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


Guller, Seth M

Senior Research Scientist in Obstetrics, Gynecology, and Reproductive Sciences
Director, Gyn/Endocrine Laboratory

Research Interests:Placental physiology; Intrauterine growth restriction; Preeclampsia; Adverse pregnancy outcomes

Clinical Interests:Dr. Guller directs the Yale Gyn/Endocrine Laboratory which uses Immulite technology to analyze hormone levels in serum from patients seen in the Division of Reproductive Endocrinology and Infertility.

  • Office:(203) 737-2532
  • Lab:(203) 737-2314

Serkalem Tadesse

Laboratory Associate in Obstetrics, Gynecology, and Reproductive Sciences

Publications

Young OM, Tang Z, Niven-Fairchild T, Tadesse S, Krikun G, Norwitz ER, Mor G, Abrahams VM and 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;73 (1) :22-35. Epub 2014 Oct 24. PMID: 25345551

Aldo PB, Racicot K, Craviero V, Guller S, Romero R and Mor G: Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol. 2014 Sep;72 (3) :270-84. Epub 2014 Jul 3. PMID: 24995492


Hoang M, Potter JA, Gysler SM, Han CS, Guller S, Norwitz ER and 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;90 (2) :39. Epub 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 and 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;9 (2) :e90020. Epub 2014 Feb 27. PMID: 24587192


Tadesse S, Kidane D, Guller S, Luo T, Norwitz NG, Arcuri F, Toti P and Norwitz ER: In vivo and in vitro evidence for placental DNA damage in preeclampsia. PLoS One. 2014;9 (1) :e86791. Epub 2014 Jan 22. PMID: 24466242

Tang Z, Buhimschi IA, Buhimschi CS, Tadesse S, Norwitz E, Niven-Fairchild T, Huang ST and 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;70 (2) :104-15. Epub 2013 Mar 11. PMID: 23480364


Racicot K, Cardenas I, Wünsche V, Aldo P, Guller S, Means RE, Romero R and Mor G: Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol. 2013 Jul 15;191 (2) :934-41. Epub 2013 Jun 10. PMID: 23752614


Aldo PB, Craveiro V, Guller S and Mor G: Effect of culture conditions on the phenotype of THP-1 monocyte cell line. Am J Reprod Immunol. 2013 Jul;70 (1) :80-6. Epub 2013 Apr 29. PMID: 23621670


Mulla MJ, Myrtolli K, Tadesse S, Stanwood NL, Gariepy A, Guller S, Norwitz ER and Abrahams VM: Cutting-edge report: TLR10 plays a role in mediating bacterial peptidoglycan-induced trophoblast apoptosis. Am J Reprod Immunol. 2013 May;69 (5) :449-53. Epub 2012 Dec 28. PMID: 23279063


Tang Z, Niven-Fairchild T, Tadesse S, Norwitz ER, Buhimschi CS, Buhimschi IA and Guller S: Glucocorticoids enhance CD163 expression in placental Hofbauer cells. Endocrinology. 2013 Jan;154 (1) :471-82. Epub 2012 Nov 9. PMID: 23142809

Krikun G, Trezza J, Shaw J, Rahman M, Guller S, Abrahams VM and 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;68 (3) :233-7. Epub 2012 Jun 4. PMID: 22672000


Schatz F, Kayisli UA, Vatandaslar E, Ocak N, Guller S, Abrahams VM, Krikun G and Lockwood CJ: Toll-like receptor 4 expression in decidual cells and interstitial trophoblasts across human pregnancy. Am J Reprod Immunol. 2012 Aug;68 (2) :146-53. Epub 2012 May 8. PMID: 22564191

Wu XX, Guller S and Rand JH: Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011 Dec;205 (6) :576.e7-14. Epub 2011 Jun 24. PMID: 21871597


Tang Z, Tadesse S, Norwitz E, Mor G, Abrahams VM and Guller S: Isolation of hofbauer cells from human term placentas with high yield and purity. Am J Reprod Immunol. 2011 Oct;66 (4) :336-48. Epub 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 and 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;18 (8) :713-22. Epub 2011 Mar 18. PMID: 21421891


Cardenas I, Mulla MJ, Myrtolli K, Sfakianaki AK, Norwitz ER, Tadesse S, Guller S and Abrahams VM: Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor. J Immunol. 2011 Jul 15;187 (2) :980-6. Epub 2011 Jun 15. PMID: 21677137


Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, Tadesse S, Norwitz ER, Guller S and Abrahams VM: Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia. Am J Reprod Immunol. 2011 Jun;65 (6) :542-8. PMID: 21352397


Toti P, Arcuri F, Tang Z, Schatz F, Zambrano E, Mor G, Niven-Fairchild T, Abrahams VM, Krikun G, Lockwood CJ and 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;65 (5) :470-9. Epub 2010 Nov 19. PMID: 21087336


Tang Z, Abrahams VM, Mor G and Guller S: Placental Hofbauer cells and complications of pregnancy. Ann N Y Acad Sci. 2011 Mar;1221 :103-8. PMID: 21401637


Mor G, Cardenas I, Abrahams V and Guller S: Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011 Mar;1221 :80-7. PMID: 21401634

Lee HJ, Snegovskikh VV, Park JS, Foyouzi N, Han KT, Hodgson EJ, Guller S and Norwitz ER: Role of GnRH-GnRH receptor signaling at the maternal-fetal interface. Fertil Steril. 2010 Dec;94 (7) :2680-7. Epub 2010 Apr 18. PMID: 20400076

Guller S: Role of the syncytium in placenta-mediated complications of preeclampsia. Thromb Res. 2009 Sep;124 (4) :389-92. Epub 2009 Jun 16. PMID: 19535132


Mulla MJ, Yu AG, Cardenas I, Guller S, Panda B and Abrahams VM: Regulation of Nod1 and Nod2 in first trimester trophoblast cells. Am J Reprod Immunol. 2009 Apr;61 (4) :294-302. PMID: 19260860

Guller S, Buhimschi CS, Ma YY, Huang ST, Yang L, Kuczynski E, Zambrano E, Lockwood CJ and Buhimschi IA: Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia. Lab Invest. 2008 Oct;88 (10) :1057-67. Epub 2008 Aug 4. PMID: 18679377


Guller S, Ma YY, Fu HH, Krikun G, Abrahams VM and 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;1127 :129-33. PMID: 18443340


Bulletti C, Guller S, DE Ziegler D and Lockwood CJ: Preface: novel features of the physiology and pathology of human reproduction. Ann N Y Acad Sci. 2008 Apr;1127 :xi. PMID: 18443322

Bahtiyar MO, Buhimschi C, Ravishankar V, Copel J, Norwitz E, Julien S, Guller S and 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;196 (1) :72.e1-6. PMID: 17240241

Lockwood CJ, Arcuri F, Toti P, Felice CD, Krikun G, Guller S, Buchwalder LF and 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;169 (4) :1294-302. PMID: 17003486


Buhimschi CS, Magloire L, Funai E, Norwitz ER, Kuczynski E, Martin R, Richman S, Guller S, Lockwood CJ and Buhimschi IA: Fractional excretion of angiogenic factors in women with severe preeclampsia. Obstet Gynecol. 2006 May;107 (5) :1103-13. PMID: 16648417


Koklanaris N, Nwachukwu JC, Huang SJ, Guller S, Karpisheva K, Garabedian M and Lee MJ: First-trimester trophoblast cell model gene response to hypoxia. Am J Obstet Gynecol. 2006 Mar;194 (3) :687-93. PMID: 16522398


Ma Y, Mor G, Abrahams VM, Buhimschi IA, Buhimschi CS and Guller S: Alterations in syncytiotrophoblast cytokine expression following treatment with lipopolysaccharide. Am J Reprod Immunol. 2006 Jan;55 (1) :12-8. PMID: 16364007

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R and Mor G: A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15;175 (12) :8096-104. PMID: 16339547


Lee MJ, Wang Z, Yee H, Ma Y, Swenson N, Yang L, Kadner SS, Baergen RN, Logan SK, Garabedian MJ and Guller S: Expression and regulation of glucocorticoid receptor in human placental villous fibroblasts. Endocrinology. 2005 Nov;146 (11) :4619-26. Epub 2005 Jul 28. PMID: 16055431


Stephenson CD, Lockwood CJ, Ma Y and Guller S: Thrombin-dependent regulation of matrix metalloproteinase (MMP)-9 levels in human fetal membranes. J Matern Fetal Neonatal Med. 2005 Jul;18 (1) :17-22. PMID: 16105787


Buhimschi CS, Norwitz ER, Funai E, Richman S, Guller S, Lockwood CJ and Buhimschi IA: Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia. Am J Obstet Gynecol. 2005 Mar;192 (3) :734-41. PMID: 15746665

Ma Y, Kadner SS and 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;1034 :236-44. PMID: 15731315


Lee MJ, Ma Y, LaChapelle L, Kadner SS and Guller S: Glucocorticoid enhances transforming growth factor-beta effects on extracellular matrix protein expression in human placental mesenchymal cells. Biol Reprod. 2004 May;70 (5) :1246-52. Epub 2003 Dec 17. PMID: 14681196


Krikun G, Mor G, Alvero A, Guller S, Schatz F, Sapi E, Rahman M, Caze R, Qumsiyeh M and Lockwood CJ: A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology. 2004 May;145 (5) :2291-6. Epub 2004 Jan 15. PMID: 14726435


Abrahams VM, Straszewski-Chavez SL, Guller S and Mor G: First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod. 2004 Jan;10 (1) :55-63. 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 and Toniolo P: Circulating soluble Fas levels and risk of ovarian cancer. BMC Cancer. 2003 Dec 22;3 :33. Epub 2003 Dec 22. PMID: 14690548