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Many of our blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the Hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis.

Hematopoiesis

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Overview of Hematopoiesis

Hematopoiesis involves a series of differentiation steps from one progenitor cell to a more committed cell type, forming the recognizable tree seen in the diagram to the right. Pluripotent Long-Term (LT)-HSCs self renew to maintain the HSC pool, as well as differentiate into Short-Term (ST)-HSCs. Through various knock-out models, several transcription factors have been found to be essential in this differentiation, such as RUNX1 and SCL [1] [2].

ST-HSCs can then differentiate into either the Common Myeloid Progenitor (CMP) or the Common Lymphoid Progenitor (CLP). The CLP then goes on to differentiate into more committed lymphoid precursor cells. The CMP can then further differentiate into the Megakaryocyte–erythroid progenitor cell (MEP), which goes on to make RBCs and platelets, or the Granulocyte/Macrophage Progenitor (GMP), which gives rise to the granulocytes of the innate immune response. MEP differentiation was found to be contingent upon the transcription factor GATA1, whereas GMP differentiation needs SPI1. When expression of either was inhibited by morpholino in zebrafish, the other lineage programming pathway resulted [3] [4].

There are 2 types of hematopoiesis that occur in humans:

  1. Primitive hematopoiesis-blood stem cells differentiate into only a few specialized blood lineages (typically isolated to early fetal development).
  2. Definitive hematopoiesis-multipotent HSCs appear (occurs through the majority of human lifetime).

Historical development of the theory

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The pioneering work of Till and McCulloch in 1961 experimentally confirmed the development of blood cells from a single precursor hematopoietic stem cell (HSC), creating the framework for the field of hematopoiesis to be studied over the following decades [5]. In 1978, after observing that the prototypical colony-forming stem cells were less capable at replacing differentiated cells than bone marrow cells injected into irradiated animals, Schofield proposed that a specialized environment in the bone marrow allows these precursor cells to maintain their cellular reconstitution potential [6].

During this time, the field exploded with studies aimed at determining the components of the “Hematopoietic stem cell niche” that made this possible. Dexter observed that mesenchymal stromal cells could maintain early HSCs ex vivo, and both Lord and Gong showed that these cells localized to the endosteal margins in long bones [7] [8] [9]. These studies and others supported the idea that bone cells create the HSC niche, and all the research that elucidated this specialized hematopoietic microenvironment stemmed from these landmark studies.

Niche localization through early fetal development

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Yolk sac and the hemangioblast theory

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Despite the vast work done in this field, there is still controversy over the origins of definitive HSCs. Primitive hematopoiesis is first found in the blood islands (Pander’s islands) of the yolk sac at E7.5 (embryonic day 7.5) in mice and 30dpc (30 days post-conception) in humans. As the embryo requires rapid oxygenation due to its high mitotic activity, these islands are the main source of red blood cell (RBC) production via fusing endothelial cells (ECs) with the developing embryonic circulation.

The hemangioblast theory, which posits that the RBCs and ECs derive from a common progenitor cell, was developed as researchers observed that receptor knockout mice, such as flk1-/-, exhibited defective RBC formation and vessel growth [10]. A year later, Choi showed that blast cells derived from ES cells displayed common gene expression of both hematopoietic and endothelial precursors [11]. However, Ueno and Weissman provided the earliest contradiction to the hemangioblast theory when they saw that distinct embryonic stem (ES) cells mixed into a blastocyst resulted in more than 1 ES cell contributing to the majority of the blood islands found in the resultant embryo [12]. Other studies done in zebrafish have more soundly indicated the existence of the hemangioblast [13] [14] [15]. While the hemangioblast theory appears to be generally supported, most of the studies done have been in vitro, indicating a need for in vivo studies to elucidate its existence [16].

Aorta-gonad-mesonephros region

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Definitive hematopoiesis then occurs later in the aorta-gonad-mesonephros (AGM) region at E10.5 in mice and 4wpc (4 weeks post-conception) in humans [17].

Niche relocation through late fetal development

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Regulation and dysregulation of the niche

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Nervous system

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Endocrine system

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Immune system

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References

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  1. ^ Orkin SH. 2000. Diversification of haematopoietic stem cells to specific lineages. Nat. Rev. Genet. 1, 57–64
  2. ^ Kim SI and Bresnick EH. 2007. Transcriptional control of erythropoiesis: emerging mechanisms and principles. Oncogene 26, 6777–6794
  3. ^ Galloway JL, Wingert RA, Thisse C, Thisse B, and Zon LI. 2005. Loss of gata1 but not gata2 converts erythropoiesis to myelopoiesis in zebrafish embryos. Dev. Cell 8, 109–116
  4. ^ Rhodes J, Hagen A, Hsu K, Deng M, Liu TX, Look AT, and Kanki JP. 2005. Interplay of pu.1 and gata1 determines myelo-erythroid progenitor cell fate in zebrafish. Dev. Cell 8, 97–108
  5. ^ Till J. E. & McCulloch E. 1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222.
  6. ^ Schofield R. 1978. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25.
  7. ^ Dexter T.M., Allen T.D. & Lajha L.G. 1977. Conditions controlling the proliferation of hemopoietic stem cells in vitro. J. Cell. Physiol. 91, 335–344.
  8. ^ Lord B.I., Testa N.G. & Hendry J.H. 1975. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46, 65–72.
  9. ^ Gong J.K. 1978. Endosteal marrow: a rich source of hematopoietic stem cells. Science 199 (4336), 1443–1445.
  10. ^ Shalaby F., Ho J., Stanford W.L., Fischer K.D., Schuh A.C., Schwartz L., Bernstein A., and Rossant J. 1997. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89, 981–990
  11. ^ Choi K., Kennedy M., Kazarov A., Papadimitriou J.C., and Keller G. 1998. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732
  12. ^ Ueno H., and Weissman I.L. (2006). Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev. Cell 11, 519–533
  13. ^ Stainier D.Y., Weinstein B.M., Detrich H.W., 3rd, Zon L.I., and Fishman M.C. 1995. Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development 121, 3141–3150
  14. ^ Vogeli K.M., Jin S.W., Martin G.R., and Stainier D.Y. (2006). A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature 443, 337–339
  15. ^ Ema M., and Rossant J. (2003). Cell fate decisions in early blood vessel formation. Trends Cardiovasc. Med. 13, 254–259
  16. ^ Orkin S.H. and Zon L.I. 2008. Hematopoiesis: An evolving paradigm for stem cell biology. Cell 132, 631-644
  17. ^ Wang L.D. and Wagers A.J. 2011. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat. Rev. Mol. Cell Biol. 12, 643-655
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