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

Heazlewood, SY; Ahmad, T; Cao, B; Cao, H; Domingues, M; Sun, X; Heazlewood, CK; Li, S; Williams, B; Fulton, M; White, JF; Nebl, T; Nefzger, CM; Polo, JM; Kile, BT; Kraus, F; Ryan, MT; Sun, YB; Choong, PFM; Ellis, SL; Anko, ML; Nilsson, SK

Author(s): Heazlewood, SY; Ahmad, T; Cao, B; Cao, H; Domingues, M; Sun, X; Heazlewood, CK; Li, S; Williams, B; Fulton, M; White, JF; Nebl, T; Nefzger, CM; Polo, JM; Kile, BT; Kraus, F; Ryan, MT; Sun, YB; Choong, PFM; Ellis, SL; Anko, ML; Nilsson, SK;
Details: Publication Year 2023-04-13,Volume 14,Issue #1,Page 2099
Journal Title: Nature Communications
Publication Type: Research article
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-Srsf3(Delta/Delta)) 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.
Publisher: Springer Nature
Keywords: Humans; Animals; *Megakaryocytes/metabolism; Hematopoietic Stem Cells/metabolism; Blood Platelets; Thrombopoiesis/genetics; Hematopoiesis/genetics; *Thrombocytopenia/metabolism; Disease Models, Animal; Ploidies; Serine-Arginine Splicing Factors/metabolism
Department(s): Surgical Oncology; Laboratory Research
PubMed ID: 37055407
Publisher's Version: https://doi.org/10.1038/s41467-023-37780-7
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-37780-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-07-25 05:27:35

Last Modified: 2023-07-25 05:28:06