Você está na página 1de 44

See discussions, stats, and author profiles for this publication at:

<a href=See d i scuss i o n s, stats, a n d aut h o r p r o fi les f o r t hi s publ ication at: https://www.researchgate.net/publication/234019222 Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia Article in Molecular Aspects of Medicine · December 2012 DOI: 10.1016/j.mam.2012.12.008 · Source: PubMed CITATIONS 55 READS 79 6 authors , including: Lei Ji Chinese Academy of Sciences 20 PUBLICATIONS 350 CITATIONS SEE PROFILE Guodong Fu Mount Sinai Hospital, Toronto 21 PUBLICATIONS 480 CITATIONS SEE PROFILE Jelena Brkic York University 5 PUBLICATIONS 142 CITATIONS SEE PROFILE Hui-xia Yang Beijing Medical University 136 PUBLICATIONS 942 CITATIONS SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Available from: Guodong Fu Retrieved on: 29 August 2016 " id="pdf-obj-0-29" src="pdf-obj-0-29.jpg">

Article in Molecular Aspects of Medicine · December 2012

DOI: 10.1016/j.mam.2012.12.008 · Source: PubMed

CITATIONS

55

READS

79

6 authors, including:

5 PUBLICATIONS 142 CITATIONS SEE PROFILE

136 PUBLICATIONS 942 CITATIONS SEE PROFILE

All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

Available from: Guodong Fu Retrieved on: 29 August 2016

<a href=Molecular Aspects of Medicine 34 (2013) 981–1023 Contents lists available at SciVerse ScienceDirect Molecular Aspects of Medicine journal homepage: www.else vier.com/locate/mam Review Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia Lei Ji , Jelena Brkic´ , Ming Liu , Guodong Fu , Chun Peng , Yan-Ling Wang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3 article info Article history: Available online 28 December 2012 Keywords: Placental development Trophoblast differentiation Invasive pathway Preeclampsia Biomarker abstract The placenta is a transient organ that forms during pregnancy to support the growth and development of the fetus. During human placental development, trophoblast cells differen- tiate through two major pathways. In the villous pathway, cytotrophoblast cells fuse to form multinucleated syncytiotrophoblast. In the extravillous pathway, cytotrophoblast cells acquire an invasive phenotype and differentiate into either (1) interstitial extravillous trophoblasts, which invade the decidua and a portion of the myometrium, or (2) endovas- cular extravillous trophoblasts, which remodel the maternal vasculature. These differenti- ation events are tightly controlled by the interplay of oxygen tension, transcription factors, hormones, growth factors, and other signaling molecules. More recently, microRNAs have been implicated in this regulatory process. Abnormal placental development, particularly the limited invasion of trophoblast cells into the uterus and the subsequent failure of the remodeling of maternal spiral arteries, is believed to cause preeclampsia, a severe preg- nancy related disorder characterized by hypertension and proteinuria. Oxidative stress, the abnormal production and/or function of signaling molecules, as well as aberrant microR- NAs expression have been suggested to participate in the pathogenesis of preeclampsia. Several potential biomarkers for preeclampsia have been identified, creating new opportu- nities for the development of strategies to diagnose, prevent, and treat this disorder. Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 2. Pathways of human placental trophoblast cell differentiation . 983 2.1. Trophoblast cell fusion – differentiation pathway toward multinucleated syncytiotrophoblasts . . . . . . . . . . . . . . . . . . . 983 2.1.1. Formation of STBs is downstream of the fusogenic event . 983 2.1.2. Balance between tissue renewal and tissue loss in the syncytial layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984 2.2. Trophoblast cell differentiation along the invasive pathway 985 2.2.1. Interstitial trophoblast cells – invasion into uterine stroma . 985 2.2.2. Endovascular trophoblast cells – remodeling of uterine spiral arteries . 986 2.2.3. Endoglandular trophoblast cells – uterine glandular remodeling . 988 2.3. Summary of the characteristics of the various trophoblast subtypes 988 ⇑ Corresponding authors. Addresses: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3. Tel.: +1 416 736 2100x40558; fax: +1 416 736 5698 (C. Peng), State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, People’s Republic of China. Tel./fax: +86 10 64807195 (Y.-L. Wang). E-mail addresses: cpeng@yorku.ca (C. Peng), wangyl@ioz.ac.cn (Y.-L. Wang). Equal contribution. 0098-2997/$ - see front matter Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2012.12.008 " id="pdf-obj-1-5" src="pdf-obj-1-5.jpg">

Contents lists available at SciVerse ScienceDirect

Molecular Aspects of Medicine

journal homepage: www.else vier.com/locate/mam

<a href=Molecular Aspects of Medicine 34 (2013) 981–1023 Contents lists available at SciVerse ScienceDirect Molecular Aspects of Medicine journal homepage: www.else vier.com/locate/mam Review Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia Lei Ji , Jelena Brkic´ , Ming Liu , Guodong Fu , Chun Peng , Yan-Ling Wang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3 article info Article history: Available online 28 December 2012 Keywords: Placental development Trophoblast differentiation Invasive pathway Preeclampsia Biomarker abstract The placenta is a transient organ that forms during pregnancy to support the growth and development of the fetus. During human placental development, trophoblast cells differen- tiate through two major pathways. In the villous pathway, cytotrophoblast cells fuse to form multinucleated syncytiotrophoblast. In the extravillous pathway, cytotrophoblast cells acquire an invasive phenotype and differentiate into either (1) interstitial extravillous trophoblasts, which invade the decidua and a portion of the myometrium, or (2) endovas- cular extravillous trophoblasts, which remodel the maternal vasculature. These differenti- ation events are tightly controlled by the interplay of oxygen tension, transcription factors, hormones, growth factors, and other signaling molecules. More recently, microRNAs have been implicated in this regulatory process. Abnormal placental development, particularly the limited invasion of trophoblast cells into the uterus and the subsequent failure of the remodeling of maternal spiral arteries, is believed to cause preeclampsia, a severe preg- nancy related disorder characterized by hypertension and proteinuria. Oxidative stress, the abnormal production and/or function of signaling molecules, as well as aberrant microR- NAs expression have been suggested to participate in the pathogenesis of preeclampsia. Several potential biomarkers for preeclampsia have been identified, creating new opportu- nities for the development of strategies to diagnose, prevent, and treat this disorder. Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 2. Pathways of human placental trophoblast cell differentiation . 983 2.1. Trophoblast cell fusion – differentiation pathway toward multinucleated syncytiotrophoblasts . . . . . . . . . . . . . . . . . . . 983 2.1.1. Formation of STBs is downstream of the fusogenic event . 983 2.1.2. Balance between tissue renewal and tissue loss in the syncytial layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984 2.2. Trophoblast cell differentiation along the invasive pathway 985 2.2.1. Interstitial trophoblast cells – invasion into uterine stroma . 985 2.2.2. Endovascular trophoblast cells – remodeling of uterine spiral arteries . 986 2.2.3. Endoglandular trophoblast cells – uterine glandular remodeling . 988 2.3. Summary of the characteristics of the various trophoblast subtypes 988 ⇑ Corresponding authors. Addresses: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3. Tel.: +1 416 736 2100x40558; fax: +1 416 736 5698 (C. Peng), State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, People’s Republic of China. Tel./fax: +86 10 64807195 (Y.-L. Wang). E-mail addresses: cpeng@yorku.ca (C. Peng), wangyl@ioz.ac.cn (Y.-L. Wang). Equal contribution. 0098-2997/$ - see front matter Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2012.12.008 " id="pdf-obj-1-16" src="pdf-obj-1-16.jpg">

Review

Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia

<a href=Molecular Aspects of Medicine 34 (2013) 981–1023 Contents lists available at SciVerse ScienceDirect Molecular Aspects of Medicine journal homepage: www.else vier.com/locate/mam Review Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia Lei Ji , Jelena Brkic´ , Ming Liu , Guodong Fu , Chun Peng , Yan-Ling Wang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3 article info Article history: Available online 28 December 2012 Keywords: Placental development Trophoblast differentiation Invasive pathway Preeclampsia Biomarker abstract The placenta is a transient organ that forms during pregnancy to support the growth and development of the fetus. During human placental development, trophoblast cells differen- tiate through two major pathways. In the villous pathway, cytotrophoblast cells fuse to form multinucleated syncytiotrophoblast. In the extravillous pathway, cytotrophoblast cells acquire an invasive phenotype and differentiate into either (1) interstitial extravillous trophoblasts, which invade the decidua and a portion of the myometrium, or (2) endovas- cular extravillous trophoblasts, which remodel the maternal vasculature. These differenti- ation events are tightly controlled by the interplay of oxygen tension, transcription factors, hormones, growth factors, and other signaling molecules. More recently, microRNAs have been implicated in this regulatory process. Abnormal placental development, particularly the limited invasion of trophoblast cells into the uterus and the subsequent failure of the remodeling of maternal spiral arteries, is believed to cause preeclampsia, a severe preg- nancy related disorder characterized by hypertension and proteinuria. Oxidative stress, the abnormal production and/or function of signaling molecules, as well as aberrant microR- NAs expression have been suggested to participate in the pathogenesis of preeclampsia. Several potential biomarkers for preeclampsia have been identified, creating new opportu- nities for the development of strategies to diagnose, prevent, and treat this disorder. Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 2. Pathways of human placental trophoblast cell differentiation . 983 2.1. Trophoblast cell fusion – differentiation pathway toward multinucleated syncytiotrophoblasts . . . . . . . . . . . . . . . . . . . 983 2.1.1. Formation of STBs is downstream of the fusogenic event . 983 2.1.2. Balance between tissue renewal and tissue loss in the syncytial layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984 2.2. Trophoblast cell differentiation along the invasive pathway 985 2.2.1. Interstitial trophoblast cells – invasion into uterine stroma . 985 2.2.2. Endovascular trophoblast cells – remodeling of uterine spiral arteries . 986 2.2.3. Endoglandular trophoblast cells – uterine glandular remodeling . 988 2.3. Summary of the characteristics of the various trophoblast subtypes 988 ⇑ Corresponding authors. Addresses: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3. Tel.: +1 416 736 2100x40558; fax: +1 416 736 5698 (C. Peng), State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, People’s Republic of China. Tel./fax: +86 10 64807195 (Y.-L. Wang). E-mail addresses: cpeng@yorku.ca (C. Peng), wangyl@ioz.ac.cn (Y.-L. Wang). Equal contribution. 0098-2997/$ - see front matter Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2012.12.008 " id="pdf-obj-1-23" src="pdf-obj-1-23.jpg">

Lei Ji a ,1 , Jelena Brkic´ b ,1 , Ming Liu a ,1 , Guodong Fu b , Chun Peng b , , Yan-Ling Wang a ,

a State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China b Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3

article info

Article history:

Available online 28 December 2012

Keywords:

Placental development Trophoblast differentiation Invasive pathway Preeclampsia Biomarker

abstract

The placenta is a transient organ that forms during pregnancy to support the growth and development of the fetus. During human placental development, trophoblast cells differen-

tiate through two major pathways. In the villous pathway, cytotrophoblast cells fuse to form multinucleated syncytiotrophoblast. In the extravillous pathway, cytotrophoblast cells acquire an invasive phenotype and differentiate into either (1) interstitial extravillous trophoblasts, which invade the decidua and a portion of the myometrium, or (2) endovas- cular extravillous trophoblasts, which remodel the maternal vasculature. These differenti- ation events are tightly controlled by the interplay of oxygen tension, transcription factors, hormones, growth factors, and other signaling molecules. More recently, microRNAs have been implicated in this regulatory process. Abnormal placental development, particularly the limited invasion of trophoblast cells into the uterus and the subsequent failure of the remodeling of maternal spiral arteries, is believed to cause preeclampsia, a severe preg- nancy related disorder characterized by hypertension and proteinuria. Oxidative stress, the abnormal production and/or function of signaling molecules, as well as aberrant microR- NAs expression have been suggested to participate in the pathogenesis of preeclampsia. Several potential biomarkers for preeclampsia have been identified, creating new opportu- nities for the development of strategies to diagnose, prevent, and treat this disorder. Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . .
1.
Introduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
982
2.
Pathways of human placental trophoblast cell differentiation
. 983
2.1.
Trophoblast cell fusion – differentiation pathway toward multinucleated syncytiotrophoblasts
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
983
2.1.1.
Formation of STBs is downstream of the fusogenic event
. 983
2.1.2.
Balance between tissue renewal and tissue loss in the syncytial layer
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
984
2.2.
Trophoblast cell differentiation along the invasive pathway
985
2.2.1.
Interstitial trophoblast cells – invasion into uterine stroma
. 985
2.2.2.
Endovascular trophoblast cells – remodeling of uterine spiral arteries
. 986
2.2.3.
Endoglandular trophoblast cells – uterine glandular remodeling
. 988
2.3.
Summary of the characteristics of the various trophoblast subtypes
988

Corresponding authors. Addresses: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3. Tel.: +1 416 736 2100x40558; fax: +1 416 736 5698 (C. Peng), State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, People’s Republic of China. Tel./fax: +86 10 64807195 (Y.-L. Wang). E-mail addresses: cpeng@yorku.ca (C. Peng), wangyl@ioz.ac.cn (Y.-L. Wang). 1 Equal contribution.

0098-2997/$ - see front matter Crown Copyright 2012 Published by Elsevier Ltd. All rights reserved.

  • 982 L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

  • 3. Model systems for examining placental trophoblast cell functions

 

.

989

3.1.

Primary cultures of human trophoblast cells

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

989

3.2.

Trophoblastic

cell lines

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

989

3.3.

Trophoblast

stem

 

cell

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

990

3.4.

Co-culture of trophoblast cells/placental villi and other cell types or explants

 

.

990

3.5.

Animal models for investigating placental development

 

.

991

3.5.1.

Placenta-specific

 

transgene

 

expression

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

991

3.5.2.

Virus-mediated genetic manipulation in rodent placenta

 

.

992

3.5.3.

Transplantation

 

of cells into

 

placenta .

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

992

  • 4. Regulatory mechanisms involved in human trophoblast cell differentiation toward the invasive pathway

 

.

992

4.1.

Oxygen tension

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

993

4.1.1.

Oxygen tension regulates the balance between trophoblast cell proliferation and

 

.

993

4.1.2.

Hypoxia induces trophoblast cell apoptosis

 

.

994

4.1.3.

HIFs are oxygen

 

sensors

 

in placenta

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

994

4.2.

4.1.4.

Growth

Role of HIFs

factors

.

.

in normoxic condition .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

995

995

4.2.1.

VEGF family

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

995

4.2.2.

TGF-b superfamily

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

996

4.2.3.

HGF/c-Met

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

997

4.2.4.

Notch

signaling

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

998

4.2.5.

Wnt signaling

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

999

4.3.

Hormones

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

999

4.3.1.

GnRH

 

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

999

4.3.2.

hCG

.........................................................................

 

1000

4.4.

MicroRNAs (miRNAs)

 

1000

4.4.1.

Expression of miRNAs in the human placenta

 

...................................

 

1000

4.4.2.

Regulation of miRNA expression in trophoblast

 

...................................

1001

4.4.3.

Modulation of trophoblast cellular activities by

...................................

1001

4.4.4.

The imprinted H19 gene functions via encoding miR-675 in the

 

................

1003

  • 5. Implications for the pathogenesis of preeclampsia (PE)

 

1004

5.1.

Overview of

 

1004

5.2.

The injury from hypoxia–reoxygenation

 

1004

5.3.

Placental factors that contribute to preeclampsia

 

1005

5.3.1.

Angiogenic and anti-angiogenic factors

 

......................................................

 

1005

5.3.2.

Catechol-O-methyltransferase (COMT) and 2-methoxyestradiol (2-ME)

 

................

1006

5.3.3.

Corin

 

.........................................................................

1006

5.3.4.

Notch signaling

 

.........................................................................

1006

5.3.5.

Nodal, Activin A and Inhibin A

 

......................................................

1007

5.3.6.

.........................................................................

1007

5.3.7.

hCG

.........................................................................

1007

5.3.8.

miRNAs

 

.........................................................................

1007

5.4.

Genetic alterations in association with

 

1008

  • 6. Summary and perspectives

 

1009

Acknowledgements

 

1009

References

 

1010

1. Introduction

The placenta is a transient organ that has a multitude of critical roles in the maintenance and protection of the developing fetus throughout the entire pregnancy (Anin et al., 2004). The multifaceted nature of the placenta has been demonstrated, through animal models and studies of human pregnancies, to be vital for the survival and health of the embryo and the mother (Rossant and Cross, 2001). Serving as the interface between the fetal and maternal environments, the placenta is in- volved in the exchange of gases, nutrients and waste products between the mother and the growing fetus (Cross, 1998). Moreover, the placenta serves as an endocrine organ, producing several pregnancy-associated hormones and growth factors and ensuring the protection of the fetus from maternal immune attack (Regnault et al., 2002). Embryonic implantation begins with the adherence of the blastocyst to the uterine lumen epithelium. The blastocyst then invades deep into the uterine wall via an interaction between trophoblasts and the uterine endometrium. In humans, this initial invasion is characterized by the penetration of the uterine epithelium by the multinucleated syncytiotrophoblast (STB) (Popek, 1999). The human placenta has been demonstrated to be one of the most invasive placenta types, with tropho- blast cells invading into the inner third of the myometrium along with the maternal vasculature (Norwitz, 2007). Feto- maternal contact reduces to one trophoblastic cell layer by the third trimester (Wang and Zhao, 2010).

L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

983

The trophectoderm of the blastocyst is the first cell lineage that exhibits a highly differentiated function during embry- onic development. In humans, highly proliferative, undifferentiated primitive cytotrophoblast (CTB) cells that are derived from the trophectoderm give rise to differentiated trophoblast cells through two general pathways. Firstly, the mononucle- ated CTBs fuse into multinucleated STBs that cover the floating villi, which is surrounded by the maternal blood. STBs are primarily involved in pregnancy-related hormone production and in the exchange of nutrients and waste between the mother and the fetus. Secondly, CTBs proliferate to form anchoring villi that attach to the uterine wall (Knofler, 2010; Red-Horse et al., 2004). From the cell columns of the anchoring villi, extravillous trophoblasts (EVTs) can form by detaching from the placental villi and migrating into the decidua. A subset of these, interstitial trophoblasts (iEVTs), migrate into the deep layer of the maternal endometrium and even into the inner third of the myometrium, thereby anchoring the fetus to the mother. Another subset of EVTs acquires endothelial-like characteristics and become endovascular trophoblasts (enE- VTs). They penetrate the uterine spiral arteries and replace maternal endothelial cells. In this way, the uterine spiral arteries are remodeled into low-resistance, high-capacity utero-placental arteries that provide the increased blood flow towards the placenta that is needed to meet the requirements of the growing fetus (Lyall, 2006). Trophoblast differentiation during placental development is precisely regulated by environmental factors, such as oxygen tension within the maternal–fetal interface, and by various hormones and growth factors. Recently, microRNAs (miRNAs) have also been suggested to participate in placental development. The dysregulation of trophoblast activities, especially de- fects in the invasion of EVTs into the uterus and the subsequent failure in the remodeling of the maternal spiral arteries, are the key mechanisms that underlie the development of preeclampsia, a pregnancy-associated disorder characterized by hypertension and proteinurea (Red-Horse et al., 2004; Reynolds and Redmer, 2001; Rossant and Cross, 2001). Elucidating the regulatory mechanism of trophoblast cell differentiation, especially differentiation toward the invasive pathway, is a key way to explore the pathogenesis of preeclampsia and to identify reliable biomarkers that can be used as predictive or therapeutic targets in the context of preeclampsia. In this review, we summarize the current views on human trophoblast cell differentiation pathways and models available for examining human trophoblast cell differentiation and functions. We concentrate on recent advances regarding the reg- ulatory roles of oxygen tension, hormones, growth factors, and microRNAs on trophoblast differentiation toward the invasive pathway. Lastly, the mechanisms by which the deregulation on trophoblast activities can contribute to the onset of pre- eclampsia is discussed.

2. Pathways of human placental trophoblast cell differentiation

Human cytotrophoblast progenitor cells differentiate toward two general pathways: villous trophoblasts and invasive extravillous trophoblasts. Interestingly, first trimester cytotrophoblasts, unlike their term placenta counterparts, favor the invasive pathway rather than the syncytial pathway, suggesting that trophoblast cell differentiation is dynamic and change throughout gestation.

2.1. Trophoblast cell fusion – differentiation pathway toward multinucleated syncytiotrophoblasts

In the villous pathway, mononucleated CTBs fuse into multinucleated STBs, forming the syncytial layer that covers the placental villous tree. These cells are intimately involved in the exchange of gases, nutrients and waste across the mater- nal–fetal interface (Kaufmann et al., 2003). The absorptive capabilities of this layer are maximized by the presence of micro- villi that considerably increase the surface area (Teasdale and Jean-Jacques, 1985). The syncytial layer also plays a major role in the maintenance of pregnancy via the production of pregnancy-related hormones, such as human chorionic gonadotropin (hCG) and human placental lactogen (hPL) (Graham and Lala, 1992). Additionally, STBs are in direct contact with the mater- nal blood and are therefore required to exhibit a degree of immune tolerance. This tolerance is achieved in large part through their lack of expression of the classical class I human leucocyte antigens (HLA) (Nakamura, 2009). Syncytiotrophoblasts are non-proliferative and are therefore continually replenished throughout pregnancy via the fusion of the underlying CTB cell layer and the shedding of the aged portions of the STBs, i.e., syncytial knots (Kar et al., 2007; Ri- chart, 1961). Interestingly, this cell fusion occurs exclusively between the CTB and the overlaying syncytium, not between neighboring CTBs. The process of trophoblast cell fusion is poorly understood, although there is unsurpassed evidence that supports the involvement of a number of hormones, growth factors, cytokines, membrane proteins, protein kinases, intra- cellular proteases and transcription factors. The roles of these factors have been thoroughly reviewed by Huppertz and Gaus- ter (2011) and Pidoux et al. (2012).

2.1.1. Formation of STBs is downstream of the fusogenic event It is generally accepted that trophoblast differentiation into endocrine STBs is downstream of the fusogenic event. Spe- cifically, the cascade is believed to begin with increased cAMP levels, which occurs via the activation of adenylyl cyclase and the consequent activation of protein kinase A (PKA). The downstream activation of transcription factors, such as glial cells missing-1 (GCM-1) and its target genes, such as the well-characterized fusion peptide synctytin-1, induces syncytial- ization and subsequent increase in hCG production (Baczyk et al., 2009). Syncytins are envelope proteins encoded by human endogenous retroviral genes (HERVs) that are nearly exclusively expressed in the placenta (Potgens et al., 2004), and

  • 984 L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

Syncitin-1 is encoded by a defective HERV, HERV-W. Among the best-characterized placenta specific HERVs, Syncitin-1 is localized to the syncytiotrophoblast cells with its expression maintained throughout gestation (Mi et al., 2000; Okahara et al., 2004). Evidence from studies in BeWo cells, which is a well-established human choriocarcinoma cell line and in vitro model of trophoblast fusion, conclusively demonstrate the role of syncytin-1 in triggering cell fusion (Knerr et al., 2005; Mi et al., 2000). Another placenta specific HERV from the HERV-FRD family, Syncytin-2, also demonstrates a potential role as a fusogenic protein. Unlike Syncitin-1, its localization is restricted to the villous cytotrophoblast cells with its expres- sion slowly decreasing throughout gestation (Blaise et al., 2003; Okahara et al., 2004). Similarly to Syncitin-1, transient trans- fection of Syncytin-2 is also shown to promote cell fusion in a variety of cell types. However, unlike Syncytin-1, its expression levels significantly decreases after STB formation (Malassine et al., 2008). Though Syncytin-1 and Syncytin-2 have similar structure and fusogenic capabilities, their roles in regulating trophoblast differentiation are mediated through different receptors (Blaise et al., 2003; Blond et al., 2000; Esnault et al., 2008). To date, these two HERVs show a clear evolutionary selection and consequently the strongest evidence for trophoblast cell differentiation. However, the different localization of the Syncytins, their receptors, and related proteins in trophoblast cells, as well as the observation that STB is not com- pletely absent in syncytin knockout mice, raise the possibility that Syncytins are not the only fusogens that participate in syncytialization (Dupressoir et al., 2005, 2009, 2011; Handwerger, 2010; Huppertz and Gauster, 2011). Accumulating evi- dences reveals that there are several other HERVs believed to be putative fusogens. For example, ERV-3, although not a pla- centa-specific HERV, is shown to be upregulated in forskolin-treated BeWo cells, while its overexpression is capable of inducing the differentiated phenotype though to a lesser extent (Lin et al., 1999). The in vivo evidence for ERV-3 is not com- pelling, mainly due to a premature termination mutation in its transmembrane region. Several other trophoblast-specific HERVs have been characterized in human placental tissues. HERV-Fb1 expression remains constant throughout gestation, while HERV-H7/F(XA34) and HERV-HML6-c14 expressions are greatest at term (Okahara et al., 2004). The exact functions of these HERVs remains unknown, however their expression in the syncytiotrophoblast subpopulation suggests potentially similar roles to Syncitins in regulating trophoblast cell differentiation. Recent data indicate that envelope glycoproteins of HERVs have more diverse effects in trophoblast cells than previously thought. For instance, Syncytin-2 and ERV3 are shown to have additional immunosuppressive abilities. Their strong expres- sion in the placenta may suggest a role in maternal tolerance which is essential at early gestation (Mangeney et al., 2007). The ubiquitously expressed EnvP(b) and placenta-specific EnvV, two conserved HERV gene-encoded envelope proteins, have been suggested to intervene in the placenta development, but are not required in trophoblast syncytialization (Blaise et al., 2005; Vargas et al., 2012). Interestingly, while the other placenta-specific HERVs are localized in the cytoplasm, HERV- HML6-c14 expression is localized to the nucleus. Furthermore, HERV-HML6-c14 is the only upregulated placenta-specific HERV in tissues from women suffering from pregnancy-induced hypertension with the other HERVs being downregulated (Kudaka et al., 2008). The functional identification of these HERVs will provide novel insights into the mechanics of human placental development. Alternatively, there is growing evidence for the hypothesis that the mechanisms that govern the fusogenic and endocrine properties of STBs, although linked, are independently regulated. As demonstrated by Orendi et al., H-89, a selective inhibitor of cAMP dependent PKA, prevented cell fusion event in BeWo cells without affecting the production of hCG. This result sug- gests a second, PKA-independent pathway in hCG synthesis (Orendi et al., 2010). Early studies report a promoting effect of Activin A in hCG and progesterone secretion. However, studies of human trisomy 21 placentas reveal that Activin A is able to stimulate the fusogenic event without increasing hormonal markers of differentiation (Pidoux et al., 2012). Leukemia inhib- itory factor (LIF), which is actively secreted by the decidua, has been demonstrated to induce trophoblast cell fusion in an hCG-dependent manner (Hambartsoumian, 1998; Sawai et al., 1995). However, a recent study demonstrated that, although LIF contributes to forskolin-induced cell fusion in BeWo cells, it reduced hCG hormone production via a signal transducer and activator of transcription (STAT)1 and STAT3-dependent mechanism (Leduc et al., 2012). Thus, it is possible that morpholog- ical and functional differentiation of STBs may be differentially regulated.

2.1.2. Balance between tissue renewal and tissue loss in the syncytial layer

The continual fusion of CTBs into a growing syncytial layer raises questions regarding the balance between tissue renewal and tissue loss. Whether the syncytium continues to accumulate nuclei throughout pregnancy or if aging nuclei are selec- tively shed via apoptosis into the maternal circulation is widely debate, and there is a great deal of evidence to support both claims. On one side of the debate, there is supporting evidence that aging nuclei must be shed to maintain the balance be- tween renewal and loss as new CTBs join the STB layer. Studies that have examined the STB layer have indicated that these nuclei become packaged into membrane bound vesicles, termed syncytial knots, and released into the maternal circulation (Nelson, 1996; Yasuda et al., 1995). It has been suggested that it takes approximately 3–4 weeks following syncytial fusion for one aging nucleus to be removed from the growing cell (Huppertz and Kingdom, 2004). Alternatively, another argument states that the nuclei in the STB layer continue to accumulate throughout gestation and that their heterogeneous appearance is primarily a result of their differential ages (Burton and Jones, 2009). A large part of this debate focuses on the evidence for the role of apoptosis in trophoblast turnover. One hypothesis proposes a two-phase apoptotic mechanism. The first phase is described as the pre-apoptotic phase that commits the CTB to the syncytium and is involved in the fusion process. This step is followed by a possible brief execution phase that leads to the shedding of syncytial knots from the STB layer (Huppertz et al., 1998a; Mayhew et al., 1999). The first phase encom- passes the events of syncytial formation that appear to be confined to a subset of the CTB population. Although the precise

L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

985

mechanism by which these cells become committed is still unclear, there is evidence that suggests the transcription factor GCM-1 plays a key role. In situ studies of GCM-1 mRNA and protein localization in human placentas have reported a very het- erogeneous pattern of expression throughout the CTB population. Interestingly, this expression pattern appears to be con- served based on mouse studies, which report no GCM-1 expression in the cells at the base of villous columns that are destined for the invasive extravillous pathway (Baczyk et al., 2004). Further support is provided with a later study of GCM- 1 function. This study indicated that the silencing of GCM-1 inhibited de novo syncytialization in human floating villi cultures (Baczyk et al., 2009). This subset of progenitor cells is believed to undergo biochemical alterations that are representative of the early, reversible, phase of apoptosis. The activation of the initiator caspase, caspase 8, is demonstrated to be a prerequisite for CTB fusion and has been used to visualize the syncytialization process (Black et al., 2004; Gauster et al., 2009). The exact events of the transition from the early apoptotic events that are involved in CTB fusion to the activation of effec- tor caspases and downstream cell death are poorly understood. Several studies have attempted to elucidate this process by examining the expression patterns of known molecules within the apoptotic cascade. The evidence appears to suggest that the execution phase is regulated both spatially and temporally within the STBs, resulting in the formation of syncytial knots (Huppertz et al., 1998a; Nelson, 1996; Ratts et al., 2000; Uckan et al., 1997). However, comparative studies have reported a higher occurrence of apoptosis in CTBs compared to STBs (Crocker et al., 2001). Most recently, Lontine et al. brought forth a limitation to previous studies with their findings that apoptosis in term villi occur in CTBs but not in the STB layer. They showed that by using a membrane marker, E-cadherin, the apoptotic cells within the STB were in fact deeply integrated CTBs that account for one third of the entire CTB population (Longtine et al., 2012). Therefore, the exact events that are involved in trophoblast turnover and differentiation will likely be deciphered in the near future.

2.2. Trophoblast cell differentiation along the invasive pathway

In addition to the formation of floating villi is the establishment of anchoring villi, which serve to attach the placenta to the uterine wall and to create the degree of placental perfusion that is necessary to sustain the growing fetus. The anchoring sites are established as early as the second week of gestation and are composed of a heterogeneous population of CTBs (Vico- vac et al., 1995). A subpopulation of rapidly proliferating CTBs, which participate in the creation of the cell column bridge between the placental villous tip and the maternal decidualized stroma, can be found at the proximal ends of the anchoring sites. Studies of human placental and decidual explant cultures suggest that decidual contact signals the proliferative burst of CTBs to break through the STB layer (Vicovac et al., 1995). The stability of this interaction is believed to be mediated by the upreg- ulation of integrin a5b1 and a fibronectin-rich matrix on the CTBs that are located in the distal portions of the trophoblast cell columns (Damsky et al., 1992; Vicovac et al., 1995). There is also evidence that the L-Selectin adhesion system may par- ticipate in the formation and maintenance of the anchoring villi early in pregnancy (Prakobphol et al., 2006). At the distal ends of the columns, CTBs exit the cell cycle and begin to lose their cell–cell contacts. These CTBs detach from columns and, as they come into contact with the decidual extracellular matrix, they differentiate into iEVTs and enEVTs, which have distinct roles in maternal deciduas (Kemp et al., 2002). The differentiation process within the heterogeneous trophoblast column population is unclear; however, in vitro studies suggest that this process may be intrinsic (Knofler and Pollheimer, 2012). A large part of this differentiation process is com- posed of a switch in adhesion molecule profiles and the production and regulation of several proteases.

2.2.1. Interstitial trophoblast cells – invasion into uterine stroma Interstitial EVTs are described as having two distinct phenotypes: large polygonal iEVTs (or X cells) and small spindle- shaped iEVTs. The large iEVTs are believed to remain around the placental–decidua transition, securing the placenta to the uterus throughout gestation by producing a ‘‘trophoblast glue’’ that is made of a matrix-type firbrinoid (Huppertz, 2007). In contrast, the small iEVTs have been demonstrated to invade deep into the decidua as far as the inner third of the myometrium. Interstitial EVTs have a distinct adhesion molecule and histocompatibility antigen profile. There is a marked downregu- lation of integrin a6b4 and an upregulation of the fibronectin integrin, a5b1, within the distal part of the cell column. The collegen IV integrin, a 1b1, is expressed at higher levels in the iEVTs that invade deeply in the decidua (Damsky and Fisher, 1998; Damsky et al., 1992). The downregulation of E-cadherin is observed in the distal portion of cell column and is believed to contribute both to the loss of cell–cell contact and to the increase in invasiveness in iEVTs (Zhou et al., 1997b). Consistent with their invasive phenotype, iEVTs have been demonstrated to secrete several proteases that facilitate the breakdown of the decidual extracellular matrix. Specifically, the immunolocalization of urokinase-type plasminogen activator (uPA) and several matrix metalloproteinases (MMPs), most notably gelatinases MMP-2 and MMP-9, have been reported. Interestingly, the inhibitors of these enzymes, plasminogen activator inhibitor 1/2 (PAI-1/2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), are observed to be co-localized to iEVTs, indicating a certain degree of fine-tuning with respect to limiting the inva- siveness of these cells (Hofmann et al., 1994; Huppertz et al., 1998a). Furthermore, unlike the villous CTBs, iEVTs express HLA class I major histocompatibility complex (MHC) antigens. Specifically, these cells express HLA-E, trophoblast specific HLA-G and the polymorphic HLA-C (Loke et al., 1997; Sasagawa et al., 1987; Trowsdale and Moffett, 2008). How the movement of iEVTs through the immune cell-dense decidua during the first trimester does not elicit a maternal immune response remains a great topic of discussion (Hammer, 2011). Most notable in this regard is the interaction of iEVTs

  • 986 L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

with decidua-specific natural killer (dNK) cells, which differ from the NK cells that are found in the peripheral blood, and which make up the largest proportion of leukocytes at the implantation site. The receptor profiles on dNK cells allow them to interact with all three of the HLA antigens that are expressed on iEVTs. Likewise, all of these HLA antigens contribute to the immune tolerance that is observed at the maternal-fetal interface. HLA-E binds with higher affinity to the more abundant inhibitor dNK receptor suggesting its role in inhibiting cytotoxicity of dNKs (Hammer, 2011; King et al., 2000a; Moffett-King, 2002). Work by Apps et al. indicates that the inhibitory leukocyte immunoglobulin-like receptor (LILR), LILRB1 has highest affinity for dimerized HLA-G on iEVTs, suggesting that this placenta-specific process modulates the maternal immune re- sponse (Apps et al., 2007). Lastly, studies of the interaction between HLA-C and corresponding dNK killer cell immunoglob- ulin-like receptors (KIRs) provides important evidence regarding the importance of this interaction in fetal growth and blood supply (Trowsdale and Moffett, 2008). The invading iEVTs finally differentiate into placental bed giant cells. Similar to STBs, these cells have the capacity to pro- duce both hPL and hCG, suggesting their role in the maintenance of normal pregnancy. Furthermore, these giant cells pro- duce protease inhibitors that may be involved in limiting EVT invasion past the myometrium (al-Lamki et al., 1999).

2.2.2. Endovascular trophoblast cells – remodeling of uterine spiral arteries

Placental circulation is established between 8 and 12 weeks of gestation, with the spiral arteries being fully remodeled by

approximately 20–22 weeks. Endovascular EVTs are believed to play key roles in this remodeling process (Lyall, 2006). Decid- ual biopsies indicate that enEVTs invade maternal vasculature in the decidua and the inner third portion of the myometrium (Burton et al., 2009). The remodeling of the spiral arteries from high-resistance, low-flow muscular vessels to low-resistance

986 L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023 with decidua-specific natural

Fig. 1. A schematic map to illustrate the pathways of human placental trophoblast cell differentiation. (A) The growing fetus is anchored to the uterus (u) through the formation of the placenta. The umbilical cord (uc) contains fetal arteries and vein that branch into the placental villi (v). The villi are immersed in maternal blood that is perfused into intervillous spaces (ivs) through the process of uterine spiral artery remodeling. (B) Magnification of chorionic membrane (chm) where trophoblast progenitor cells (TBPC) are located. The TBPCs are believed to give rise to various trophoblast subtypes throughout gestation. (C) Magnification of a floating villus (fv). The mononucleated cytotrophoblast cells (CTB) are covered by a layer of multinucleated syncytiotrophoblasts (STB). Within the villous core, there exist mesenchymal cells (m) and villous capillaries (vc). (D) Magnification of an anchoring villus (av). The actively proliferating cytotrophoblast cells form column cytotrophoblast. At the distal portion of the column, cytotrophoblast cells detach from the villus and migrate into the decidua (dec). Interstitial trophoblasts (iEVT) invade into the deep layer of the decidua and stop at the inner third of the myometrium (myo) by differentiating into placental bed giant cells. Endovascular trophoblasts (enEVT) penetrate the uterine spiral artery (sa) and replace the endothelial cells (en), remodeling the spiral artery into low-resistance, high-capacity utero-placental artery. Endoglandular trophoblasts (egEVT) invade into the endometrial gland and may provide histotrophic nutrition to the embryo prior to the establishment of proper placental perfusion. Various immune cells, including dNK cells (red, round ones), macrophage (purple ones), and T lymphocytes (small blue ones), exist in the decidua. st, decidual stromal cells. (E) The primary characteristics and the differentiation relationship of different trophoblast subtypes are briefly presented.

L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

Table 1

The specific biomarkers that have been identified for different trophoblast subtypes.

987

Markers

Location

Sampling trimester

References

STBs

CTBs

Column CTB

iEVT

enEVT

CK7

+

+

+

+

NA

1st

Blaschitz et al. (2000)

Vimentin

NA

1st

Shorter et al. (1993)

VE-Cadherin

+

+

2nd

Damsky and Fisher (1998)

E-Cadherin

+

+

+

2nd

Damsky and Fisher (1998)

PECAM

+

+

+

+

2nd

Damsky and Fisher (1998)

NCAM (CD56)

+

2nd

Damsky and Fisher (1998)

CD9

+

NA

NA

1st

Blaschitz et al. (2000)

Fibulin-5

+

+

NA

NA

1st

Gauster et al. (2011)

Integrin a1b1

+

+

1st

Damsky et al. (1992)

Integrin a5b1

NA

+

NA

1st

Damsky et al. (1992)

Integrin a6b4

+

+

NA

1st

Damsky et al. (1992)

Integrin avb5

+

+

2nd

Zhou et al. (1997b)

Integrin avb3

+

+

2nd

Zhou et al. (1997b)

hPL

+

+

+

NA

1st

Damsky et al. (1992)

hCG a

+

+

+/

+/

+/

1st

Handschuh et al. (2007a)

hCG b

+

+/

1st

Handschuh et al. (2007a)

EGF/TGF a

+

+

+

+

NA

1st

Lysiak et al. (1993)

EGF-R

+

+

+

NA

1st

Muhlhauser et al. (1993)

TGFb

+++

NA

1st

Selick et al. (1994)

Endoglin

+

+

NA

1st

St-Jacques et al. (1994)

VEGF

+

NA

NA

+

NA

3rd

Pietro et al. (2010)

Flt-1

+

NA

NA

+

NA

3rd

Pietro et al. (2010)

KDR

+

NA

NA

+

NA

3rd

Pietro et al. (2010)

pro-Renin

+

+

+

NA

NA

1st

Pringle et al. (2011)

Renin-R

+

+

NA

NA

1st

Pringle et al. (2011)

IL-1R

+

+

+

NA

1st

Simon et al. (1994)

IL-1b

+

+

+

+

NA

1st

Simon et al. (1994)

HLA class I

+

NA

1st

Shorter et al. (1993)

HLA-G

+

NA

1st

Shorter et al. (1993)

HIF-1

+

+

NA

3rd

Genbacev et al. (2001)

pVHL

+

+

NA

3rd

Genbacev et al. (2001)

Galectin-8

+/

+

+

+/

NA

1st

Kolundzic et al. (2011)

PAI-1

+

+

+

+

NA

1st

Hofmann et al. (1994)

PAI-2

+

+

+

+

NA

1st

Hofmann et al. (1994)

uPA

+

+

+

+

NA

1st

Hofmann et al. (1994)

MMP-1

NA

NA

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

MMP-2

NA

NA

+

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

MMP-3

NA

NA

+

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

MMP-7

+

+

+

+

NA

1st, 2nd & 3rd

Vettraino et al. (1996)

MMP-9

NA

NA

+

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

TIMP-1

NA

NA

+

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

TIMP-2

NA

NA

+

NA

1st, 2nd & 3rd

Huppertz et al. (1998b)

Arginase I

+

NA

NA

NA

1st & 3rd

Ishikawa et al. (2007)

Arginase II

+

+

NA

NA

NA

1st & 3rd

Ishikawa et al. (2007)

CTBs, cytotrophoblasts; enEVT: endovascular trophoblast; iEVT, interstitial trophoblast; STBs, syncytiotrophoblasts; +, positively staining; , negatively staining; NA, data not available.

and high-flow sac-like vessels involves cross-talk between different cell types, with enEVTs as the key players. These events can be divided into five stages: (1) decidua-associated early vascular remodeling, (2) iEVT-associated early vascular remod- eling (3) enEVT migration, (4) the incorporation of enEVTs into the vessel wall and (5) the re-endothelization and subintimal thickening (Cartwright et al., 2010; Kaufmann et al., 2003; Pijnenborg et al., 2006). During the decidualization process, the maternal vessels are modified to prepare them for EVT invasion. This ‘‘priming’’ process appear to be trophoblast-independent based on studies of ectopic pregnancies (Harris, 2010). These alterations in- clude smooth muscle swelling and endothelial cell vacuolation (Pijnenborg et al., 2006). Leukocytes, specifically dNKs and macrophages, have been implicated in this process. MMP-dependent matrix degradation and cell apoptosis are the sug- gested mechanisms by which trophoblast-independent early vascular remodeling occurs (Smith et al., 2009). Two possible origins of the enEVTs, iEVTs and enEVT plugs have been suggested. During early pregnancy, spiral arteries in the superficial decidua are surrounded by iEVTs (Pijnenborg et al., 1980). These iEVTs position themselves along the arteries and begin to disrupt and disorganize the vascular smooth muscle cell layer. As these iEVTs invade the lumen of the arteries, they are believed to switch to the endovascular phenotype. However, it has been suggested that the switch from iEVTs to enEVTs occurs only in regions of the spiral arteries in the superficial zone of the decidua and that deeper regions of the arter- ies are remodeled by enEVTs from a second origin, i.e., enEVT plugs (Pijnenborg et al., 2006). Endovascular EVTs from the initial plugs are believed to retrogradely travel down the vessel lumen (Cartwright et al., 2010; Kaufmann et al., 2003). This

  • 988 L. Ji et al. / Molecular Aspects of Medicine 34 (2013) 981–1023

infiltration by the EVTs results in maternal vascular apoptosis, the detachment of these cells from the surrounding extracel- lular matrix and their migration away from the vessels (Cartwright et al., 2010). These enEVTs go on to replace the endothe- lial cells of the maternal vessels through a process that is referred to as pseudovasculogenesis or vascular mimicry (Damsky and Fisher, 1998; Khankin et al., 2010; Zhou et al., 1997b). Endovascular EVTs are able to exist within the maternal vasculature in a manner that is similar to endothelial cells primarily due to their switch from an epithelial to an endothelial adhesion molecule phenotype (Anin et al., 2004). These cells downregulate the epithelial-type markers E-cadherin and a6b4 and upregulate the expression of the adhesion molecules VE-Cadherin, PECAM, and NCAM (CD56) as well as integrins a5b1, a1b1 and a Vb3 (Damsky and Fisher, 1998; Zhou et al., 1997b). Lastly, studies in mice have provided evidence for maternal vascular repair. This process encompasses re-endothelization and by the appearance of subintimal thickening between the restored endothelium and the fibrinoid layer that surrounds the enEVTs (Pijnenborg et al., 2006; Zhou et al., 1997a). The remodeling of maternal spiral arteries continues until the mid-second trimester, and can be observed as deeply as the inner third of the myometrium (Cartwright et al., 2010). This process does not occur uniformly throughout the entire pla- centa; it is most prominent in the central placental bed and less prominent at the periphery (Kaufmann et al., 2003). The remodeled spiral arteries are increased in length, exhibit a several-fold increase in lumen diameter and are unresponsive to vaso-constrictive agents (Anin et al., 2004; Kam et al., 1999). This low resistant and high capacity phenotype provides for the necessary flow of maternal blood into the intervillous spaces, which sustains the growing demands of the fetus throughout gestation.

2.2.3. Endoglandular trophoblast cells – uterine glandular remodeling

Evidence has recently emerged to suggest the existence of another subpopulation of EVTs, termed the endoglandular EVTs (egEVTs). In vitro first trimester decidua parietalis and placental villous explant co-cultures provided the first evidence of glandular remodeling by egEVTs, a process that is similar to the enEVT remodeling of spiral arteries (Moser et al., 2010). It is suggested that the replacement of glandular cells by egEVTs may provide a mechanism both for the opening of the uter- ine gland to the intravillous space and for histotrophic nutrition to the embryo prior to the establishment of proper placental

perfusion (Fitzgerald et al., 2010). More studies are required to confirm the presence of egEVTs and their role in remodeling uterine glands.

2.3. Summary of the characteristics of the various trophoblast subtypes

As discussed in the previous section, mammalian placentation represents a remarkable biological process, during which diverse trophoblast populations are generated. Much work has been performed to identify trophoblast subtypes, especially at early gestational stages, when trophoblasts are actively differentiating. The morphological characteristics and the specific biomarkers of different trophoblast populations are summarized in Fig. 1 and Table 1. It is easy to see that enEVTs have been

Table 2

The origin and characterization of the immortalized human trophoblast cell lines.

 
 

Cell line

Origin