Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin

Christopher Hoover; Yuji Kondo; Bojing Shao; Michael J. McDaniel; Robert Lee; Samuel McGee; Sidney Whiteheart; Wolfgang Bergmeier; Rodger P. McEver; Lijun Xia

doi:10.1182/blood.2020010310

Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin

Christopher Hoover, Yuji Kondo, Bojing Shao, Michael J. McDaniel, Robert Lee, Samuel McGee, Sidney Whiteheart, Wolfgang Bergmeier, Rodger P. McEver, Lijun Xia

Molecular and Cellular Biochemistry

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

16 Scopus citations

Abstract

During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1–induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

Original language	English
Pages (from-to)	2756-2769
Number of pages	14
Journal	Blood
Volume	137
Issue number	20
DOIs	https://doi.org/10.1182/blood.2020010310
State	Published - May 20 2021

Bibliographical note

Publisher Copyright:
© 2021 American Society of Hematology

Funding

The authors thank James George for critical comments, and the Imaging Core Facility of the Oklahoma Medical Research Foundation for tissue processing and electron microscopy. The study is supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute grants HL128390, HL149860, HL153728 (L.X.), HL134210 (C.H.), and HL133668 (W.B.); NIH, National Institute of Child Health and Human Development grant HD083418 (L.X.); and NIH, National Institute of General Medical Sciences grant GM114731 (R.P.M.). The study is supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute grants HL128390, HL149860, HL153728 (L.X.), HL134210 (C.H.), and HL133668 (W.B.); NIH, National Institute of Child Health and Human Development grant HD083418 (L.X.); and NIH, National Institute of General Medical Sciences grant GM114731 (R.P.M.).

Funders	Funder number
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	HL128390, HL134210, HL149860, HL133668, HL153728
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	GM114731
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	R01HD083418
Oklahoma Medical Research Foundation

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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title = "Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin",

abstract = "During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1–induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.",

author = "Christopher Hoover and Yuji Kondo and Bojing Shao and McDaniel, \{Michael J.\} and Robert Lee and Samuel McGee and Sidney Whiteheart and Wolfgang Bergmeier and McEver, \{Rodger P.\} and Lijun Xia",

note = "Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

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doi = "10.1182/blood.2020010310",

language = "English",

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AU - Hoover, Christopher

AU - Kondo, Yuji

AU - Shao, Bojing

AU - McDaniel, Michael J.

AU - Lee, Robert

AU - McGee, Samuel

AU - Whiteheart, Sidney

AU - Bergmeier, Wolfgang

AU - McEver, Rodger P.

AU - Xia, Lijun

PY - 2021/5/20

Y1 - 2021/5/20

N2 - During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1–induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

AB - During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1–induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

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Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin

Abstract

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