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

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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.

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, University of Freiburg, Faculty of Medicine, Hugstetter Strasse 55, 79106, Freiburg, Germany

    Daniel Ewerth, Stefanie Kreutmair, Andrea Schmidts, Marie Follo, Dagmar Wider, Julia Felthaus, Justus Duyster, Anna Lena Illert, Monika Engelhardt & Ralph Wäsch

  2. Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104, Freiburg, Germany

    Daniel Ewerth

  3. Clinical Trials Unit, University of Freiburg, Faculty of Medicine, Freiburg, Germany

    Gabriele Ihorst

  4. Oncotest GmbH, Freiburg, Germany

    Julia Schüler

  5. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Justus Duyster & Anna Lena Illert

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  1. Daniel Ewerth
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  2. Stefanie Kreutmair
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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.

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Correspondence to Ralph Wäsch.

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Ewerth, D., Kreutmair, S., Schmidts, A. et al. APC/CCdh1 regulates the balance between maintenance and differentiation of hematopoietic stem and progenitor cells. Cell. Mol. Life Sci. 76, 369–380 (2019). https://doi.org/10.1007/s00018-018-2952-3

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