Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Maria N. Barrachina; Gerard Pernes; Isabelle C. Becker; Isabelle Allaeys; Thomas I. Hirsch; Dafna J. Groeneveld; Abdullah O. Khan; Daniela Freire; Karen Guo; Estelle Carminita; Pooranee K. Morgan; Thomas J.C. Collins; Natalie A. Mellett; Zimu Wei; Ibrahim Almazni; Joseph E. Italiano; James Luyendyk; Peter J. Meikle; Mark Puder; Neil V. Morgan; Eric Boilard; Andrew J. Murphy; Kellie R. Machlus

doi:10.1038/s44161-023-00305-y

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Maria N. Barrachina, Gerard Pernes, Isabelle C. Becker, Isabelle Allaeys, Thomas I. Hirsch, Dafna J. Groeneveld, Abdullah O. Khan, Daniela Freire, Karen Guo, Estelle Carminita, Pooranee K. Morgan, Thomas J.C. Collins, Natalie A. Mellett, Zimu Wei, Ibrahim Almazni, Joseph E. Italiano, James Luyendyk, Peter J. Meikle, Mark Puder, Neil V. MorganEric Boilard, Andrew J. Murphy, Kellie R. Machlus

Research output: Contribution to journal › Article › Research › peer-review

6 Citations (Scopus)

Abstract

Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.

Original language	English
Pages (from-to)	746-763
Number of pages	18
Journal	Nature Cardiovascular Research
Volume	2
Issue number	8
DOIs	https://doi.org/10.1038/s44161-023-00305-y
Publication status	Published - Aug 2023
Externally published	Yes

Access to Document

10.1038/s44161-023-00305-y

Cite this

Barrachina, M. N., Pernes, G., Becker, I. C., Allaeys, I., Hirsch, T. I., Groeneveld, D. J., Khan, A. O., Freire, D., Guo, K., Carminita, E., Morgan, P. K., Collins, T. J. C., Mellett, N. A., Wei, Z., Almazni, I., Italiano, J. E., Luyendyk, J., Meikle, P. J., Puder, M., ... Machlus, K. R. (2023). Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36. Nature Cardiovascular Research, 2(8), 746-763. https://doi.org/10.1038/s44161-023-00305-y

@article{8c481e6fcfec40cea62c1439f1e2669b,

title = "Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36",

abstract = "Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.",

author = "Barrachina, {Maria N.} and Gerard Pernes and Becker, {Isabelle C.} and Isabelle Allaeys and Hirsch, {Thomas I.} and Groeneveld, {Dafna J.} and Khan, {Abdullah O.} and Daniela Freire and Karen Guo and Estelle Carminita and Morgan, {Pooranee K.} and Collins, {Thomas J.C.} and Mellett, {Natalie A.} and Zimu Wei and Ibrahim Almazni and Italiano, {Joseph E.} and James Luyendyk and Meikle, {Peter J.} and Mark Puder and Morgan, {Neil V.} and Eric Boilard and Murphy, {Andrew J.} and Machlus, {Kellie R.}",

note = "Funding Information: This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124746 to K.R.M., R01DK112778 to J.L.) and the National Heart, Lung, and Blood Institute (R01HL151494 to K.R.M., 5T32HL007734 to T.I.H. and R35HL161175 to J.E.I.) (National Institutes of Health); fellowships from the American Society of Hematology (ASH Restart Award to M.N.B.) and the American Heart Association (23POST1011433 to M.N.B.); a Walter Benjamin Fellowship from the German Research Foundation (BE 7766/2-1 to I.C.B.); the Boston Children{\textquoteright}s Hospital Surgical Foundation (T.I.H. and M.P.); the Wellcome Trust (218649/Z/19/Z to A.O.K.); the Saudi Arabia Cultural Bureau in London (I.A.); the National Health and Medical Research Council of Australia (APP1194329 to A.J.M. and Investigator Grant 2009965 to P.J.M.); the Fonds de Recherche en Sant{\'e} du Qu{\'e}bec and Canadian Institutes of Health Research (E.B.); and the US Department of Agriculture National Institute of Food and Agriculture (to J.L.). Funding Information: This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124746 to K.R.M., R01DK112778 to J.L.) and the National Heart, Lung, and Blood Institute (R01HL151494 to K.R.M., 5T32HL007734 to T.I.H. and R35HL161175 to J.E.I.) (National Institutes of Health); fellowships from the American Society of Hematology (ASH Restart Award to M.N.B.) and the American Heart Association (23POST1011433 to M.N.B.); a Walter Benjamin Fellowship from the German Research Foundation (BE 7766/2-1 to I.C.B.); the Boston Children{\textquoteright}s Hospital Surgical Foundation (T.I.H. and M.P.); the Wellcome Trust (218649/Z/19/Z to A.O.K.); the Saudi Arabia Cultural Bureau in London (I.A.); the National Health and Medical Research Council of Australia (APP1194329 to A.J.M. and Investigator Grant 2009965 to P.J.M.); the Fonds de Recherche en Sant{\'e} du Qu{\'e}bec and Canadian Institutes of Health Research (E.B.); and the US Department of Agriculture National Institute of Food and Agriculture (to J.L.). We would like to thank C. Koo and M. Tomlinson from the University of Birmingham (Birmingham, UK) for assistance with in vitro characterization of the CD36 mutation and B. Nolan (Trinity College Dublin) for referring the patients to the GAPP study. We would also like to thank M. Laplante (University of Laval, Quebec, Canada) and his team for their help with experiments and for being an excellent collaborator. Thank you to J. Cardenas (The University of Texas Health Science Center at Houston) and L. Batista (Washington University in St. Louis) for their critical review of the manuscript, excellent edits and support during the publishing process. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = aug,

doi = "10.1038/s44161-023-00305-y",

language = "English",

volume = "2",

pages = "746--763",

journal = "Nature Cardiovascular Research",

issn = "2731-0590",

publisher = "Nature Publishing Group",

number = "8",

}

Barrachina, MN, Pernes, G, Becker, IC, Allaeys, I, Hirsch, TI, Groeneveld, DJ, Khan, AO, Freire, D, Guo, K, Carminita, E, Morgan, PK, Collins, TJC, Mellett, NA, Wei, Z, Almazni, I, Italiano, JE, Luyendyk, J, Meikle, PJ, Puder, M, Morgan, NV, Boilard, E, Murphy, AJ & Machlus, KR 2023, 'Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36', Nature Cardiovascular Research, vol. 2, no. 8, pp. 746-763. https://doi.org/10.1038/s44161-023-00305-y

TY - JOUR

T1 - Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

AU - Barrachina, Maria N.

AU - Pernes, Gerard

AU - Becker, Isabelle C.

AU - Allaeys, Isabelle

AU - Hirsch, Thomas I.

AU - Groeneveld, Dafna J.

AU - Khan, Abdullah O.

AU - Freire, Daniela

AU - Guo, Karen

AU - Carminita, Estelle

AU - Morgan, Pooranee K.

AU - Collins, Thomas J.C.

AU - Mellett, Natalie A.

AU - Wei, Zimu

AU - Almazni, Ibrahim

AU - Italiano, Joseph E.

AU - Luyendyk, James

AU - Meikle, Peter J.

AU - Puder, Mark

AU - Morgan, Neil V.

AU - Boilard, Eric

AU - Murphy, Andrew J.

AU - Machlus, Kellie R.

N1 - Funding Information: This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124746 to K.R.M., R01DK112778 to J.L.) and the National Heart, Lung, and Blood Institute (R01HL151494 to K.R.M., 5T32HL007734 to T.I.H. and R35HL161175 to J.E.I.) (National Institutes of Health); fellowships from the American Society of Hematology (ASH Restart Award to M.N.B.) and the American Heart Association (23POST1011433 to M.N.B.); a Walter Benjamin Fellowship from the German Research Foundation (BE 7766/2-1 to I.C.B.); the Boston Children’s Hospital Surgical Foundation (T.I.H. and M.P.); the Wellcome Trust (218649/Z/19/Z to A.O.K.); the Saudi Arabia Cultural Bureau in London (I.A.); the National Health and Medical Research Council of Australia (APP1194329 to A.J.M. and Investigator Grant 2009965 to P.J.M.); the Fonds de Recherche en Santé du Québec and Canadian Institutes of Health Research (E.B.); and the US Department of Agriculture National Institute of Food and Agriculture (to J.L.). Funding Information: This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124746 to K.R.M., R01DK112778 to J.L.) and the National Heart, Lung, and Blood Institute (R01HL151494 to K.R.M., 5T32HL007734 to T.I.H. and R35HL161175 to J.E.I.) (National Institutes of Health); fellowships from the American Society of Hematology (ASH Restart Award to M.N.B.) and the American Heart Association (23POST1011433 to M.N.B.); a Walter Benjamin Fellowship from the German Research Foundation (BE 7766/2-1 to I.C.B.); the Boston Children’s Hospital Surgical Foundation (T.I.H. and M.P.); the Wellcome Trust (218649/Z/19/Z to A.O.K.); the Saudi Arabia Cultural Bureau in London (I.A.); the National Health and Medical Research Council of Australia (APP1194329 to A.J.M. and Investigator Grant 2009965 to P.J.M.); the Fonds de Recherche en Santé du Québec and Canadian Institutes of Health Research (E.B.); and the US Department of Agriculture National Institute of Food and Agriculture (to J.L.). We would like to thank C. Koo and M. Tomlinson from the University of Birmingham (Birmingham, UK) for assistance with in vitro characterization of the CD36 mutation and B. Nolan (Trinity College Dublin) for referring the patients to the GAPP study. We would also like to thank M. Laplante (University of Laval, Quebec, Canada) and his team for their help with experiments and for being an excellent collaborator. Thank you to J. Cardenas (The University of Texas Health Science Center at Houston) and L. Batista (Washington University in St. Louis) for their critical review of the manuscript, excellent edits and support during the publishing process. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/8

Y1 - 2023/8

N2 - Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.

AB - Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.

UR - http://www.scopus.com/inward/record.url?scp=85164928085&partnerID=8YFLogxK

U2 - 10.1038/s44161-023-00305-y

DO - 10.1038/s44161-023-00305-y

M3 - Article

AN - SCOPUS:85164928085

SN - 2731-0590

VL - 2

SP - 746

EP - 763

JO - Nature Cardiovascular Research

JF - Nature Cardiovascular Research

IS - 8

ER -

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Abstract

Access to Document

Other files and links

Cite this