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Stem cell biology

Smad4 in osteoblasts exerts a differential impact on HSC fate depending on osteoblast maturation stage

Leukemia volume 30, pages 2039–2046 (2016)Cite this article

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Abstract

Osteoblasts (OBs) are indispensable for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow microenvironment. Here we investigated how Smad4 modulates HSC fate at distinct stages of OB development. For this, we conditionally knocked out Smad4 in cells expressing type I collagen (Col1a1) and osteocalcin (OC), respectively. Col1a1-expressing OBs were widely present in both the trabecular and cortical compartment, whereas OC-expressing OBs were predominantly located in the cortical compartment. HSCs from Col1a1 mutants displayed senescence-associated phenotypes. OC mutants did not exhibit HSC senescence-related phenotypes, but instead showed preferential HSC death. Of note, stromal cell-derived factor 1 expression was lower in Col1a1 mutants than control littermates, suggesting potential impairment of CXCR4–CXCL12-mediated HSC retention. Disruption of the CXCR4–CXCL12 axis by AMD3100 administration led to an increase in the senescence-associated β-galactosidase activity and low competitive potential. Collectively, our findings indicate that deletion of Smad4 in OBs differentially modulates HSC fate in a stage-dependent manner.

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Acknowledgements

This work was supported by the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education (2014R1A1A2004343) and by the Ministry of Science, Information and Communications Technology and Future Planning, Korea (NRF-2013R1A2A2A01967207 and 2013R1A2A1A01007642).

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Authors and Affiliations

  1. Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju, South Korea

    S-H Kook, H-J Sim & J-C Lee

  2. Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea

    S-H Kook, C-Y Yun, G Bhattarai, K-Y Lee, E-S Cho & J-C Lee

  3. Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    B-C Lee

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  1. S-H Kook
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Correspondence to E-S Cho or J-C Lee.

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Kook, SH., Yun, CY., Sim, HJ. et al. Smad4 in osteoblasts exerts a differential impact on HSC fate depending on osteoblast maturation stage. Leukemia 30, 2039–2046 (2016). https://doi.org/10.1038/leu.2016.133

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