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A view of human haematopoietic development from the Petri dish

Key Points

  • Human pluripotent stem cells (hPSCs) provide outstanding new opportunities to study human haematopoietic development and blood cell disease processes in vitro. In addition, they represent a novel and potentially unlimited source of haematopoietic stem cells (HSCs) and progenitor cells for the treatment of a range of blood cell disorders.

  • Vertebrate embryonic haematopoietic development is complex and consists of multiple programmes that give rise to distinct subpopulations of haematopoietic progeny, in defined temporal patterns and at different sites within the embryo. HSCs are only generated from the definitive programme.

  • Haematopoietic development from hPSCs in vitro recapitulates many aspects of embryonic haematopoiesis, including the generation of distinct programmes. Although definitive haematopoiesis can be induced in the hPSC differentiation cultures, HSCs have not yet been produced.

  • Analyses of different stages of haematopoietic development in the hPSC differentiation cultures have provided new insights into the specification of the different haematopoietic programmes and into the generation and identity of haemogenic endothelial cells, the precursors to embryonic HSCs.

  • One of the remaining challenges in the field is the generation of hPSC-derived HSCs. Strategies that accurately mimic the processes in the embryo that lead to HSC development will be required to successfully generate these cells in vitro.

Abstract

Human pluripotent stem cells (hPSCs) provide an unparalleled opportunity to establish in vitro differentiation models that will transform our approach to the study of human development. In the case of the blood system, these models will enable investigation of the earliest stages of human embryonic haematopoiesis that was previously not possible. In addition, they will provide platforms for studying the origins of human blood cell diseases and for generating de novo haematopoietic stem and progenitor cell populations for cell-based regenerative therapies.

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Figure 1: A model of mouse development depicting the origin and temporal development of the different embryonic haematopoietic programmes.
Figure 2: Schematic representation of the human embryo during early gastrulation.
Figure 3: A model of human HEC development.
Figure 4: A model of human primitive, EMP and definitive haematopoietic mesoderm development.
Figure 5: A model of human HSC specification from HECs.

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Acknowledgements

The referenced work from the Keller lab was supported by the US National Institutes of Health grants U01 HL100395 and 5R01HL091724 and by the Canadian Institutes of Health Research grant MOP126117.

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Correspondence to Gordon Keller.

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Glossary

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells generated from adult somatic cells through genetic reprogramming with transcription factors. Similar to human embryonic stem cells, iPSCs can be propagated indefinitely in culture while retaining the capacity to differentiate and give rise to virtually all cell types found in the human body. iPSCs should theoretically be an identical immunological match to the patient they are derived from.

CRISPR–Cas9 technology

The enzyme Cas9 causes a DNA double-strand break at a site (or sites) within the genome that harbours complementarity to homologous short RNA sequences that can be easily synthesized and delivered to cells in vitro. This permits easy, cost-effective generation of in-frame deletions, or insertional mutagenesis, within human pluripotent stem cells.

Yolk sac

An extra-embryonic developmental tissue that harbours the first site of haematopoietic development.

Embryo proper

The anatomical structure that ultimately gives rise to the mature embryo and all tissues found in fetal and adult life. It does not include the extra-embryonic annexes.

Aorta–gonad–mesonephros

(AGM). A region in the caudal portion of the embryo containing the developing aorta, genital ridges and mesonephros that gives rise to haematopoietic stem cells.

OP9 stromal cells

A stromal cell line derived from the op/op mouse that does not produce macrophage colony-stimulating factor (M-CSF). These cells are commonly used to support differentiation and expansion of mouse and human haematopoietic progenitor populations.

Ontogeny

The development of a specific cell type within an organism.

B-1 cells

A subclass of B lymphocytes that are not part of the adaptive immune system and lack the ability to form memory B cells.

γδ T cells

A subset of T cells that have a distinct T cell receptor composed of a γ- and δ-chain.

Primitive streak

A dorsally located structure that forms in the epiblast of the early vertebrate embryo. The primitive streak establishes bilateral symmetry and is commonly associated with the onset of gastrulation and the generation of the three germ layers. Undifferentiated epiblast cells adopt either a mesoderm or an endoderm fate as they move through the primitive streak.

Viral marking

The use of a virus that inserts randomly into the genome as a means of tracking the progression of a cell within a population of other cells.

Somites

An embryonic tissue of paraxial mesoderm found in segments along the head-to-tail axis of the developing embryo. Somites ultimately give rise to the vertebrae, rib cage and occipital bone, as well as to cartilage, tendons and muscle.

Teratoma

A tumour that possesses tissue components derived from more than one germ layer.

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Ditadi, A., Sturgeon, C. & Keller, G. A view of human haematopoietic development from the Petri dish. Nat Rev Mol Cell Biol 18, 56–67 (2017). https://doi.org/10.1038/nrm.2016.127

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