Study of the mechanisms underlying the salutary effects of Heme Oxygenase-1 in implantation, placentation and fetal growth using a mouse model and in vitro approaches. Participation of carbon monoxide in the preparation of the murine uterine microenvironment for pregnancy.

• Applicant: Professorin Dr. Ana Claudia Zenclussen
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277699676

• Final Report Year: 2022

Final Report Abstract

In conclusion, during this project we: a) established a valuable method to follow up pregnancy in vivo and clearly analyze implantation numbers, implantation sizes, fetal growth, placental growth, fetal and placental parameters. Additionally, using Doppler measurements we were able to measure maternal and fetal blood flow. This is a valuable and top-class method to enormously reduce the number of animals used in experiments while maximizing the information obtained within them. b) observed that, contrary to our hypothesis and expectations, Hmox1 partial deficiency did not impact the superovulation yield, nor did influence the fertilization success rate. Additionally, CO exposure during fertilization could not significantly improve the outcome. c) showed that not only maternal, but also paternal HO-1 expression is relevant for pregnancy success in vivo. This could be done using Hmox1 wildtype, heterozygous and knockout female and male mice. We therefore refrained to do IVF and transfer experiments as they were not longer relevant. d) were able to demonstrate the importance of HO-1 expression in human trophoblasts for their attachment to endometrial cells during the process of implantation using a cell line-based approach. We additionally showed that CO was able to restore attachment if HO-1 was knocked-down by siRNA. Thus, HO-1 facilitates attachment by releasing CO. In conclusion, we contributed to the knowledge as how HO-1 and its prominent metabolite CO contribute to fertilization, implantation and pregnancy.

Publications

• Bisphenol A exposure during early pregnancy impairs uterine spiral artery remodeling and provokes intrauterine growth restriction in mice. Sci Rep. 2018 Jun 15;8(1):9196
  Müller JE, Meyer N, Santamaria CG, Schumacher A, Luque EH, Zenclussen ML, Rodriguez HA, Zenclussen AC
  
• High Frequency Ultrasound for the Analysis of Fetal and Placental Development In Vivo. J Vis Exp. 2018 Nov 8;(141)
  Meyer N, Schüler T, Zenclussen AC
  
• Simultaneous Ablation of Uterine Natural Killer Cells and Uterine Mast Cells in Mice Leads to Poor Vascularization and Abnormal Doppler Measurements That Compromise Fetal Well-being. Front Immunol. 2018 Jan 8;8:1913
  Meyer N, Schüler T, Zenclussen AC
  
• Chymase-Cre; Mcl-1fl/fl Mice Exhibit Reduced Numbers of Mucosal Mast Cells. Front Immunol. 2019 Oct 15;10:2399
  Luo Y, Meyer N, Jiao Q, Scheffel J, Zimmermann C, Metz M, Zenclussen AC, Maurer M, Siebenhaar F
  
• Exposure to 17α-ethinyl estradiol during early pregnancy affects fetal growth and survival in mice. Environ Pollut. 2019 Aug; 251:493-501
  Meyer N, Santamaria CG, Müller JE, Schumacher A, Rodriguez HA, Zenclussen AC
  
• The UV filter benzophenone 3, alters early follicular assembly in rat whole ovary cultures. Toxicol Lett. 2019 Mar 15;303:48-54
  Santamaría CG, Abud JE, Porporato MM, Meyer N, Zenclussen AC, Kass L, Rodríguez HA
  
• Heme Oxygenase-1 Is a Pivotal Modulator of Bone Turnover and Remodeling: Molecular Implications for Prostate Cancer Bone Metastasis. Antioxid Redox Signal. 2020 Jun 10; 32(17):1243-1258
  Anselmino N, Starbuck M, Labanca E, Cotignola J, Navone N, Gueron G, Zenclussen AC, Vazquez E
  
• Using ultrasound to define the time point of intrauterine growth retardation in a mouse model of heme oxygenase-1 deficiency. Biol Reprod. 2020 Jun 23; 103(1):126-134
  Meyer N, Langwisch S, Scharm M, Zenclussen AC
  
• Y-Box Binding Protein 1 Expression in Trophoblast Cells Promotes Fetal and Placental Development. Cells. 2020 Aug 22; 9(9):1942
  Meyer N, Schumacher A, Coenen U, Woidacki K, Schmidt H, Lindquist JA, Mertens PR, Zenclussen AC
  
• Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny. Int J Mol Sci. 2021 May 20; 22(10):5403
  Jeschke L, Santamaria CG, Meyer N, Zenclussen AC, Bartley J, Schumacher A
  
• Maternal B Cell-Intrinsic MyD88 Signaling Mediates LPS-Driven Intrauterine Fetal Death. Cells. 2021 Oct 8; 10(10):2693
  Busse M, Plenagl S, Campe NKJ, Müller AJ, Tedford K, Schumacher A, Zenclussen AC
  
• Depletion of Foxp3+ regulatory T cells but not the absence of CD19+IL-10+ regulatory B cells hinders tumor growth in a para-orthotopic neuroblastoma mouse model. Int J Cancer. 2022 Dec 1; 151(11):2031-2042
  Weißenborn C, von Lenthe S, Hinz N, Langwisch S, Busse M, Schumacher A, Zenclussen AC, Fest S
  
• Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses. Front Immunol. 2022 Sep 20; 13:989247
  Lentz LS, Stutz AJ, Meyer N, Schubert K, Karkossa I, von Bergen M, Zenclussen AC, Schumacher A
  
• Maternal B cell signaling orchestrates fetal development in mice. Development. 2022 Apr 15; 149(8):dev199783
  Busse M, Langwisch S, Tedford K, Fischer KD, Zenclussen AC