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Cellular and Molecular Life Sciences

, Volume 76, Issue 2, pp 369–380 | Cite as

APC/CCdh1 regulates the balance between maintenance and differentiation of hematopoietic stem and progenitor cells

  • Daniel Ewerth
  • Stefanie Kreutmair
  • Andrea Schmidts
  • Gabriele Ihorst
  • Marie Follo
  • Dagmar Wider
  • Julia Felthaus
  • Julia Schüler
  • Justus Duyster
  • Anna Lena Illert
  • Monika Engelhardt
  • Ralph WäschEmail author
Original Article

Abstract

Hematopoietic stem and progenitor cells (HSPCs) represent the lifelong source of all blood cells and continuously regenerate the hematopoietic system through differentiation and self-renewal. The process of differentiation is initiated in the G1 phase of the cell cycle, when stem cells leave their quiescent state. During G1, the anaphase-promoting complex or cyclosome associated with the coactivator Cdh1 is highly active and marks proteins for proteasomal degradation to regulate cell proliferation. Following Cdh1 knockdown in HSPCs, we analyzed human and mouse hematopoiesis in vitro and in vivo in competitive transplantation assays. We found that Cdh1 is highly expressed in human CD34+ HSPCs and downregulated in differentiated subsets; whereas, loss of Cdh1 restricts myeloid differentiation, supports B cell development and preserves immature short-term HSPCs without affecting proliferation or viability. Our data highlight a role of Cdh1 as a regulator of balancing the maintenance of HSPCs and differentiation into mature blood cells.

Keywords

Anaphase-promoting complex Cdh1 Ubiquitin–proteasome system (UPS) Hematopoiesis Differentiation Self-renewal 

Notes

Acknowledgements

This work is supported by the Jose-Carreras Leukemia Foundation (R.W., M.E.) and the Government of Baden-Württemberg (A.L.I.).

Author contributions

ME and RW conceived and designed the project. DE, SK, AS, GI, MF, DW, JF and JS performed the experiments. SK analyzed data and helped writing the manuscript. JD critically discussed and interpreted data. DE, ALI, ME and RW analyzed and interpreted the data and wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2018_2952_MOESM1_ESM.pdf (32 kb)
Supplementary material 1 (PDF 32 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daniel Ewerth
    • 1
    • 2
  • Stefanie Kreutmair
    • 1
  • Andrea Schmidts
    • 1
  • Gabriele Ihorst
    • 3
  • Marie Follo
    • 1
  • Dagmar Wider
    • 1
  • Julia Felthaus
    • 1
  • Julia Schüler
    • 4
  • Justus Duyster
    • 1
    • 5
  • Anna Lena Illert
    • 1
    • 5
  • Monika Engelhardt
    • 1
  • Ralph Wäsch
    • 1
    Email author
  1. 1.Department of Hematology, Oncology and Stem Cell Transplantation, Medical CenterUniversity of Freiburg, Faculty of MedicineFreiburgGermany
  2. 2.Faculty of BiologyUniversity of FreiburgFreiburgGermany
  3. 3.Clinical Trials UnitUniversity of Freiburg, Faculty of MedicineFreiburgGermany
  4. 4.Oncotest GmbHFreiburgGermany
  5. 5.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany

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