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Peer-reviewedCC BY 4.0EMBO Molecular Medicine

Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment

  • Simon J Pöllmann1
  • Marcel G E Rommel2,3
  • Leal Oburoglu1
  • Tanja Hirch1
  • Fabiola Valdivia-Francia4
  • Kah Mun Siow1
  • Timon Menzi1
  • Julia Ackva1
  • Franziska Schenk1
  • Matthias J Neeracher1
  • Ataman Sendoel4
  • Janine Reichenbach1,5,6
2 more authors
  • E Camilla Forsberg2,3
  • Ute Modlich1
6 affiliations
  1. 1Division of Gene and Cell Therapy, Institute for Regenerative Medicine (IREM), University of Zurich, 8952 Schlieren, Switzerland
  2. 2Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA 95064 USA
  3. 3Biomolecular Engineering, University of California, Santa Cruz, CA 95064 USA
  4. 4Translational Stem Cell Biology, Institute for Regenerative Medicine (IREM), University of Zurich, 8952 Schlieren, Switzerland
  5. 5Department of Somatic Gene Therapy, University Children’s Hospital Zurich, 8008 Zurich, Switzerland
  6. 6Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, 8057 Zurich, Switzerland
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Abstract

Hematopoietic stem cells (HSCs) are the definitive source of all blood cells and replenish them for life. The endothelial protein C receptor (EPCR) which signals via its coreceptor protease-activated receptor 1 (PAR1) is expressed on a subpopulation of highly quiescent HSCs with high engraftment potential after transplantation. We demonstrate that EPCR/PAR1 on human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be activated by both thrombin (THR) and activated protein C (aPC), inducing distinct signaling. PAR1 activation by THR in HSPCs led to Ca2+ flux, phosphorylation of CREB and ERK1/2 and increased glycolysis. In contrast, aPC activated CREB and AKT, but not ERK1/2, Ca2+ flux or metabolic changes. Functionally, stimulation of human CD34+ cells with aPC decreased differentiation and enhanced clonogenic potential. aPC counteracted the enforced proliferation of HSPCs by interleukin 1α in vitro. Short stimulation of CD34+ cells with aPC enhanced their short-term serial engraftment in immunodeficient mice. Our findings identify aPC/PAR1 signaling as a key target supporting CD34+ HSPC maintenance, stress resistance and regeneration, while THR/PAR1 signaling has opposing effects.

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Cite

BibTeXRIS
BibTeX
@article{pollmann2026activated,
  title = {{Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment}},
  author = {Simon J Pöllmann and Marcel G E Rommel and Leal Oburoglu and Tanja Hirch and Fabiola Valdivia-Francia and Kah Mun Siow and Timon Menzi and Julia Ackva and Franziska Schenk and Matthias J Neeracher and Ataman Sendoel and Janine Reichenbach and E Camilla Forsberg and Ute Modlich},
  journal = {EMBO Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s44321-026-00529-y},
  url = {https://doi.org/10.1038/s44321-026-00529-y},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment
AU  - Simon J Pöllmann
AU  - Marcel G E Rommel
AU  - Leal Oburoglu
AU  - Tanja Hirch
AU  - Fabiola Valdivia-Francia
AU  - Kah Mun Siow
AU  - Timon Menzi
AU  - Julia Ackva
AU  - Franziska Schenk
AU  - Matthias J Neeracher
AU  - Ataman Sendoel
AU  - Janine Reichenbach
AU  - E Camilla Forsberg
AU  - Ute Modlich
PY  - 2026
DA  - 2026/10/09
JO  - EMBO Molecular Medicine
DO  - 10.1038/s44321-026-00529-y
UR  - https://doi.org/10.1038/s44321-026-00529-y
AB  - Hematopoietic stem cells (HSCs) are the definitive source of all blood cells and replenish them for life. The endothelial protein C receptor (EPCR) which signals via its coreceptor protease-activated receptor 1 (PAR1) is expressed on a subpopulation of highly quiescent HSCs with high engraftment potential after transplantation. We demonstrate that EPCR/PAR1 on human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be activated by both thrombin (THR) and activated protein C (aPC), inducing distinct signaling. PAR1 activation by THR in HSPCs led to Ca2+ flux, phosphorylation of CREB and ERK1/2 and increased glycolysis. In contrast, aPC activated CREB and AKT, but not ERK1/2, Ca2+ flux or metabolic changes. Functionally, stimulation of human CD34+ cells with aPC decreased differentiation and enhanced clonogenic potential. aPC counteracted the enforced proliferation of HSPCs by interleukin 1α in vitro. Short stimulation of CD34+ cells with aPC enhanced their short-term serial engraftment in immunodeficient mice. Our findings identify aPC/PAR1 signaling as a key target supporting CD34+ HSPC maintenance, stress resistance and regeneration, while THR/PAR1 signaling has opposing effects.
SN  - 1757-4676
SN  - 1757-4684
ER  -