Advanced

Signaling via Smad2 and Smad3 is dispensable for adult murine hematopoietic stem cell function in vivo

Billing, Matilda LU ; Rörby, Emma LU ; Dahl, Maria LU ; Blank, Ulrika; Andradottír, Silja LU ; Ehinger, Mats LU and Karlsson, Stefan LU (2017) In Experimental Hematology
Abstract

Transforming growth factor-β (TGFβ) is a member of a large family of polypeptide growth factors. TGFβ signals mainly through the intracellular proteins Smad2 and Smad3, which are highly similar in amino acid sequence identity. A number of studies have shown that these proteins, dependent on context, have distinct roles in the TGFβ signaling pathway. TGFβ is one of the most potent inhibitors of hematopoietic stem and progenitor cell proliferation in vitro, but its role in hematopoiesis in vivo is still being determined. To circumvent possible redundancies at the receptor level and to address specifically the role of the Smad circuitry downstream of TGFβ and activin in hematopoiesis, we studied the effect of genetically deleting both... (More)

Transforming growth factor-β (TGFβ) is a member of a large family of polypeptide growth factors. TGFβ signals mainly through the intracellular proteins Smad2 and Smad3, which are highly similar in amino acid sequence identity. A number of studies have shown that these proteins, dependent on context, have distinct roles in the TGFβ signaling pathway. TGFβ is one of the most potent inhibitors of hematopoietic stem and progenitor cell proliferation in vitro, but its role in hematopoiesis in vivo is still being determined. To circumvent possible redundancies at the receptor level and to address specifically the role of the Smad circuitry downstream of TGFβ and activin in hematopoiesis, we studied the effect of genetically deleting both Smad2 and Smad3 in adult murine hematopoietic cells. Indeed, TGFβ signaling is impaired in vitro in primitive bone marrow (BM) cells of Smad2 and Smad3 single knockout models. However, blood parameters appear normal under steady state and in the transplantation setting. Interestingly, upon deletion of both Smad2 and Smad3 in vivo, mice quickly develop a lethal inflammatory disease, suggesting that activin/TGFβ signaling is crucial for immune cell homeostasis in the adult context. Furthermore, concurrent deletion of Smad2 and Smad3 in BM cells in immune-deficient nude mice did not result in any significant alterations of the hematopoietic system. Our findings suggest that Smad2 and Smad3 function to mediate crucial aspects of the immunoregulatory properties of TGFβ, but are dispensable for any effect that TGFβ has on primitive hematopoietic cells in vivo.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Experimental Hematology
publisher
Elsevier
external identifiers
  • scopus:85026268435
ISSN
0301-472X
DOI
10.1016/j.exphem.2017.06.005
language
English
LU publication?
yes
id
bce13590-de3a-41a5-88ef-18d3995cc22a
date added to LUP
2017-08-30 14:54:52
date last changed
2017-08-31 03:00:03
@article{bce13590-de3a-41a5-88ef-18d3995cc22a,
  abstract     = {<p>Transforming growth factor-β (TGFβ) is a member of a large family of polypeptide growth factors. TGFβ signals mainly through the intracellular proteins Smad2 and Smad3, which are highly similar in amino acid sequence identity. A number of studies have shown that these proteins, dependent on context, have distinct roles in the TGFβ signaling pathway. TGFβ is one of the most potent inhibitors of hematopoietic stem and progenitor cell proliferation in vitro, but its role in hematopoiesis in vivo is still being determined. To circumvent possible redundancies at the receptor level and to address specifically the role of the Smad circuitry downstream of TGFβ and activin in hematopoiesis, we studied the effect of genetically deleting both Smad2 and Smad3 in adult murine hematopoietic cells. Indeed, TGFβ signaling is impaired in vitro in primitive bone marrow (BM) cells of Smad2 and Smad3 single knockout models. However, blood parameters appear normal under steady state and in the transplantation setting. Interestingly, upon deletion of both Smad2 and Smad3 in vivo, mice quickly develop a lethal inflammatory disease, suggesting that activin/TGFβ signaling is crucial for immune cell homeostasis in the adult context. Furthermore, concurrent deletion of Smad2 and Smad3 in BM cells in immune-deficient nude mice did not result in any significant alterations of the hematopoietic system. Our findings suggest that Smad2 and Smad3 function to mediate crucial aspects of the immunoregulatory properties of TGFβ, but are dispensable for any effect that TGFβ has on primitive hematopoietic cells in vivo.</p>},
  author       = {Billing, Matilda and Rörby, Emma and Dahl, Maria and Blank, Ulrika and Andradottír, Silja and Ehinger, Mats and Karlsson, Stefan},
  issn         = {0301-472X},
  language     = {eng},
  month        = {06},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Signaling via Smad2 and Smad3 is dispensable for adult murine hematopoietic stem cell function in vivo},
  url          = {http://dx.doi.org/10.1016/j.exphem.2017.06.005},
  year         = {2017},
}