Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis
Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3',5'-monophosphate-adenosine 5'-monophosphate synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in nonpregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN-regulated genes were also induced in mouse HSCs after serial bleeding and, in human HSCs, during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant but not in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.
Authors
- Animesh Paul (ORCID: https://orcid.org/0000-0001-8357-8024)
- Brandon Chen
- Anna‐Sophia Leven (ORCID: https://orcid.org/0000-0002-5247-1125)
- Dirk Schadendorf (ORCID: https://orcid.org/0000-0003-3524-7858)
- Marcel Mettlen (ORCID: https://orcid.org/0000-0001-7047-2749)
- Alpaslan Tasdogan (ORCID: https://orcid.org/0000-0003-2543-852X)
- Alexandra Gellhaus (ORCID: https://orcid.org/0000-0001-9506-4581)
- Feyza Cansiz (ORCID: https://orcid.org/0009-0006-6526-990X)
- Rainer Kimmig (ORCID: https://orcid.org/0000-0003-1118-2199)
- Zhiyu Zhao (ORCID: https://orcid.org/0000-0001-6308-6997)
- Gabriele Allies (ORCID: https://orcid.org/0009-0000-0784-9021)
- Sean J. Morrison (ORCID: https://orcid.org/0000-0003-1587-8329)
- Antonella Iannaccone (ORCID: https://orcid.org/0000-0002-3982-7027)
- Annamaria Spina (ORCID: https://orcid.org/0000-0002-2877-3158)
- J. Phan (ORCID: https://orcid.org/0000-0002-2439-816X)
Institutions
- Howard Hughes Medical Institute (US)
- Southwestern Medical Center (US)
- Essen University Hospital (DE)
- West German Heart and Vascular Center Essen (DE)
- University of Duisburg-Essen (DE)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1126/science.ado6836
- Citations
- 18
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 6.96
Funders
- University of Texas Southwestern Medical Center
- Children’s Hospital of Wisconsin Research Institute
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- Universitätsklinikum Essen
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases