Skip to main content
SpringerLink
Log in

Blockade of stromal cell-derived factor-1 signaling disturbs the invasiveness of human extravillous trophoblast cells

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

The invasion of trophoblast cells into the maternal uterine decidua is crucial for the formation of the placenta and establishment of pregnancy. Stromal cell-derived factor-1 (SDF-1) regulates cellular functions such as migration, adhesion, and proliferation. During pregnancy, both SDF-1 and its receptor CXCR4 are expressed in the placenta. Abnormal expression of the SDF-1 system has been linked to pregnancy disorders such as pre-eclampsia.

Objective

The purpose of this study was to investigate the effect of SDF-1/CXCR4 signaling on trophoblast cells and the related molecular mechanism(s).

Results

The invasiveness of HTR8/SVneo human trophoblast cells was stimulated by extracellular SDF-1. SDF-1 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. The ability of SDF-1 to stimulate HTR8/SVneo cell invasion was blocked in the presence of a PI3K inhibitor (wortmannin), an ERK1/2 MAPK inhibitor (U0126), or a P38 MAPK inhibitor (SB203580). The expression of the matrix metalloproteinase (MMP)-2 and MMP-9 genes increased in SDF-1-treated HTR8/SVneo cells, and the up-regulation of MMPs expression was inhibited by blocking the SDF-1 receptor. Additionally, SDF-1 treatment increased MMP-2 and MMP-9 protein levels in HTR8/SVneo cells, and the increase of MMP-2 and MMP-9 was reduced by inhibiting the PI3K and/or MAPK intracellular signaling pathway.

Conclusion

These findings provide evidence that appropriate SDF-1-mediated signaling pathways contribute to the regulation of trophoblast invasiveness into the endometrium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Bajetto A et al (1999) Expression of chemokine receptors in the rat brain. Ann N Y Acad Sci 876:201–209

    Article  ADS  CAS  PubMed  Google Scholar 

  • Balabanian K et al (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 280:35760–35766

    Article  CAS  PubMed  Google Scholar 

  • Boij R et al (2012) Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am J Reprod Immunol 68:258–270

    Article  CAS  PubMed  Google Scholar 

  • Carlino C et al (2008) Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 111:3108–3115

    Article  CAS  PubMed  Google Scholar 

  • Cartwright JE, Tse WK, Whitley GS (2002) Hepatocyte growth factor induced human trophoblast motility involves phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and inducible nitric oxide synthase. Exp Cell Res 279:219–226

    Article  CAS  PubMed  Google Scholar 

  • Chaddha V, Viero S, Huppertz B, Kingdom J (2004) Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 9:357–369

    Article  PubMed  Google Scholar 

  • Chen JZ, Sheehan PM, Brennecke SP, Keogh RJ (2012) Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol 349:138–144

    Article  CAS  PubMed  Google Scholar 

  • Cheng G, Liu X, Li P, Li Y (2021) Down-regulation of PTTG1 suppresses PDGF-BB-induced proliferation, migration and extracellular matrix production of airway smooth muscle cells (ASMCs) by regulating PI3K/AKT/mTOR signaling pathway. Mol Cell Toxicol 17:485–492

    Article  CAS  Google Scholar 

  • D’Apuzzo M et al (1997) The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol 27:1788–1793

    Article  CAS  PubMed  Google Scholar 

  • Feil C, Augustin HG (1998) Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusin) under the control of autocrine activity and exogenous cytokines. Biochem Biophys Res Commun 247:38–45

    Article  CAS  PubMed  Google Scholar 

  • Gleeson LM, Chakraborty C, McKinnon T, Lala PK (2001) Insulin-like growth factor-binding protein 1 stimulates human trophoblast migration by signaling through alpha 5 beta 1 integrin via mitogen-activated protein Kinase pathway. J Clin Endocrinol Metab 86:2484–2493

    CAS  PubMed  Google Scholar 

  • Graham CH et al (1993) Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res 206:204–211

    Article  CAS  PubMed  Google Scholar 

  • Han J et al (2010) Epidermal growth factor stimulates human trophoblast cell migration through Rho A and Rho C activation. Endocrinology 151:1732–1742

    Article  CAS  PubMed  Google Scholar 

  • He YY et al (2012) The decidual stromal cells-secreted CCL2 induces and maintains decidual leukocytes into Th2 bias in human early pregnancy. Clin Immunol 145:161–173

    Article  CAS  PubMed  Google Scholar 

  • Huber AV, Saleh L, Bauer S, Husslein P, Knofler M (2006) TNFalpha-mediated induction of PAI-1 restricts invasion of HTR-8/SVneo trophoblast cells. Placenta 27:127–136

    Article  CAS  PubMed  Google Scholar 

  • Hunkapiller NM, Fisher SJ (2008) Chapter 12. Placental remodeling of the uterine vasculature. Method Enzymol 445:281–302

    Article  CAS  Google Scholar 

  • Jaleel MA, Tsai AC, Sarkar S, Freedman PV, Rubin LP (2004) Stromal cell-derived factor-1 (SDF-1) signalling regulates human placental trophoblast cell survival. Mol Hum Reprod 10:901–909

    Article  CAS  PubMed  Google Scholar 

  • Ji JF, He BP, Dheen ST, Tay SS (2004) Expression of chemokine receptors CXCR4, CCR2, CCR5 and CX3CR1 in neural progenitor cells isolated from the subventricular zone of the adult rat brain. Neurosci Lett 355:236–240

    Article  CAS  PubMed  Google Scholar 

  • Kantele JM, Kurk S, Jutila MA (2000) Effects of continuous exposure to stromal cell-derived factor-1 alpha on T cell rolling and tight adhesion to monolayers of activated endothelial cells. J Immunol 164:5035–5040

    Article  CAS  PubMed  Google Scholar 

  • Karmakar S, Das C (2002) Regulation of trophoblast invasion by IL-1beta and TGF-beta1. Am J Reprod Immunol 48:210–219

    Article  PubMed  Google Scholar 

  • Kaufmann P, Black S, Huppertz B (2003) Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 69:1–7

    Article  CAS  PubMed  Google Scholar 

  • Kawabata K et al (1999) A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc Natl Acad Sci USA 96:5663–5667

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Knofler M, Pollheimer J (2012) IFPA award in placentology lecture: molecular regulation of human trophoblast invasion. Placenta 33(Suppl):S55-62

    Article  PubMed  PubMed Central  Google Scholar 

  • Koch C, Engele J (2020) Functions of the CXCL12 receptor ACKR3/CXCR7-what has been perceived and what has been overlooked. Mol Pharmacol 98:577–585

    Article  CAS  PubMed  Google Scholar 

  • Li H et al (2015) Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1/2 and PI3K signaling pathways in human early pregnancy. Reproduction 150:417–427

    Article  CAS  PubMed  Google Scholar 

  • Lim KH et al (1997) Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 151:1809–1818

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Dai LI, Zhou R (2015) Association between preeclampsia and the CXC chemokine family (Review). Exp Ther Med 9:1572–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loetscher M et al (1994) Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem 269:232–237

    Article  CAS  PubMed  Google Scholar 

  • Makrigiannakis A, Minas V, Kalantaridou SN, Nikas G, Chrousos GP (2006) Hormonal and cytokine regulation of early implantation. Trends Endocrinol Metab 17:178–185

    Article  CAS  PubMed  Google Scholar 

  • McKinnon T, Chakraborty C, Gleeson LM, Chidiac P, Lala PK (2001) Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK. J Clin Endocrinol Metab 86:3665–3674

    Article  CAS  PubMed  Google Scholar 

  • Naiyer AJ et al (1999) Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long-term culture-initiating cells) through endothelial cells is mediated by E-selectin. Blood 94:4011–4019

    Article  CAS  PubMed  Google Scholar 

  • Norwitz ER (2006) Defective implantation and placentation: laying the blueprint for pregnancy complications. Reprod Biomed Online 13:591–599

    Article  CAS  PubMed  Google Scholar 

  • Oreshkova T, Dimitrov R, Mourdjeva M (2012) A cross-talk of decidual stromal cells, trophoblast, and immune cells: a prerequisite for the success of pregnancy. Am J Reprod Immunol 68:366–373

    Article  CAS  PubMed  Google Scholar 

  • Paiva P et al (2011) Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum Reprod 26:1153–1162

    Article  CAS  PubMed  Google Scholar 

  • Qiu Q, Yang M, Tsang BK, Gruslin A (2004) Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. Mol Hum Reprod 10:677–684

    Article  CAS  PubMed  Google Scholar 

  • Schanz A et al (2011) Pre-eclampsia is associated with elevated CXCL12 levels in placental syncytiotrophoblasts and maternal blood. Eur J Obstet Gynecol Reprod Biol 157:32–37

    Article  CAS  PubMed  Google Scholar 

  • Shah DM (2001) Perinatal implications of maternal hypertension. Semin Pediatr Neurol 8:108–119

    Article  CAS  PubMed  Google Scholar 

  • Singh M et al (2011) Matrix metalloproteinases and their inhibitors and inducer in gestational trophoblastic diseases and normal placenta. Gynecol Oncol 122:178–182

    Article  CAS  PubMed  Google Scholar 

  • Sozzani S et al (1997) Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. J Immunol 159:1993–2000

    Article  CAS  PubMed  Google Scholar 

  • Staun-Ram E, Goldman S, Gabarin D, Shalev E (2004) Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol 2:59

    Article  PubMed  PubMed Central  Google Scholar 

  • Timeva T, Shterev A, Kyurkchiev S (2014) Recurrent implantation failure: the role of the endometrium. J Reprod Infertil 15:173–183

    PubMed  PubMed Central  Google Scholar 

  • Wallace AE et al (2013) Trophoblast-induced changes in C-x-C motif chemokine 10 expression contribute to vascular smooth muscle cell dedifferentiation during spiral artery remodeling. Arterioscler Thromb Vasc Biol 33:e93–e101

    Article  CAS  PubMed  Google Scholar 

  • Wu X et al (2005) Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol 175:61–68

    Article  CAS  PubMed  Google Scholar 

  • Zhu JY, Pang ZJ, Yu YH (2012) Regulation of trophoblast invasion: the role of matrix metalloproteinases. Rev Obstet Gynecol 5:e137–e143

    PubMed  PubMed Central  Google Scholar 

  • Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12:121–127

    Article  CAS  PubMed  Google Scholar 

  • Zlotnik A, Yoshie O (2012) The chemokine superfamily revisited. Immunity 36:705–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2022RIS-005) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1I1A3060225).

Author information

Author notes

  1. Yeongju Bae, Jiho Jang and Han-Soo Kim have contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Department of Biomedical Sciences, Catholic Kwandong University, Gangneung, 25601, Republic of Korea

    Yeongju Bae, Jiho Jang, Han-Soo Kim & Wooyoung Jeong

  2. Biomedical Institute of Mycological Resource, International St. Mary’s Hospital and College of Medicine, Catholic Kwandong University, Incheon, 22711, Republic of Korea

    Han-Soo Kim & Wooyoung Jeong

  3. Research Center for Marine Bio-Food and Medicine, Catholic Kwandong University, Gangneung, 25601, Republic of Korea

    Wooyoung Jeong

Authors
  1. Yeongju Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiho Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wooyoung Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YB performed the experiments and analyzed the data. JK analyzed and reviewed the data. WJ performed the experiments and wrote the manuscript.

Corresponding author

Correspondence to Wooyoung Jeong.

Ethics declarations

Conflict of interest

Yeongju Bae, Jiho Jang, Han-Soo Kim, Wooyoung Jeong declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bae, Y., Jang, J., Kim, HS. et al. Blockade of stromal cell-derived factor-1 signaling disturbs the invasiveness of human extravillous trophoblast cells. Mol. Cell. Toxicol. 20, 307–314 (2024). https://doi.org/10.1007/s13273-023-00344-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-023-00344-3

Keywords

Search

Navigation