TAK1 (MAP3K7) Signaling Regulates Hematopoietic Stem Cells through TNF-Dependent and -Independent Mechanisms

Giichi Takaesu, Maiko Inagaki, Keiyo Takubo, Yuji Mishina, Paul R. Hess, Gregg A. Dean, Akihiko Yoshimura, Kunihiro Matsumoto, Toshio Suda, Jun Ninomiya-Tsuji

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A cytokine/stress signaling kinase Tak1 (Map3k7) deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs) harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2) using a competitive transplantation assay in a mouse model. Tak1 single or Tab1/Tab2 double deletions completely eliminated the reconstitution activity of HSCs, whereas Tab1 or Tab2 single deletion did not cause any abnormality. Tak1 single or Tab1/Tab2 double deficient lineage-negative, Sca-1+, c-Kit+ (LSK) cells did not proliferate and underwent cell death. We found that Tnfr1 deficiency restored the reconstitution activity of Tak1 deficient bone marrow cells for 6-18 weeks. However, the reconstitution activity of Tak1- and Tnfr1-double deficient bone marrow cells declined over the long term, and the number of phenotypically identified long-term hematopoietic stem cells were diminished. Our results indicate that TAB1- or TAB2-dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms: one is prevention of TNF-dependent cell death and the other is TNF-independent maintenance of long-term HSC.

Original languageEnglish
Article numbere51073
JournalPLoS One
Volume7
Issue number11
DOIs
Publication statusPublished - 2012 Nov 30

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Hematopoietic Stem Cells
Stem cells
Hematopoietic System
bone marrow cells
Cell death
Bone Marrow Cells
cell death
Bone
Cell Death
Cells
stem cells
binding proteins
Assays
Carrier Proteins
phosphotransferases (kinases)
cytokines
Phosphotransferases
Stem Cells
Transplantation
animal models

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Takaesu, G., Inagaki, M., Takubo, K., Mishina, Y., Hess, P. R., Dean, G. A., ... Ninomiya-Tsuji, J. (2012). TAK1 (MAP3K7) Signaling Regulates Hematopoietic Stem Cells through TNF-Dependent and -Independent Mechanisms. PLoS One, 7(11), [e51073]. https://doi.org/10.1371/journal.pone.0051073

TAK1 (MAP3K7) Signaling Regulates Hematopoietic Stem Cells through TNF-Dependent and -Independent Mechanisms. / Takaesu, Giichi; Inagaki, Maiko; Takubo, Keiyo; Mishina, Yuji; Hess, Paul R.; Dean, Gregg A.; Yoshimura, Akihiko; Matsumoto, Kunihiro; Suda, Toshio; Ninomiya-Tsuji, Jun.

In: PLoS One, Vol. 7, No. 11, e51073, 30.11.2012.

Research output: Contribution to journalArticle

Takaesu, G, Inagaki, M, Takubo, K, Mishina, Y, Hess, PR, Dean, GA, Yoshimura, A, Matsumoto, K, Suda, T & Ninomiya-Tsuji, J 2012, 'TAK1 (MAP3K7) Signaling Regulates Hematopoietic Stem Cells through TNF-Dependent and -Independent Mechanisms', PLoS One, vol. 7, no. 11, e51073. https://doi.org/10.1371/journal.pone.0051073
Takaesu, Giichi ; Inagaki, Maiko ; Takubo, Keiyo ; Mishina, Yuji ; Hess, Paul R. ; Dean, Gregg A. ; Yoshimura, Akihiko ; Matsumoto, Kunihiro ; Suda, Toshio ; Ninomiya-Tsuji, Jun. / TAK1 (MAP3K7) Signaling Regulates Hematopoietic Stem Cells through TNF-Dependent and -Independent Mechanisms. In: PLoS One. 2012 ; Vol. 7, No. 11.
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abstract = "A cytokine/stress signaling kinase Tak1 (Map3k7) deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs) harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2) using a competitive transplantation assay in a mouse model. Tak1 single or Tab1/Tab2 double deletions completely eliminated the reconstitution activity of HSCs, whereas Tab1 or Tab2 single deletion did not cause any abnormality. Tak1 single or Tab1/Tab2 double deficient lineage-negative, Sca-1+, c-Kit+ (LSK) cells did not proliferate and underwent cell death. We found that Tnfr1 deficiency restored the reconstitution activity of Tak1 deficient bone marrow cells for 6-18 weeks. However, the reconstitution activity of Tak1- and Tnfr1-double deficient bone marrow cells declined over the long term, and the number of phenotypically identified long-term hematopoietic stem cells were diminished. Our results indicate that TAB1- or TAB2-dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms: one is prevention of TNF-dependent cell death and the other is TNF-independent maintenance of long-term HSC.",
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