High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production

Shen Y. Heazlewood, Tanveer Ahmad, Benjamin Cao, Huimin Cao, Melanie Domingues, Xuan Sun, Chad K. Heazlewood, Songhui Li, Brenda Williams, Madeline Fulton, Jacinta F. White, Tom Nebl, Christian M. Nefzger, Jose M. Polo, Benjamin T. Kile, Felix Kraus, Michael T. Ryan, Yu B. Sun, Peter F. M. Choong, Sarah L. Ellis, Minna-Liisa Anko and Susan K. Nilsson ()
Additional contact information
Shen Y. Heazlewood: Commonwealth Scientific and Industrial Research Organization
Tanveer Ahmad: Commonwealth Scientific and Industrial Research Organization
Benjamin Cao: Commonwealth Scientific and Industrial Research Organization
Huimin Cao: Commonwealth Scientific and Industrial Research Organization
Melanie Domingues: Commonwealth Scientific and Industrial Research Organization
Xuan Sun: Commonwealth Scientific and Industrial Research Organization
Chad K. Heazlewood: Commonwealth Scientific and Industrial Research Organization
Songhui Li: Commonwealth Scientific and Industrial Research Organization
Brenda Williams: Commonwealth Scientific and Industrial Research Organization
Madeline Fulton: Commonwealth Scientific and Industrial Research Organization
Jacinta F. White: Commonwealth Scientific and Industrial Research Organization
Tom Nebl: Commonwealth Scientific and Industrial Research Organization
Christian M. Nefzger: Monash University
Jose M. Polo: Monash University
Benjamin T. Kile: Monash University
Felix Kraus: Monash Biomedicine Discovery Institute
Michael T. Ryan: Monash Biomedicine Discovery Institute
Yu B. Sun: Monash University
Peter F. M. Choong: St. Vincent’s Hospital, University of Melbourne
Sarah L. Ellis: Peter MacCallum Cancer Centre
Minna-Liisa Anko: Hudson Institute of Medical Research
Susan K. Nilsson: Commonwealth Scientific and Industrial Research Organization

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Megakaryocytes (MK) generate platelets. Recently, we and others, have reported MK also regulate hematopoietic stem cells (HSC). Here we show high ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of HSC and critical for platelet formation. Using a mouse knockout model (Pf4-Srsf3Δ/Δ) with normal MK numbers, but essentially devoid of LCM, we demonstrate a pronounced increase in BM HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. Severe thrombocytopenia is observed in animals with diminished LCM, although there is no change in MK ploidy distribution, uncoupling endoreduplication and platelet production. When HSC isolated from a microenvironment essentially devoid of LCM reconstitute hematopoiesis in lethally irradiated mice, the absence of LCM increases HSC in BM, blood and spleen, and the recapitulation of thrombocytopenia. In contrast, following a competitive transplant using minimal numbers of WT HSC together with HSC from a microenvironment with diminished LCM, sufficient WT HSC-generated LCM regulates a normal HSC pool and prevents thrombocytopenia. Importantly, LCM are conserved in humans.

Date: 2023
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DOI: 10.1038/s41467-023-37780-7

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