Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Trista E. North; Wolfram Goessling; Carl R. Walkley; Claudia Lengerke; Kamden R. Kopani; Allegra M. Lord; Gerhard J. Weber; Teresa V. Bowman; Il Ho Jang; Tilo Grosser; Garret A. Fitzgerald; George Q. Daley; Stuart H. Orkin; Leonard I. Zon

doi:10.1038/nature05883

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Trista E. North, Wolfram Goessling, Carl R. Walkley, Claudia Lengerke, Kamden R. Kopani, Allegra M. Lord, Gerhard J. Weber, Teresa V. Bowman, Il Ho Jang, Tilo Grosser, Garret A. Fitzgerald, George Q. Daley, Stuart H. Orkin, Leonard I. Zon

Research output: Contribution to journal › Article › peer-review

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Abstract

Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

Original language	English (US)
Pages (from-to)	1007-1011
Number of pages	5
Journal	Nature
Volume	447
Issue number	7147
DOIs	https://doi.org/10.1038/nature05883
State	Published - Jun 21 2007
Externally published	Yes

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@article{bebf48dc7ab6431ba877ca9df1a98d19,

title = "Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis",

abstract = "Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.",

author = "North, {Trista E.} and Wolfram Goessling and Walkley, {Carl R.} and Claudia Lengerke and Kopani, {Kamden R.} and Lord, {Allegra M.} and Weber, {Gerhard J.} and Bowman, {Teresa V.} and Jang, {Il Ho} and Tilo Grosser and Fitzgerald, {Garret A.} and Daley, {George Q.} and Orkin, {Stuart H.} and Zon, {Leonard I.}",

note = "Funding Information: Acknowledgements We thank the Institute of Chemical and Cellular Biology at Harvard Medical School for access to the chemical libraries used in the screen. We thank: A. Flint, E. Mayhall and C.E. Burns for technical assistance and advice on the kidney marrow analysis; C. Thisse and B. Thisse for information and plasmids for PTGER2; and A. Meyers and J. Ojeda for technical help with the zebrafish chemical screen. This work was supported by grants from the National Institutes of Health (T.E.N., W.G., G.Q.D., S.H.O., G.A.F. and L.I.Z), the American Cancer Socitey (T.E.N.), the American Gastroenterological Association (W.G.), the Leukemia and Lymphoma Society (C.R.W.), the American Heart Association (T.G.) and the Dr. Mildred Scheel Foundation for Cancer Research (C.L.). S.H.O. and L.I.Z. are Howard Hughes Medical Institute investigators.",

year = "2007",

month = jun,

day = "21",

doi = "10.1038/nature05883",

language = "English (US)",

volume = "447",

pages = "1007--1011",

journal = "Nature",

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T1 - Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

AU - North, Trista E.

AU - Goessling, Wolfram

AU - Walkley, Carl R.

AU - Lengerke, Claudia

AU - Kopani, Kamden R.

AU - Lord, Allegra M.

AU - Weber, Gerhard J.

AU - Bowman, Teresa V.

AU - Jang, Il Ho

AU - Grosser, Tilo

AU - Fitzgerald, Garret A.

AU - Daley, George Q.

AU - Orkin, Stuart H.

AU - Zon, Leonard I.

N1 - Funding Information: Acknowledgements We thank the Institute of Chemical and Cellular Biology at Harvard Medical School for access to the chemical libraries used in the screen. We thank: A. Flint, E. Mayhall and C.E. Burns for technical assistance and advice on the kidney marrow analysis; C. Thisse and B. Thisse for information and plasmids for PTGER2; and A. Meyers and J. Ojeda for technical help with the zebrafish chemical screen. This work was supported by grants from the National Institutes of Health (T.E.N., W.G., G.Q.D., S.H.O., G.A.F. and L.I.Z), the American Cancer Socitey (T.E.N.), the American Gastroenterological Association (W.G.), the Leukemia and Lymphoma Society (C.R.W.), the American Heart Association (T.G.) and the Dr. Mildred Scheel Foundation for Cancer Research (C.L.). S.H.O. and L.I.Z. are Howard Hughes Medical Institute investigators.

PY - 2007/6/21

Y1 - 2007/6/21

N2 - Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

AB - Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

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DO - 10.1038/nature05883

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SP - 1007

EP - 1011

JO - Nature

JF - Nature

IS - 7147

ER -

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

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