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; Susan K. Nilsson

doi:10.1038/s41467-023-37780-7

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, Susan K. Nilsson^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

38 Sitaatiot (Scopus)

26 Lataukset (Pure)

Abstrakti

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.

Alkuperäiskieli	Englanti
Artikkeli	2099
Sivumäärä	18
Julkaisu	Nature Communications
Vuosikerta	14
Numero	1
DOI - pysyväislinkit	https://doi.org/10.1038/s41467-023-37780-7
Tila	Julkaistu - 13 huhtik. 2023
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship. The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship.

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

Yleinen kemia
Yleinen biokemia, genetiikka ja molekyylibiologia
General
Yleinen fysiikka ja tähtitiede

Pääsy asiakirjaan

10.1038/s41467-023-37780-7Lisenssi: CC BY

s41467-023-37780-7-1Final published version, 4,5 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi:tuni-202305316351Lisenssi: CC BY

Siteeraa tätä

Heazlewood, S. Y., Ahmad, T., Cao, B., Cao, H., Domingues, M., Sun, X., Heazlewood, C. K., Li, S., Williams, B., Fulton, M., White, J. F., Nebl, T., Nefzger, C. M., Polo, J. M., Kile, B. T., Kraus, F., Ryan, M. T., Sun, Y. B., Choong, P. F. M., ... Nilsson, S. K. (2023). High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production. Nature Communications, 14(1), Artikkeli 2099. https://doi.org/10.1038/s41467-023-37780-7

@article{ee5a08e4e5a9409f9216a77bc8f16991,

title = "High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production",

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. ",

author = "Heazlewood, \{Shen Y.\} and Tanveer Ahmad and Benjamin Cao and Huimin Cao and Melanie Domingues and Xuan Sun and Heazlewood, \{Chad K.\} and Songhui Li and Brenda Williams and Madeline Fulton and White, \{Jacinta F.\} and Tom Nebl and Nefzger, \{Christian M.\} and Polo, \{Jose M.\} and Kile, \{Benjamin T.\} and Felix Kraus and Ryan, \{Michael T.\} and Sun, \{Yu B.\} and Choong, \{Peter F.M.\} and Ellis, \{Sarah L.\} and Anko, \{Minna Liisa\} and Nilsson, \{Susan K.\}",

note = "Funding Information: The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship. Funding Information: The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship. Publisher Copyright: {\textcopyright} 2023, Crown.",

year = "2023",

month = apr,

day = "13",

doi = "10.1038/s41467-023-37780-7",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

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 2023, 'High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production', Nature Communications, Vuosikerta 14, Nro 1, 2099. https://doi.org/10.1038/s41467-023-37780-7

TY - JOUR

T1 - High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production

AU - Heazlewood, Shen Y.

AU - Ahmad, Tanveer

AU - Cao, Benjamin

AU - Cao, Huimin

AU - Domingues, Melanie

AU - Sun, Xuan

AU - Heazlewood, Chad K.

AU - Li, Songhui

AU - Williams, Brenda

AU - Fulton, Madeline

AU - White, Jacinta F.

AU - Nebl, Tom

AU - Nefzger, Christian M.

AU - Polo, Jose M.

AU - Kile, Benjamin T.

AU - Kraus, Felix

AU - Ryan, Michael T.

AU - Sun, Yu B.

AU - Choong, Peter F.M.

AU - Ellis, Sarah L.

AU - Anko, Minna Liisa

AU - Nilsson, Susan K.

N1 - Funding Information: The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship. Funding Information: The authors acknowledge technical assistance from Jessica Hatwell-Humble, Daniela Cardozo and Andrea Reitsma as well as staff and use of facilities at FlowCore, Monash Micro Imaging and Monash Animal Research Platform (Monash University, Australia). The authors thank Patrick Tam for RFP mice, Klaus Matthaei for GFP mice, Angela Cochrane and Michelle Dowsey for co-ordinating the provision and collection of human samples and Samir Taoudi for his rigorous discussion. We acknowledge Ana Oteiza for her contribution in generating some of the schematics. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. SKN is supported by a CSIRO OCE Science Leader Fellowship. Publisher Copyright: © 2023, Crown.

PY - 2023/4/13

Y1 - 2023/4/13

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-023-37780-7

DO - 10.1038/s41467-023-37780-7

M3 - Article

C2 - 37055407

AN - SCOPUS:85152471293

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2099

ER -

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

Abstrakti

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!!ASJC Scopus subject areas

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