Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo.
(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:
https://lup.lub.lu.se/record/3123558
- author
- Rörby, Emma LU ; Billing, Matilda LU ; Blank Savukinas, Ulrika LU ; Karlsson, Göran LU and Karlsson, Stefan LU
- organization
- publishing date
- 2012-09-27
- 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
- 2016-04-04 07:36:50
- date last changed
- 2024-01-12 01:58:22
@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}}, doi = {{10.1182/blood-2012-02-408658}}, volume = {{120}}, year = {{2012}}, }