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Role of the angiotensin-converting enzyme in the G-CSF-induced mobilization of progenitor cells

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Abstract

In addition to being a peptidase, the angiotensin-converting enzyme (ACE) can be phosphorylated and involved in signal transduction. We evaluated the role of ACE in granulocyte-colony-stimulating factor (G-CSF)-induced hematopoietic progenitor cell (HPC) mobilization and detected a significant increase in mice-lacking ACE. Transplantation experiments revealed that the loss of ACE in the HPC microenvironment rather than in the HPCs increased mobilization. Indeed, although ACE was expressed by a small population of bone-marrow cells, it was more strongly expressed by endosteal bone. Interestingly, there was a physical association of ACE with the G-CSF receptor (CD114), and G-CSF elicited ACE phosphorylation on Ser1270 in vivo and in vitro. A transgenic mouse expressing a non-phosphorylatable ACE (ACES/A) mutant demonstrated increased G-CSF-induced HPC mobilization and decreased G-CSF-induced phosphorylation of STAT3 and STAT5. These results indicate that ACE expression/phosphorylation in the bone-marrow niche interface negatively regulates G-CSF-induced signaling and HPC mobilization.

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Acknowledgements

The authors are indebted to Isabel Winter, Marie von Reutern, Mechthild Piepenbrock, and Katharina Herbig for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (FL 364/1-3 to I.F., KO 4263/2-1 to K.K., SFB 834/Z1 to R.H., and Exzellenzcluster 147 “Cardio-Pulmonary Systems”). The authors declare no competing financial interests.

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Authors and Affiliations

  1. Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Karin Kohlstedt, Caroline Trouvain, Timo Frömel, Thomas Mudersbach & Ingrid Fleming

  2. German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany

    Karin Kohlstedt, Timo Frömel, Thomas Mudersbach & Ingrid Fleming

  3. Blood Donor Services Zürich and Chur, Swiss Red Cross, Zurich, Switzerland

    Reinhard Henschler

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  1. Karin Kohlstedt
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  2. Caroline Trouvain
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  5. Reinhard Henschler
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  6. Ingrid Fleming
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Contributions

KK planned experiments, interpreted data, and drafted the manuscript. TF was responsible for designing the generation of the transgenic mouse. CT performed experiments and interpreted data. TM performed immunohistochemistry for ACE. RH provided valuable expertise and laboratory facilities for the study of progenitor cell populations. IF planned experiments, interpreted data, and took a lead role in writing the manuscript.

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Correspondence to Ingrid Fleming.

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Kohlstedt, K., Trouvain, C., Frömel, T. et al. Role of the angiotensin-converting enzyme in the G-CSF-induced mobilization of progenitor cells. Basic Res Cardiol 113, 18 (2018). https://doi.org/10.1007/s00395-018-0677-y

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