Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

Luciene Borges; Vanessa K.P. Oliveira; June Baik; Sean C. Bendall; Rita C.R. Perlingeiro

doi:10.1182/blood-2018-09-874677

Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

Luciene Borges, Vanessa K.P. Oliveira, June Baik, Sean C. Bendall, Rita C.R. Perlingeiro

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

13 Scopus citations

Abstract

Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence. However, the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs; however, its necessity in adult HSCs is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin -Sca +Kit +-CD48 - CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence.

Original language	English (US)
Pages (from-to)	688-696
Number of pages	9
Journal	Blood
Volume	133
Issue number	7
DOIs	https://doi.org/10.1182/blood-2018-09-874677
State	Published - Feb 14 2019

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL085840 and U01-HL100407, and NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR055299 and R01-AR071439 (R.C.R.P.), and NIH, NHLBI grant T32HL007062 (J.B.). J.B. is the recipient of a Hartwell Foundation Fellowship.

Publisher Copyright:
© 2019 by The American Society of Hematology.

Keywords

Animals
Cell Cycle
Endoglin/genetics
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells/cytology
Mice
Mice, Inbred C57BL
Phosphorylation
Signal Transduction
Transforming Growth Factor beta/metabolism

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

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10.1182/blood-2018-09-874677

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376279

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title = "Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence",

abstract = "Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence. However, the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs; however, its necessity in adult HSCs is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin -Sca +Kit +-CD48 - CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence. ",

keywords = "Animals, Cell Cycle, Endoglin/genetics, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells/cytology, Mice, Mice, Inbred C57BL, Phosphorylation, Signal Transduction, Transforming Growth Factor beta/metabolism",

author = "Luciene Borges and Oliveira, {Vanessa K.P.} and June Baik and Bendall, {Sean C.} and Perlingeiro, {Rita C.R.}",

note = "Funding Information: This work was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL085840 and U01-HL100407, and NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR055299 and R01-AR071439 (R.C.R.P.), and NIH, NHLBI grant T32HL007062 (J.B.). J.B. is the recipient of a Hartwell Foundation Fellowship. Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology.",

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month = feb,

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doi = "10.1182/blood-2018-09-874677",

language = "English (US)",

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pages = "688--696",

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T1 - Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

AU - Borges, Luciene

AU - Oliveira, Vanessa K.P.

AU - Baik, June

AU - Bendall, Sean C.

AU - Perlingeiro, Rita C.R.

N1 - Funding Information: This work was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL085840 and U01-HL100407, and NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR055299 and R01-AR071439 (R.C.R.P.), and NIH, NHLBI grant T32HL007062 (J.B.). J.B. is the recipient of a Hartwell Foundation Fellowship. Publisher Copyright: © 2019 by The American Society of Hematology.

PY - 2019/2/14

Y1 - 2019/2/14

N2 - Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence. However, the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs; however, its necessity in adult HSCs is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin -Sca +Kit +-CD48 - CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence.

AB - Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence. However, the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs; however, its necessity in adult HSCs is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin -Sca +Kit +-CD48 - CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence.

KW - Animals

KW - Cell Cycle

KW - Endoglin/genetics

KW - Hematopoietic Stem Cell Transplantation

KW - Hematopoietic Stem Cells/cytology

KW - Mice

KW - Mice, Inbred C57BL

KW - Phosphorylation

KW - Signal Transduction

KW - Transforming Growth Factor beta/metabolism

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DO - 10.1182/blood-2018-09-874677

M3 - Article

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AN - SCOPUS:85061492160

SN - 0006-4971

VL - 133

SP - 688

EP - 696

JO - Blood

JF - Blood

IS - 7

ER -

Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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