Dr. Guller's Lab

Research Interests

Research in Dr. Guller’s laboratory focuses on placental dysfunction in adverse preterm pregnancy outcomes including preeclampsia (PE), intrauterine growth restriction, and chorioamnionitis (CAM). The overall goal of his work is to elucidate the role of major cell types of the placental villus, including syncytiotrophoblast, Hofbauer cells (HBCs, fetal macrophages), fibroblasts, and fetal endothelial cells, in mediating responses to glucocorticoid, hypoxia-reperfusion injury, and intrauterine infection.

1. Role of Hofbauer Cells in Adverse Pregnancy Outcomes: Our previous studies indicate that HBC phenotype and function provide key insight into placental pathophysiology in CAM and PE. CAM was found to be associated with a focal increase in the numbers of HBCs in the placental villus, whereas PE was associated with a reduction in HBC numbers. In addition, our recent report demonstrated that glucocorticoid treatment of HBCs in vitro, as well as maternal administration of glucococorticoid, has a profound effect on HBC gene expression and function. Ongoing studies will determine the role of HBCs in infection- as well as hypoxia/reperfusion injury-driven placental damage. We will first identify aberrant patterns of HBC gene/protein expression and function in placentas from pregnancies with PE and CAM, and then use primary cultures of HBCs and macrophage cell lines to establish molecular mechanisms resulting in placental dysfunction. The importance of cell:cell communication in the placental villus will be determined using co-culture experiments with major placental cell types. These studies will provide new markers and insight into the mechanism of placental dysfunction in major adverse obstetrical outcomes. 

2. Role of Placental Factors in Maternal Endothelial Dysfunction in Preeclampsia: We recently demonstrated that the system of dual (maternal+fetal) placental perfusion affords a unique opportunity to study the role of placental factors associated with elevated maternal blood pressure and proteinuria in PE (e.g. syncytiotrophoblast microparticles, sFlt-1, endoglin, plasminogen activator inhibitors). In current studies we are dissecting the specific contributions of factors released by the placenta during perfusion– including microparticles, cytokines, and chemokines– on endothelial inflammation, activation and function. These studies will lead to interventions which reduce the severity of maternal symptoms associated with PE and reduce the incidence of iatrogenic preterm delivery.

Lab Members

Bio Profile

Seth Guller, PhD

Senior Research Scientist in Obstetrics, Gynecology, and Reproductive Sciences

Director, Gyn/Endocrine Laboratory

Research Interests

Gynecology; Obstetrics; Placenta Diseases; Pre-Eclampsia; Pregnancy Outcome

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Kisanga EP, Tang Z, Guller S, Whirledge S: In Vitro Assays to Evaluate the Migration, Invasion, and Proliferation of Immortalized Human First-trimester Trophoblast Cell Lines. J Vis Exp. 2019 Mar 5; 2019 Mar 5. PMID: 30907868

Lee B, Koeppel AF, Wang ET, Gonzalez TL, Sun T, Kroener L, Lin Y, Joshi NV, Ghadiali T, Turner SD, Rich SS, Farber CR, Rotter JI, Ida Chen YD, Goodarzi MO, Guller S, Harwood B, Serna TB, Williams J 3rd, Pisarska MD: Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies. Fertil Steril. 2019 Mar; 2019 Jan 2. PMID: 30611556

Heim KR, Mulla MJ, Potter JA, Han CS, Guller S, Abrahams VM: Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll-Like receptor 4. Am J Reprod Immunol. 2018 Nov; 2018 Sep 2. PMID: 30175447

Kisanga EP, Tang Z, Guller S, Whirledge S: Glucocorticoid signaling regulates cell invasion and migration in the human first-trimester trophoblast cell line Sw.71. Am J Reprod Immunol. 2018 Jul; 2018 May 18. PMID: 29774963

Guller S: In memoriam: mortimer levitz. Steroids. 2018 May 8; 2018 May 8. PMID: 29750995

Quao ZC, Tong M, Bryce E, Guller S, Chamley LW, Abrahams VM: Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies. Am J Reprod Immunol. 2018 Jan; 2017 Nov 14. PMID: 29135051

Cross SN, Potter JA, Aldo P, Kwon JY, Pitruzzello M, Tong M, Guller S, Rothlin CV, Mor G, Abrahams VM: Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation. J Immunol. 2017 Oct 15; 2017 Sep 15. PMID: 28916522

Tadesse S, Norwitz NG, Guller S, Arcuri F, Toti P, Norwitz ER, Kidane D: Dynamics of Base Excision Repair at the Maternal-Fetal Interface in Pregnancies Complicated by Preeclampsia. Reprod Sci. 2017 Jun; 2016 Oct 5. PMID: 27707956

Minior VK, Levine B, Ferber A, Guller S, Divon MY: Nucleated Red Blood Cells as a Marker of Acute and Chronic Fetal Hypoxia in a Rat Model. Rambam Maimonides Med J. 2017 Apr 28; 2017 Apr 28. PMID: 28467759

Simoni MK, Jurado KA, Abrahams VM, Fikrig E, Guller S: Zika virus infection of Hofbauer cells. Am J Reprod Immunol. 2017 Feb; 2016 Dec 14. PMID: 27966815

Pisarska MD, Akhlaghpour M, Lee B, Barlow GM, Xu N, Wang ET, Mackey AJ, Farber CR, Rich SS, Rotter JI, Chen YI, Goodarzi MO, Guller S, Williams J 3rd: Optimization of techniques for multiple platform testing in small, precious samples such as human chorionic villus sampling. Prenat Diagn. 2016 Nov; 2016 Nov 7. PMID: 27718505

Jurado KA, Simoni MK, Tang Z, Uraki R, Hwang J, Householder S, Wu M, Lindenbach BD, Abrahams VM, Guller S, Fikrig E: Zika virus productively infects primary human placenta-specific macrophages. JCI Insight. 2016 Aug 18. PMID: 27595140

Shaw J, Tang Z, Schneider H, Saljé K, Hansson SR, Guller S: Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-α: Implications in preeclampsia (PE). Placenta. 2016 Jul; 2016 Apr 19. PMID: 27324092

Zuckerwise L, Li J, Lu L, Men Y, Geng T, Buhimschi CS, Buhimschi IA, Bukowski R, Guller S, Paidas M, Huang Y: H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction. Oncotarget. 2016 Jun 21. PMID: 27223264

Schatz F, Guzeloglu-Kayisli O, Basar M, Buchwalder LF, Ocak N, Guzel E, Guller S, Semerci N, Kayisli UA, Lockwood CJ: Enhanced Human Decidual Cell-Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal. Am J Pathol. 2015 Sep; 2015 Jul 21. PMID: 26207680

Young OM, Tang Z, Niven-Fairchild T, Tadesse S, Krikun G, Norwitz ER, Mor G, Abrahams VM, Guller S: Toll-like receptor-mediated responses by placental Hofbauer cells (HBCs): a potential pro-inflammatory role for fetal M2 macrophages. Am J Reprod Immunol. 2015 Jan; 2014 Oct 24. PMID: 25345551

Aldo PB, Racicot K, Craviero V, Guller S, Romero R, Mor G: Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol. 2014 Sep; 2014 Jul 3. PMID: 24995492

Hoang M, Potter JA, Gysler SM, Han CS, Guller S, Norwitz ER, Abrahams VM: Human fetal membranes generate distinct cytokine profiles in response to bacterial Toll-like receptor and nod-like receptor agonists. Biol Reprod. 2014 Feb; 2014 Feb 27. PMID: 24429216

Cronqvist T, Saljé K, Familari M, Guller S, Schneider H, Gardiner C, Sargent IL, Redman CW, Mörgelin M, Åkerström B, Gram M, Hansson SR: Syncytiotrophoblast vesicles show altered micro-RNA and haemoglobin content after ex-vivo perfusion of placentas with haemoglobin to mimic preeclampsia. PLoS One. 2014; 2014 Feb 27. PMID: 24587192

Tadesse S, Kidane D, Guller S, Luo T, Norwitz NG, Arcuri F, Toti P, Norwitz ER: In vivo and in vitro evidence for placental DNA damage in preeclampsia. PLoS One. 2014; 2014 Jan 22. PMID: 24466242

Tang Z, Buhimschi IA, Buhimschi CS, Tadesse S, Norwitz E, Niven-Fairchild T, Huang ST, Guller S: Decreased levels of folate receptor-β and reduced numbers of fetal macrophages (Hofbauer cells) in placentas from pregnancies with severe pre-eclampsia. Am J Reprod Immunol. 2013 Aug; 2013 Mar 11. PMID: 23480364

Racicot K, Cardenas I, Wünsche V, Aldo P, Guller S, Means RE, Romero R, Mor G: Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol. 2013 Jul 15; 2013 Jun 10. PMID: 23752614

Aldo PB, Craveiro V, Guller S, Mor G: Effect of culture conditions on the phenotype of THP-1 monocyte cell line. Am J Reprod Immunol. 2013 Jul; 2013 Apr 29. PMID: 23621670

Mulla MJ, Myrtolli K, Tadesse S, Stanwood NL, Gariepy A, Guller S, Norwitz ER, Abrahams VM: Cutting-edge report: TLR10 plays a role in mediating bacterial peptidoglycan-induced trophoblast apoptosis. Am J Reprod Immunol. 2013 May; 2012 Dec 28. PMID: 23279063

Tang Z, Niven-Fairchild T, Tadesse S, Norwitz ER, Buhimschi CS, Buhimschi IA, Guller S: Glucocorticoids enhance CD163 expression in placental Hofbauer cells. Endocrinology. 2013 Jan; 2012 Nov 9. PMID: 23142809

Krikun G, Trezza J, Shaw J, Rahman M, Guller S, Abrahams VM, Lockwood CJ: Lipopolysaccharide appears to activate human endometrial endothelial cells through TLR-4-dependent and TLR-4-independent mechanisms. Am J Reprod Immunol. 2012 Sep; 2012 Jun 4. PMID: 22672000

Schatz F, Kayisli UA, Vatandaslar E, Ocak N, Guller S, Abrahams VM, Krikun G, Lockwood CJ: Toll-like receptor 4 expression in decidual cells and interstitial trophoblasts across human pregnancy. Am J Reprod Immunol. 2012 Aug; 2012 May 8. PMID: 22564191

Wu XX, Guller S, Rand JH: Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011 Dec; 2011 Jun 24. PMID: 21871597

Tang Z, Tadesse S, Norwitz E, Mor G, Abrahams VM, Guller S: Isolation of hofbauer cells from human term placentas with high yield and purity. Am J Reprod Immunol. 2011 Oct; 2011 May 4. PMID: 21545365

Tadesse S, Luo G, Park JS, Kim BJ, Snegovskikh VV, Zheng T, Hodgson EJ, Arcuri F, Toti P, Parikh CR, Guller S, Norwitz ER: Intra-amniotic infection upregulates neutrophil gelatinase-associated lipocalin (NGAL) expression at the maternal-fetal interface at term: implications for infection-related preterm birth. Reprod Sci. 2011 Aug; 2011 Mar 18. PMID: 21421891

Cardenas I, Mulla MJ, Myrtolli K, Sfakianaki AK, Norwitz ER, Tadesse S, Guller S, Abrahams VM: Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor. J Immunol. 2011 Jul 15; 2011 Jun 15. PMID: 21677137

Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, Tadesse S, Norwitz ER, Guller S, Abrahams VM: Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia. Am J Reprod Immunol. 2011 Jun. PMID: 21352397

Toti P, Arcuri F, Tang Z, Schatz F, Zambrano E, Mor G, Niven-Fairchild T, Abrahams VM, Krikun G, Lockwood CJ, Guller S: Focal increases of fetal macrophages in placentas from pregnancies with histological chorioamnionitis: potential role of fibroblast monocyte chemotactic protein-1. Am J Reprod Immunol. 2011 May; 2010 Nov 19. PMID: 21087336

Tang Z, Abrahams VM, Mor G, Guller S: Placental Hofbauer cells and complications of pregnancy. Ann N Y Acad Sci. 2011 Mar. PMID: 21401637

Mor G, Cardenas I, Abrahams V, Guller S: Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011 Mar. PMID: 21401634

Lee HJ, Snegovskikh VV, Park JS, Foyouzi N, Han KT, Hodgson EJ, Guller S, Norwitz ER: Role of GnRH-GnRH receptor signaling at the maternal-fetal interface. Fertil Steril. 2010 Dec; 2010 Apr 18. PMID: 20400076

Guller S: Role of the syncytium in placenta-mediated complications of preeclampsia. Thromb Res. 2009 Sep; 2009 Jun 16. PMID: 19535132

Mulla MJ, Yu AG, Cardenas I, Guller S, Panda B, Abrahams VM: Regulation of Nod1 and Nod2 in first trimester trophoblast cells. Am J Reprod Immunol. 2009 Apr. PMID: 19260860

Guller S, Buhimschi CS, Ma YY, Huang ST, Yang L, Kuczynski E, Zambrano E, Lockwood CJ, Buhimschi IA: Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia. Lab Invest. 2008 Oct; 2008 Aug 4. PMID: 18679377

Guller S, Ma YY, Fu HH, Krikun G, Abrahams VM, Mor G: The placental syncytium and the pathophysiology of preeclampsia and intrauterine growth restriction: a novel assay to assess syncytial protein expression. Ann N Y Acad Sci. 2008 Apr. PMID: 18443340

Bulletti C, Guller S, DE Ziegler D, Lockwood CJ: Preface: novel features of the physiology and pathology of human reproduction. Ann N Y Acad Sci. 2008 Apr. PMID: 18443322

Bahtiyar MO, Buhimschi C, Ravishankar V, Copel J, Norwitz E, Julien S, Guller S, Buhimschi IA: Contrasting effects of chronic hypoxia and nitric oxide synthase inhibition on circulating angiogenic factors in a rat model of growth restriction. Am J Obstet Gynecol. 2007 Jan. PMID: 17240241

Lockwood CJ, Arcuri F, Toti P, Felice CD, Krikun G, Guller S, Buchwalder LF, Schatz F: Tumor necrosis factor-alpha and interleukin-1beta regulate interleukin-8 expression in third trimester decidual cells: implications for the genesis of chorioamnionitis. Am J Pathol. 2006 Oct. PMID: 17003486

Buhimschi CS, Magloire L, Funai E, Norwitz ER, Kuczynski E, Martin R, Richman S, Guller S, Lockwood CJ, Buhimschi IA: Fractional excretion of angiogenic factors in women with severe preeclampsia. Obstet Gynecol. 2006 May. PMID: 16648417

Koklanaris N, Nwachukwu JC, Huang SJ, Guller S, Karpisheva K, Garabedian M, Lee MJ: First-trimester trophoblast cell model gene response to hypoxia. Am J Obstet Gynecol. 2006 Mar. PMID: 16522398

Ma Y, Mor G, Abrahams VM, Buhimschi IA, Buhimschi CS, Guller S: Alterations in syncytiotrophoblast cytokine expression following treatment with lipopolysaccharide. Am J Reprod Immunol. 2006 Jan. PMID: 16364007

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G: A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15. PMID: 16339547

Lee MJ, Wang Z, Yee H, Ma Y, Swenson N, Yang L, Kadner SS, Baergen RN, Logan SK, Garabedian MJ, Guller S: Expression and regulation of glucocorticoid receptor in human placental villous fibroblasts. Endocrinology. 2005 Nov; 2005 Jul 28. PMID: 16055431

Stephenson CD, Lockwood CJ, Ma Y, Guller S: Thrombin-dependent regulation of matrix metalloproteinase (MMP)-9 levels in human fetal membranes. J Matern Fetal Neonatal Med. 2005 Jul. PMID: 16105787

Buhimschi CS, Norwitz ER, Funai E, Richman S, Guller S, Lockwood CJ, Buhimschi IA: Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia. Am J Obstet Gynecol. 2005 Mar. PMID: 15746665

Ma Y, Kadner SS, Guller S: Differential effects of lipopolysaccharide and thrombin on interleukin-8 expression in syncytiotrophoblasts and endothelial cells: implications for fetal survival. Ann N Y Acad Sci. 2004 Dec. PMID: 15731315

Lee MJ, Ma Y, LaChapelle L, Kadner SS, Guller S: Glucocorticoid enhances transforming growth factor-beta effects on extracellular matrix protein expression in human placental mesenchymal cells. Biol Reprod. 2004 May; 2003 Dec 17. PMID: 14681196

Krikun G, Mor G, Alvero A, Guller S, Schatz F, Sapi E, Rahman M, Caze R, Qumsiyeh M, Lockwood CJ: A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology. 2004 May; 2004 Jan 15. PMID: 14726435

Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G: First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod. 2004 Jan. PMID: 14665707

Akhmedkhanov A, Lundin E, Guller S, Lukanova A, Micheli A, Ma Y, Afanasyeva Y, Zeleniuch-Jacquotte A, Krogh V, Lenner P, Muti P, Rinaldi S, Kaaks R, Berrino F, Hallmans G, Toniolo P: Circulating soluble Fas levels and risk of ovarian cancer. BMC Cancer. 2003 Dec 22; 2003 Dec 22. PMID: 14690548

From left to right: Zhonghua Tang, Nick Norwitz, Julianna Brown, Seth Guller, Jeff Shaw, Jawaad Farrukh, and Serkalem Tadesse.