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

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

doi:10.1371/journal.pone.0051073

Giichi Takaesu, Gregg A Dean + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0051073

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Journal: PloS one	Publication Date: Nov 30, 2012
Citations: 11	License type: CC BY 4.0

Affiliation: Keio University, University of Michigan–Ann Arbor

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.

Highlights

Hematopoiesis is maintained by self-renewal of hematopoietic stem cells (HSCs) and differentiation and proliferation of HSCderived hematopoietic progenitors [1,2,3]
The TAK1 Complex is Required for long-term multilineage reconstituting hematopoietic stem cells (LT-HSCs) Function
We found that the levels of mRNA of Tak1, Tab1 and Tab2 were lower in bone marrow cells, but the differences among the organs were much less pronounced, compared to the differences in the protein levels (Figure 1B)

Summary

Introduction

Hematopoiesis is maintained by self-renewal of hematopoietic stem cells (HSCs) and differentiation and proliferation of HSCderived hematopoietic progenitors [1,2,3]. Intact Tak1, Tab1 and Tab2 genes were greatly decreased in Tak1iKO, Tab1iKO and Tab2iKO in bone marrow cells at day 4 (Figure S1), indicating that these genes were efficiently deleted four days after the start of tamoxifen treatment.

Results

Conclusion