Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

Damanpreet Garcha; Susan P. Walker; Teresa M. MacDonald; Jon Hyett; Jessica Jellins; Jenny Myers; Sebastian E. Illanes; Jhy K. Nien; Manuel Schepeler; Emerson Keenan; Carole Anne Whigham; Ping Cannon; Elizabeth Murray; Tuong Vi Nguyen; Manju Kandel; Joshua Masci; Ciara Murphy; Tess Cruickshank; Natasha Pritchard; Natalie J. Hannan; Fiona Brownfoot; Alexandra Roddy Mitchell; Anna Middleton; Gabrielle Pell; Georgia P. Wong; Stephen Tong; Tu’uhevaha J. Kaitu’u-Lino

doi:10.1038/s41598-021-96077-1

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

Damanpreet Garcha
, Susan P. Walker
, Teresa M. MacDonald
, Jon Hyett
, Jessica Jellins
, Jenny Myers
, Sebastian E. Illanes
, Jhy K. Nien
, Manuel Schepeler
, Emerson Keenan
, Carole Anne Whigham
, Ping Cannon
, Elizabeth Murray
, Tuong Vi Nguyen
, Manju Kandel
, Joshua Masci
, Ciara Murphy
, Tess Cruickshank
, Natasha Pritchard
, Natalie J. Hannan

Fiona Brownfoot, Alexandra Roddy Mitchell, Anna Middleton, Gabrielle Pell, Georgia P. Wong, Stephen Tong, Tu’uhevaha J. Kaitu’u-Lino^*

^*Corresponding author for this work

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

8 Scopus citations

Abstract

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks’ gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

Original language	English
Article number	16595
Pages (from-to)	16595
Journal	Scientific Reports
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41598-021-96077-1
State	Published - 16 Aug 2021

Bibliographical note

Funding Information:
Funding for this work was provided by the National Health and Medical Research Council (#1065854, #1183854, #116071), an Australian Government Research Training Program Scholarship, and RANZCOG Taylor Hammond Scholarship to TM; National Health and Medical Research Council Fellowships to TKL (#1159261), NJH (#1146128), ST (#1136418). The funders played no role in study design or analysis.

Funding Information:
from the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan and cultured according to the publication from Okae and colleagues28. Syncytiotrophoblasts were differentiated from cyto-trophoblasts as previously described28.

Publisher Copyright:
© 2021, The Author(s).

Keywords

Adult
Area Under Curve
Birth Weight
Cell Hypoxia
Delivery, Obstetric
Diabetes, Gestational
Electron Transport
Female
Fetal Growth Retardation
Gestational Age
Humans
Hypertension
Infant, Newborn
Infant, Small for Gestational Age
Matrix Metalloproteinases
Metformin
Mitochondria
Organ Size
Overweight
Placenta
Pre-Eclampsia
Pregnancy
Pregnancy Complications
ROC Curve
Smoking
Syndecan-1
Trophoblast

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10.1038/s41598-021-96077-1

Cite this

Garcha, D., Walker, S. P., MacDonald, T. M., Hyett, J., Jellins, J., Myers, J., Illanes, S. E., Nien, J. K., Schepeler, M., Keenan, E., Whigham, C. A., Cannon, P., Murray, E., Nguyen, T. V., Kandel, M., Masci, J., Murphy, C., Cruickshank, T., Pritchard, N., ... Kaitu’u-Lino, T. J. (2021). Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria. Scientific Reports, 11(1), 16595. Article 16595. https://doi.org/10.1038/s41598-021-96077-1

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title = "Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria",

abstract = "Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks{\textquoteright} gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks{\textquoteright} gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks{\textquoteright} gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.",

keywords = "Adult, Area Under Curve, Birth Weight, Cell Hypoxia, Delivery, Obstetric, Diabetes, Gestational, Electron Transport, Female, Fetal Growth Retardation, Gestational Age, Humans, Hypertension, Infant, Newborn, Infant, Small for Gestational Age, Matrix Metalloproteinases, Metformin, Mitochondria, Organ Size, Overweight, Placenta, Pre-Eclampsia, Pregnancy, Pregnancy Complications, ROC Curve, Smoking, Syndecan-1, Trophoblast",

author = "Damanpreet Garcha and Walker, \{Susan P.\} and MacDonald, \{Teresa M.\} and Jon Hyett and Jessica Jellins and Jenny Myers and Illanes, \{Sebastian E.\} and Nien, \{Jhy K.\} and Manuel Schepeler and Emerson Keenan and Whigham, \{Carole Anne\} and Ping Cannon and Elizabeth Murray and Nguyen, \{Tuong Vi\} and Manju Kandel and Joshua Masci and Ciara Murphy and Tess Cruickshank and Natasha Pritchard and Hannan, \{Natalie J.\} and Fiona Brownfoot and \{Roddy Mitchell\}, Alexandra and Anna Middleton and Gabrielle Pell and Wong, \{Georgia P.\} and Stephen Tong and Kaitu{\textquoteright}u-Lino, \{Tu{\textquoteright}uhevaha J.\}",

note = "Funding Information: Funding for this work was provided by the National Health and Medical Research Council (\#1065854, \#1183854, \#116071), an Australian Government Research Training Program Scholarship, and RANZCOG Taylor Hammond Scholarship to TM; National Health and Medical Research Council Fellowships to TKL (\#1159261), NJH (\#1146128), ST (\#1136418). The funders played no role in study design or analysis. Funding Information: from the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan and cultured according to the publication from Okae and colleagues28. Syncytiotrophoblasts were differentiated from cyto-trophoblasts as previously described28. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = aug,

day = "16",

doi = "10.1038/s41598-021-96077-1",

language = "English",

volume = "11",

pages = "16595",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

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Garcha, D, Walker, SP, MacDonald, TM, Hyett, J, Jellins, J, Myers, J, Illanes, SE, Nien, JK, Schepeler, M, Keenan, E, Whigham, CA, Cannon, P, Murray, E, Nguyen, TV, Kandel, M, Masci, J, Murphy, C, Cruickshank, T, Pritchard, N, Hannan, NJ, Brownfoot, F, Roddy Mitchell, A, Middleton, A, Pell, G, Wong, GP, Tong, S & Kaitu’u-Lino, TJ 2021, 'Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria', Scientific Reports, vol. 11, no. 1, 16595, pp. 16595. https://doi.org/10.1038/s41598-021-96077-1

TY - JOUR

T1 - Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

AU - Garcha, Damanpreet

AU - Walker, Susan P.

AU - MacDonald, Teresa M.

AU - Hyett, Jon

AU - Jellins, Jessica

AU - Myers, Jenny

AU - Illanes, Sebastian E.

AU - Nien, Jhy K.

AU - Schepeler, Manuel

AU - Keenan, Emerson

AU - Whigham, Carole Anne

AU - Cannon, Ping

AU - Murray, Elizabeth

AU - Nguyen, Tuong Vi

AU - Kandel, Manju

AU - Masci, Joshua

AU - Murphy, Ciara

AU - Cruickshank, Tess

AU - Pritchard, Natasha

AU - Hannan, Natalie J.

AU - Brownfoot, Fiona

AU - Roddy Mitchell, Alexandra

AU - Middleton, Anna

AU - Pell, Gabrielle

AU - Wong, Georgia P.

AU - Tong, Stephen

AU - Kaitu’u-Lino, Tu’uhevaha J.

N1 - Funding Information: Funding for this work was provided by the National Health and Medical Research Council (#1065854, #1183854, #116071), an Australian Government Research Training Program Scholarship, and RANZCOG Taylor Hammond Scholarship to TM; National Health and Medical Research Council Fellowships to TKL (#1159261), NJH (#1146128), ST (#1136418). The funders played no role in study design or analysis. Funding Information: from the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan and cultured according to the publication from Okae and colleagues28. Syncytiotrophoblasts were differentiated from cyto-trophoblasts as previously described28. Publisher Copyright: © 2021, The Author(s).

PY - 2021/8/16

Y1 - 2021/8/16

N2 - Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks’ gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

AB - Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks’ gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

KW - Adult

KW - Area Under Curve

KW - Birth Weight

KW - Cell Hypoxia

KW - Delivery, Obstetric

KW - Diabetes, Gestational

KW - Electron Transport

KW - Female

KW - Fetal Growth Retardation

KW - Gestational Age

KW - Humans

KW - Hypertension

KW - Infant, Newborn

KW - Infant, Small for Gestational Age

KW - Matrix Metalloproteinases

KW - Metformin

KW - Mitochondria

KW - Organ Size

KW - Overweight

KW - Placenta

KW - Pre-Eclampsia

KW - Pregnancy

KW - Pregnancy Complications

KW - ROC Curve

KW - Smoking

KW - Syndecan-1

KW - Trophoblast

UR - https://www.scopus.com/pages/publications/85112703768

U2 - 10.1038/s41598-021-96077-1

DO - 10.1038/s41598-021-96077-1

M3 - Article

C2 - 34400721

AN - SCOPUS:85112703768

SN - 2045-2322

VL - 11

SP - 16595

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 16595

ER -

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

Abstract

Bibliographical note

Keywords

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