoiesis, as reported previously [27]. Surface marker analysis revealed that generation of CD41+ cells is impaired in the absence of Ldb1.
Figure 3.
Signaling factors involved in mammalian embryonic hematopoietic development. Initially, to form the stromal environment supportive of hematopoietic development, Nodal/bone morphogenic protein 4 (bmp4)/Wnt3a is required for patterning of the primitive streak. Once the stromal environment is established, sonic hedgehog (Shh) secreted by the notochord induces the production of vascular endothelial growth factor alpha (VEGFa) by stromal cells, which signal to activate the transcription of Notch1 in hematopoietic precursors. Notch1 signaling then induces the transcription of members of the Lim-domain-binding 1 (Ldb1) complex, which in turn induces the transcription of runt related protein 1 (Runx1). GATA2, GATA box binding protein 2; Lmo2, Lim-motif 2; Scl, stem cell leukemia; Wnt3a, wingless-type MMTV integration site family, member 3A.
Figure 4.
Hematopoietic stem cell maintenance. Purified long-term hematopoietic stem cells (HSCs) from adult animals can reconstitute immune-deficient hosts in vivo. However, hematopoietic cells generated in vitro cannot achieve the same functional outcome. The self-renewal capacity can be induced with the expression of homeobox B4 (HoxB4) ectopically in developing embryonic stem cells, indicating that this potential is present although the trigger is unknown.
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