Generic placeholder image

Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Stromal Cell-Derived Factor (SDF) 2 and the Endoplasmic Reticulum Stress Response of Trophoblast Cells in Gestational Diabetes Mellitus and In vitro Hyperglycaemic Condition

Author(s): Aline R. Lorenzon*, Jusciele Brogin Moreli, Rafaela de Macedo Melo, Felipe Yukio Namba, Anne Cathrine Staff, Hong Wa Yung, Graham J. Burton and Estela Bevilacqua*

Volume 19, Issue 2, 2021

Published on: 06 June, 2020

Page: [201 - 209] Pages: 9

DOI: 10.2174/1570161118666200606222123

Price: $65


Background and Aim: The endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) are essential cellular mechanisms to ensure the proper functioning of ER in adverse conditions. However, activation of these pathways has also been associated with insulin resistance and cell death in pathological conditions such as diabetes mellitus. In the present study, we investigated whether stromal cell-derived factor 2 (SDF2)—an ER stress-responsive factor—is related to ER response in placental cells exposed to maternal gestational diabetes mellitus (GDM) or to a hyperglycaemic in vitro condition.

Objective: The study aimed to investigate the role of SDF2 in BeWo cells , a trophoblast cell line originating from choriocarcinoma , and in placental tissue under hyperglycaemic conditions.

Methods: Protein levels of SDF2 and UPR factors, glucose-related protein 78 (GRP78) and eukaryotic initiation factor 2 alpha (elF2 alpha) were evaluated in the placentae of pregnant women diagnosed with GDM and treated by diet-control (insulin was added when necessary). The mRNA expression of SDF2 and UPR factors CHOP and sXBP1 were assessed in cultured BeWo cells challenged with glucose and treated with or without insulin.

Results: SDF2 expression was increased in the placentae of GDM women treated with diet. However, its values were similar to those of normoglycemic controls when the GDM women were treated with insulin and diet. BeWo cells cultured with high glucose and insulin showed decreased SDF2 expression, while high glucose increased CHOP and sXBP1 expression, which was then significantly reverted with insulin treatment.

Conclusion: Our findings extend the understanding of ER stress and SDF2 expression in placentae exposed to hyperglycaemia, highlighting the relevance of insulin in reducing the levels of ER stress factors in placental cells. Understanding the effect of ER stress partners such as SDF2 on signalling pathways involved in gestation, complicated by hyperglycaemia, is pivotal for basic biomedical research and may lead to new therapeutic possibilities.

Keywords: SDF2, placenta, trophoblast, gestational diabetes mellitus, ER stress, UPR.

Graphical Abstract
Hamada T, Tashiro K, Tada H, et al. Isolation and characterization of a novel secretory protein, stromal cell-derived factor-2 (SDF-2) using the signal sequence trap method. Gene 1996; 176(1-2): 211-4.
[] [PMID: 8918255]
Hoshida MS, Gorjão R, Lima C, Daher S, Curi R, Bevilacqua E. Regulation of gene expression in mouse trophoblast cells by interferon-gamma. Placenta 2007; 28(10): 1059-72.
[] [PMID: 17544503]
Lorenzon-Ojea AR, Caldeira W, Ribeiro AF, Fisher SJ, Guzzo CR, Bevilacqua E. Stromal cell derived factor-2 (Sdf2): a novel protein expressed in mouse. Int J Biochem Cell Biol 2014; 53: 262-70.
[] [PMID: 24878610]
Fukuda S, Sumii M, Masuda Y, et al. Murine and human SDF2L1 is an endoplasmic reticulum stress-inducible gene and encodes a new member of the Pmt/rt protein family. Biochem Biophys Res Commun 2001; 280(1): 407-14.
[] [PMID: 11162531]
Lorenzon-Ojea AR, Guzzo CR, Kapidzic M, Fisher SJ, Bevilacqua E. Stromal Cell-derived factor 2: a novel protein that interferes in endoplasmic reticulum stress pathway in human placental cells. Biol Reprod 2016; 95(2): 41.
[] [PMID: 27335075]
Lorenzon-Ojea AR, Yung HW, Burton GJ, Bevilacqua E. The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset. Biochim Biophys Acta Mol Basis Dis 2020; 1866(2)165386
[] [PMID: 30776414]
Fujimori T, Suno R, Iemura SI, Natsume T, Wada I, Hosokawa N. Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation. Genes Cells 2017; 22(8): 684-98.
[] [PMID: 28597544]
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334(6059): 1081-6.
[] [PMID: 22116877]
Madden E, Logue SE, Healy SJ, Manie S, Samali A. The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance. Biol Cell 2019; 111(1): 1-17.
[] [PMID: 30302777]
Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ. Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. J Pathol 2014; 234(2): 262-76.
[] [PMID: 24931423]
Yung HW, Alnæs-Katjavivi P, Jones CJ, et al. Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic in-tervention with chemical chaperones and antioxidants. Diabetologia 2016; 59(10): 2240-50.
[] [PMID: 27406815]
American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020. Diabetes Care 2020; 43(Suppl. 1): S14-31.
[] [PMID: 31862745]
Lehnen H, Zechner U, Haaf T. Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod 2013; 19(7): 415-22.
[] [PMID: 23515667]
McIntyre HD, Catalano P, Zhang C, Desoye G, Mathiesen ER, Damm P. Gestational diabetes mellitus. Nat Rev Dis Primers 2019; 5(1): 47.
[] [PMID: 31296866]
Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab 2017; 6(9): 1024-39.
[] [PMID: 28951826]
Villalobos-Labra R, Subiabre M, Toledo F, Pardo F, Sobrevia L. Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity. Mol Aspects Med 2019; 66: 49-61.
[] [PMID: 30472165]
Brozzi F, Eizirik DL. ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Ups J Med Sci 2016; 121(2): 133-9.
[] [PMID: 26899404]
Kaufman RJ, Back SH, Song B, Han J, Hassler J. The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells. Diabetes Obes Metab 2010; 12(Suppl. 2): 99-107.
[] [PMID: 21029306]
Jiao Y, Zhang S, Zhang J, Du J. Tetramethylpyrazine attenuates placental oxidative stress, inflammatory responses and endoplasmic retic-ulum stress in a mouse model of gestational diabetes mellitus. Arch Pharm Res 2019; 42(12): 1092-100.
[] [PMID: 31797253]
Gargalovic PS, Gharavi NM, Clark MJ, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26(11): 2490-6.
[] [PMID: 16931790]
Pattillo RA, Gey GO. The establishment of a cell line of human hormone-synthesizing trophoblastic cells in vitro. Cancer Res 1968; 28(7): 1231-6.
[PMID: 4299001]
Inadera H, Tachibana S, Takasaki I, Tatematsu M, Shimomura A. Hyperglycemia perturbs biochemical networks in human trophoblast BeWo cells. Endocr J 2010; 57(7): 567-77.
[] [PMID: 20467164]
Moreli JB, Santos JH, Lorenzon-Ojea AR, et al. Hyperglycemia differentially affects maternal and fetal DNA integrity and DNA damage response. Int J Biol Sci 2016; 12(4): 466-77.
[] [PMID: 27019630]
Guzmán-Gutiérrez E, Armella A, Toledo F, Pardo F, Leiva A, Sobrevia L. Insulin requires A1 adenosine receptors expression to reverse gestational diabetes-increased L-arginine transport in human umbilical vein endothelium. Purinergic Signal 2016; 12(1): 175-90.
[] [PMID: 26710791]
Desoye G, Cervar-Zivkovic M. Diabetes mellitus, obesity, and the placenta. Obstet Gynecol Clin North Am 2020; 47(1): 65-79.
[] [PMID: 32008672]
Lorenzon-Ojea AR, Rocha CRR, Bevilacqua E. SDF2 is a novel component of ER stress-induced apoptosis pathway in trophoblast cells via PERK-eIF2alpha-ATF4 branch. Reprod Sci 2017; 24: 100A.
Calderon IM, Damasceno DC, Amorin RL, Costa RA, Brasil MA, Rudge MV. Morphometric study of placental villi and vessels in women with mild hyperglycemia or gestational or overt diabetes. Diabetes Res Clin Pract 2007; 78(1): 65-71.
[] [PMID: 17360067]
Starikov R, Inman K, Chen K, et al. Comparison of placental findings in type 1 and type 2 diabetic pregnancies. Placenta 2014; 35(12): 1001-6.
[] [PMID: 25458965]
Desoye G. The human placenta in diabetes and obesity: friend or foe? The 2017 Norbert Freinkel award lecture. Diabetes Care 2018; 41(7): 1362-9.
[] [PMID: 29934479]
Lacroix M, Lizotte F, Hivert MF, Geraldes P, Perron P. Calcifediol decreases interleukin-6 secretion by cultured human trophoblasts from GDM pregnancies. J Endocr Soc 2019; 3(11): 2165-78.
[] [PMID: 31701079]
Coughlan MT, Oliva K, Georgiou HM, Permezel JM, Rice GE. Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabet Med 2001; 18(11): 921-7.
[] [PMID: 11703438]
Jayabalan N, Nair S, Nuzhat Z, et al. Cross talk between adipose tissue and placenta in obese and gestational diabetes mellitus pregnancies via exosomes. Front Endocrinol (Lausanne) 2017; 8: 239.
[] [PMID: 29021781]
Moreli JB, Corrêa-Silva S, Damasceno DC, et al. Changes in the TNF-alpha/IL-10 ratio in hyperglycemia-associated pregnancies. Diabetes Res Clin Pract 2015; 107(3): 362-9.
[] [PMID: 25648390]
Corrêa-Silva S, Alencar AP, Moreli JB, et al. Hyperglycemia induces inflammatory mediators in the human chorionic villous. Cytokine 2018; 111: 41-8.
[] [PMID: 30114628]
Roberts KA, Riley SC, Reynolds RM, et al. Placental structure and inflammation in pregnancies associated with obesity. Placenta 2011; 32(3): 247-54.
[] [PMID: 21232790]
Subiabre M, Silva L, Toledo F, et al. Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis 2018; 1864(9 Pt B): 2949-56.
[] [PMID: 29890222]
Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 2017; 11CD012037
[] [PMID: 29103210]
Burton GJ, Yung HW. Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. Pregnancy Hypertens 2011; 1(1-2): 72-8.
[] [PMID: 22242213]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy