Smad4 is critical for self-renewal of hematopoietic stem cells

Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these...

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Main Authors:	Karlsson, Göran, Blank, Ulrika, Moody, Jennifer L., Ehinger, Mats, Singbrant, Sofie, Deng, Chu-Xia, Karlsson, Stefan
Format:	Online
Language:	English
Published:	The Rockefeller University Press 2007
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137898/

id	pubmed-2137898
recordtype	oai_dc
spelling	pubmed-21378982007-12-13 Smad4 is critical for self-renewal of hematopoietic stem cells Karlsson, Göran Blank, Ulrika Moody, Jennifer L. Ehinger, Mats Singbrant, Sofie Deng, Chu-Xia Karlsson, Stefan Brief Definitive Reports Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4−/− primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal. The Rockefeller University Press 2007-03-19 /pmc/articles/PMC2137898/ /pubmed/17353364 http://dx.doi.org/10.1084/jem.20060465 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Karlsson, Göran Blank, Ulrika Moody, Jennifer L. Ehinger, Mats Singbrant, Sofie Deng, Chu-Xia Karlsson, Stefan
spellingShingle	Karlsson, Göran Blank, Ulrika Moody, Jennifer L. Ehinger, Mats Singbrant, Sofie Deng, Chu-Xia Karlsson, Stefan Smad4 is critical for self-renewal of hematopoietic stem cells
author_facet	Karlsson, Göran Blank, Ulrika Moody, Jennifer L. Ehinger, Mats Singbrant, Sofie Deng, Chu-Xia Karlsson, Stefan
author_sort	Karlsson, Göran
title	Smad4 is critical for self-renewal of hematopoietic stem cells
title_short	Smad4 is critical for self-renewal of hematopoietic stem cells
title_full	Smad4 is critical for self-renewal of hematopoietic stem cells
title_fullStr	Smad4 is critical for self-renewal of hematopoietic stem cells
title_full_unstemmed	Smad4 is critical for self-renewal of hematopoietic stem cells
title_sort	smad4 is critical for self-renewal of hematopoietic stem cells
description	Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4−/− primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal.
publisher	The Rockefeller University Press
publishDate	2007
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137898/
_version_	1611420836895391744

Smad4 is critical for self-renewal of hematopoietic stem cells

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