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Signalling pathways that control vertebrate haematopoietic stem cell specification

Nature Reviews Immunology volume 13, pages 336–348 (2013)Cite this article

Subjects

Key Points

  • Understanding the native signalling processes that specify haematopoietic stem cells (HSCs) during development could inform attempts to replicate these events in vitro for the purposes of transplantation and regenerative therapies. Recent advances have identified several proximal signalling events that regulate HSC specification.

  • Earlier embryonic patterning events sequentially generate the most immediate precursor to HSCs: endothelial cells found in the ventral floor of the primitive dorsal aorta. Understanding these more distal signalling events, including the specification of ventrolateral trunk mesoderm, is key to understanding the sequential signalling environment experienced by precursor cells and the establishment of their competence to receive the final combined HSC specification signals.

  • Notch signalling has a pivotal role in both specification of the dorsal aorta, by distinguishing it from the posterior cardinal vein, and generation of haemogenic endothelium, by controlling initiation of the definitive haematopoietic programme. It is presently unclear whether these Notch-regulated events have the same or discrete requirements.

  • Proximal signalling inputs from bone morphogenetic proteins, WNT–β-catenin, nitric oxide, prostaglandins and catecholamines are required for HSC programme initiation or early maintenance.

  • Somite gene expression is required for HSC specification. A Sonic hedgehog–Vegfa signalling axis controls Notch receptor expression in endothelial aortic cells. Also connected to this pathway are inputs from Etv6 and the calcitonin receptor-like receptor. Additional somite patterning by a Wnt16–Dlc and Wnt16–Dld signalling axis results in yet-to-be identified proximal inputs.

Abstract

Haematopoietic stem cells (HSCs) are tissue-specific stem cells that replenish all mature blood lineages during the lifetime of an individual. Clinically, HSCs form the foundation of transplantation-based therapies for leukaemias and congenital blood disorders. Researchers have long been interested in understanding the normal signalling mechanisms that specify HSCs in the embryo, in part because recapitulating these requirements in vitro might provide a means to generate immune-compatible HSCs for transplantation. Recent embryological work has demonstrated the existence of previously unknown signalling requirements. Moreover, it is now clear that gene expression in the nearby somite is integrally involved in regulating the transition of the embryonic endothelium to a haemogenic fate. Here, we review current knowledge of the intraembryonic signals required for the specification of HSCs in vertebrates.

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Figure 1: Haematopoietic stem cells.
Figure 2: Early signalling regulating HSC specification.
Figure 3: Processes regulated by Sonic hedgehog.
Figure 4: Processes regulated by Notch.
Figure 5: Model for indirect Notch-mediated haematopoietic stem cell specification in zebrafish.

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH)/National Heart, Lung and Blood Institute grant R00 HL097150 to W.K.C., as well as a California Institute for Regenerative Medicine (CIRM) New Faculty Award (RN1-00575), NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK074482-06 and an American Heart Association (AHA) Innovative Science Award (12PILT12860010) to D.T.

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Authors and Affiliations

  1. Department of Hematology, Division of Experimental Hematology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, 38105, Tennessee, USA

    Wilson K. Clements

  2. Department of Cellular and Molecular Medicine and Section of Cell and Developmental Biology, University of California at San Diego, 9500 Gilman Dr., La Jolla, 92093-0380, California, USA

    David Traver

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Glossary

Induced pluripotent stem cell

(iPS cell). An adult cell reprogrammed by one of several protocols to 'pluripotency', a state competent to form all embryonic tissues.

Ventral blood islands

A ventroposterior region of the embryo in Xenopus laevis and other species that houses primitive haematopoiesis, in particular erythropoiesis.

Dorsal lateral plate mesoderm

(DLP mesoderm). Trunk mesoderm in Xenopus laevis that is lateral to the more axial notochord and somitic mesoderm. The DLP mesoderm contains tissue fated to form haemogenic endothelium (and thus haematopoietic stem cells) and is equivalent to zebrafish lateral plate mesoderm and mammalian splanchnic mesoderm.

Mid-neurula

In Xenopus laevis, a time in the middle of formation of the neural plate that occurs between the end of gastrulation (formation of the germ layers) and the initiation of somitogenesis.

Haemogenic endothelium

Endothelial cells found most notably in the ventral floor of the dorsal aorta that give rise to haematopoietic stem cells.

Yolk sac

An extra-embryonic tissue derived from the fertilized egg in mammals that ultimately surrounds the embryo and at early times functions as a signalling centre. The yolk sac is also the site of primitive and transient definitive haematopoiesis.

Dorsal aorta

The earliest trunk vessel and precursor to the adult descending aorta. Endothelium of the dorsal aorta forms from splanchnic mesoderm and contains the haemogenic endothelium that generates the first haematopoietic stem cells.

Aorta–gonads–mesonephros

The embryonic region in the embryonic day 9.5–11.0 mouse containing the primitive dorsal aorta and bounded by the mesonephros and gonads, where haematopoietic stem cells are specified.

Lateral

Anatomical adjective defining the direction away from the midline.

Anamniotes

An informal grouping of vertebrates (including frogs and fish) that develop external to the mother in eggs without an amnion, in contrast to birds and mammals, which have amnions.

Somites

Primitive mesodermal tissue found lateral to the notochord and axial to the lateral plate or splanchnic mesoderm. This tissue is segmented and contains precursors for adult skeleton, skeletal muscle, vascular smooth muscle and dermis.

Epiblast

In mouse and chick, the embryonic portion of the embryo before formation of the primary germ layers (ectoderm, mesoderm and endoderm).

Primitive streak

The site in the epiblast of primary ingression of cells that give rise to mesoderm.

Dorsal–ventral

Anatomical adjectives defining the back and belly directions, respectively.

Anterior–posterior

Anatomical adjectives defining the head and tail directions, respectively.

Dorsal organizer

A group of cells acting as a signalling centre that patterns local tissue to a specific fate, in this case dorsal and anterior. Sometimes known as 'Spemanns organizer'.

Intermediate cell mass

A region in the axial trunk of the 23–28 hours post fertilization zebrafish embryo that is ventral to the notochord. Primitive haematopoiesis occurs here, as well as formation of the haemogenic endothelium.

Yolk ball

An extra-embryonic region of the zebrafish embryo that contains nutrients that sustain early development before feeding.

Serial transplantation

A procedure to test the longevity and self-renewal potential of putative populations of haematopoietic stem cells by transplanting into primary, secondary, tertiary and higher-order recipients.

Sclerotome

A ventromedial compartment of each somite containing a variety of tissue precursors, including vertebral column cells, breast bone cells and vascular smooth muscle cells.

Sympathetic nervous system

A neural crest-derived component of the autonomic nervous system that regulates tissue responses including the 'fight-or-flight' response. The sympathetic nervous system develops in tandem with the adrenal glands and regulates secretion of cardiovascular system regulatory hormones including the catecholamines adrenaline and noradrenaline.

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Clements, W., Traver, D. Signalling pathways that control vertebrate haematopoietic stem cell specification. Nat Rev Immunol 13, 336–348 (2013). https://doi.org/10.1038/nri3443

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