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PLoS One. 2016 Nov 17;11(11):e0165946. doi: 10.1371/journal.pone.0165946. eCollection 2016.

Notch2 Signaling Regulates the Proliferation of Murine Bone Marrow-Derived Mesenchymal Stem/Stromal Cells via c-Myc Expression.

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Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan.
Tokyo Medical and Dental University, Graduate School of Health Care Sciences, Department of Biochemistry and Biophysics, Tokyo 113-8510, Japan.
Shimane University Faculty of Medicine, Department of Life Science, Shimane 693-8501, Japan.
Department of Dentistry and Oral Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Miyagi 980-8575, Japan.
Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, United Kingdom.


Mesenchymal stem/stromal cells (MSCs) reside in the bone marrow and maintain their stemness under hypoxic conditions. However, the mechanism underlying the effects of hypoxia on MSCs remains to be elucidated. This study attempted to uncover the signaling pathway of MSC proliferation. Under low-oxygen culture conditions, MSCs maintained their proliferation and differentiation abilities for a long term. The Notch2 receptor was up-regulated in MSCs under hypoxic conditions. Notch2-knockdown (Notch2-KD) MSCs lost their cellular proliferation ability and showed reduced gene expression of hypoxia-inducible transcription factor (HIF)-1α, HIF-2α, and c-Myc. Overexpression of the c-Myc gene in Notch2-KD MSCs allowed the cells to regain their proliferation capacity. These results suggested that Notch2 signaling is linked to c-Myc expression and plays a key role in the regulation of MSC proliferation. Our findings provide important knowledge for elucidating the self-replication competence of MSCs in the bone marrow microenvironment.

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