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Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo.

Rörby, Emma LU ; Billing, Matilda LU ; Blank Savukinas, Ulrika LU ; Karlsson, Göran LU and Karlsson, Stefan LU (2012) In Blood 120. p.4343-4351
Abstract
Hematopoietic stem cells (HSCs) constitute a rare population of tissue-specific cells that can self-renew and differentiate into all lineages of the blood cell system. These properties are critical for tissue regeneration and clinical applications of HSCs. Cord blood is an easily accessible source of HSCs. However, the number of HSCs from one unit is too low to effectively transplant most adult patients, and expansion of HSCs in vitro has met with limited success due to incomplete knowledge regarding mechanisms regulating self-renewal. Members of the transforming growth factor-β (TGF-β) superfamily have been shown to regulate HSCs through the Smad signaling pathway, however, its role in human HSCs has remained relatively uncharted in vivo.... (More)
Hematopoietic stem cells (HSCs) constitute a rare population of tissue-specific cells that can self-renew and differentiate into all lineages of the blood cell system. These properties are critical for tissue regeneration and clinical applications of HSCs. Cord blood is an easily accessible source of HSCs. However, the number of HSCs from one unit is too low to effectively transplant most adult patients, and expansion of HSCs in vitro has met with limited success due to incomplete knowledge regarding mechanisms regulating self-renewal. Members of the transforming growth factor-β (TGF-β) superfamily have been shown to regulate HSCs through the Smad signaling pathway, however, its role in human HSCs has remained relatively uncharted in vivo. Therefore, we asked whether enforced expression of the common-Smad, Smad4, could reveal a role for TGF-β in human hematopoietic stem/progenitor cells (HSPCs) from cord blood. Using a lentiviral overexpression approach, we demonstrate that Smad4 overexpression sensitizes HSPCs to TGF-β, resulting in growth arrest and apoptosis in vitro. This phenotype translates in vivo into reduced HSPC reconstitution capacity yet intact lineage distribution. This suggests that the Smad pathway regulates self-renewal independently of differentiation. These findings demonstrate that the Smad signaling circuitry negatively regulates the regeneration capacity of human HSPCs in vivo. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
120
pages
4343 - 4351
publisher
American Society of Hematology
external identifiers
  • wos:000313111300016
  • pmid:23018642
  • scopus:84869744642
ISSN
1528-0020
DOI
10.1182/blood-2012-02-408658
language
English
LU publication?
yes
id
3c31a4f6-82ae-475b-a4d3-94eebddd0d87 (old id 3123558)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23018642?dopt=Abstract
date added to LUP
2012-10-03 20:26:27
date last changed
2017-09-24 04:36:54
@article{3c31a4f6-82ae-475b-a4d3-94eebddd0d87,
  abstract     = {Hematopoietic stem cells (HSCs) constitute a rare population of tissue-specific cells that can self-renew and differentiate into all lineages of the blood cell system. These properties are critical for tissue regeneration and clinical applications of HSCs. Cord blood is an easily accessible source of HSCs. However, the number of HSCs from one unit is too low to effectively transplant most adult patients, and expansion of HSCs in vitro has met with limited success due to incomplete knowledge regarding mechanisms regulating self-renewal. Members of the transforming growth factor-β (TGF-β) superfamily have been shown to regulate HSCs through the Smad signaling pathway, however, its role in human HSCs has remained relatively uncharted in vivo. Therefore, we asked whether enforced expression of the common-Smad, Smad4, could reveal a role for TGF-β in human hematopoietic stem/progenitor cells (HSPCs) from cord blood. Using a lentiviral overexpression approach, we demonstrate that Smad4 overexpression sensitizes HSPCs to TGF-β, resulting in growth arrest and apoptosis in vitro. This phenotype translates in vivo into reduced HSPC reconstitution capacity yet intact lineage distribution. This suggests that the Smad pathway regulates self-renewal independently of differentiation. These findings demonstrate that the Smad signaling circuitry negatively regulates the regeneration capacity of human HSPCs in vivo.},
  author       = {Rörby, Emma and Billing, Matilda and Blank Savukinas, Ulrika and Karlsson, Göran and Karlsson, Stefan},
  issn         = {1528-0020},
  language     = {eng},
  month        = {09},
  pages        = {4343--4351},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo.},
  url          = {http://dx.doi.org/10.1182/blood-2012-02-408658},
  volume       = {120},
  year         = {2012},
}