Differentiation of human embryonic stem cells to HOXA + hemogenic vasculature that resembles the aorta-gonad-mesonephros

Elizabeth Ng, Lisa Azzola, Freya F Bruveris, Vincenzo Calvanese, Belinda Phipson, Katerina Vlahos, Claire Hirst, Vanta J. Jokubaitis, Qing C. Yu, Jovana Maksimovic, Simone Liebscher, Vania Januar, Zhen Zhang, Brenda Williams, Aude Conscience, Jennifer Durnall, Steven Jackson, Magdaline Costa, David Elliott, David N Haylock & 7 others Susan K Nilsson, Richard Saffery, Katja Schenke-Layland, Alicia Oshlack, Hanna K.A. Mikkola, Edouard G Stanley, Andrew G Elefanty

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Abstract

The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34+ cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34+ cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34+ hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17+ vessels from which RUNX1C+ blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34+ hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.

Original languageEnglish
Pages (from-to)1168-1179
Number of pages12
JournalNature Biotechnology
Volume34
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • embryonic stem cells
  • haematopoiesis
  • stem-cell differentiation

Cite this

Ng, Elizabeth ; Azzola, Lisa ; Bruveris, Freya F ; Calvanese, Vincenzo ; Phipson, Belinda ; Vlahos, Katerina ; Hirst, Claire ; Jokubaitis, Vanta J. ; Yu, Qing C. ; Maksimovic, Jovana ; Liebscher, Simone ; Januar, Vania ; Zhang, Zhen ; Williams, Brenda ; Conscience, Aude ; Durnall, Jennifer ; Jackson, Steven ; Costa, Magdaline ; Elliott, David ; Haylock, David N ; Nilsson, Susan K ; Saffery, Richard ; Schenke-Layland, Katja ; Oshlack, Alicia ; Mikkola, Hanna K.A. ; Stanley, Edouard G ; Elefanty, Andrew G. / Differentiation of human embryonic stem cells to HOXA + hemogenic vasculature that resembles the aorta-gonad-mesonephros. In: Nature Biotechnology. 2016 ; Vol. 34, No. 11. pp. 1168-1179.
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abstract = "The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34+ cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34+ cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34+ hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17+ vessels from which RUNX1C+ blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34+ hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.",
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author = "Elizabeth Ng and Lisa Azzola and Bruveris, {Freya F} and Vincenzo Calvanese and Belinda Phipson and Katerina Vlahos and Claire Hirst and Jokubaitis, {Vanta J.} and Yu, {Qing C.} and Jovana Maksimovic and Simone Liebscher and Vania Januar and Zhen Zhang and Brenda Williams and Aude Conscience and Jennifer Durnall and Steven Jackson and Magdaline Costa and David Elliott and Haylock, {David N} and Nilsson, {Susan K} and Richard Saffery and Katja Schenke-Layland and Alicia Oshlack and Mikkola, {Hanna K.A.} and Stanley, {Edouard G} and Elefanty, {Andrew G}",
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Ng, E, Azzola, L, Bruveris, FF, Calvanese, V, Phipson, B, Vlahos, K, Hirst, C, Jokubaitis, VJ, Yu, QC, Maksimovic, J, Liebscher, S, Januar, V, Zhang, Z, Williams, B, Conscience, A, Durnall, J, Jackson, S, Costa, M, Elliott, D, Haylock, DN, Nilsson, SK, Saffery, R, Schenke-Layland, K, Oshlack, A, Mikkola, HKA, Stanley, EG & Elefanty, AG 2016, 'Differentiation of human embryonic stem cells to HOXA + hemogenic vasculature that resembles the aorta-gonad-mesonephros', Nature Biotechnology, vol. 34, no. 11, pp. 1168-1179. https://doi.org/10.1038/nbt.3702

Differentiation of human embryonic stem cells to HOXA + hemogenic vasculature that resembles the aorta-gonad-mesonephros. / Ng, Elizabeth; Azzola, Lisa; Bruveris, Freya F; Calvanese, Vincenzo; Phipson, Belinda; Vlahos, Katerina; Hirst, Claire; Jokubaitis, Vanta J.; Yu, Qing C.; Maksimovic, Jovana; Liebscher, Simone; Januar, Vania; Zhang, Zhen; Williams, Brenda; Conscience, Aude; Durnall, Jennifer; Jackson, Steven; Costa, Magdaline; Elliott, David; Haylock, David N; Nilsson, Susan K; Saffery, Richard; Schenke-Layland, Katja; Oshlack, Alicia; Mikkola, Hanna K.A.; Stanley, Edouard G; Elefanty, Andrew G.

In: Nature Biotechnology, Vol. 34, No. 11, 01.11.2016, p. 1168-1179.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Differentiation of human embryonic stem cells to HOXA + hemogenic vasculature that resembles the aorta-gonad-mesonephros

AU - Ng, Elizabeth

AU - Azzola, Lisa

AU - Bruveris, Freya F

AU - Calvanese, Vincenzo

AU - Phipson, Belinda

AU - Vlahos, Katerina

AU - Hirst, Claire

AU - Jokubaitis, Vanta J.

AU - Yu, Qing C.

AU - Maksimovic, Jovana

AU - Liebscher, Simone

AU - Januar, Vania

AU - Zhang, Zhen

AU - Williams, Brenda

AU - Conscience, Aude

AU - Durnall, Jennifer

AU - Jackson, Steven

AU - Costa, Magdaline

AU - Elliott, David

AU - Haylock, David N

AU - Nilsson, Susan K

AU - Saffery, Richard

AU - Schenke-Layland, Katja

AU - Oshlack, Alicia

AU - Mikkola, Hanna K.A.

AU - Stanley, Edouard G

AU - Elefanty, Andrew G

PY - 2016/11/1

Y1 - 2016/11/1

N2 - The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34+ cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34+ cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34+ hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17+ vessels from which RUNX1C+ blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34+ hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.

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KW - haematopoiesis

KW - stem-cell differentiation

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