The female reproductive tract is an integrated set of organs that supports women's overall endocrine health, fertility and fetal development. Each organ within the tract is composed of different cells that interact with each other, relying on a precise tissue architecture that is more effectively studied in three-dimensional (3D) tissue cultures vs. the traditional 2D petri dish cell culture methods. Our project goal is to develop an integrated ex vivo female reproductive tract using 3D cultures of reproductive tissues (Patent pending: 61/932,592). Our bioengineered system, termed FemKUBE includes the major reproductive tissues: ovarian follicles, fallopian tube, uterus, endocervix, and ectocervix and can be used to measure responses to normal hormones, endocrine disruptors, other reproductive hazards, and as a screening tool in the drug development pipeline. Furthermore, we aim to establish renewable resources from patients for many of the tissues that will populate the system. This type of research has never been attempted for the reproductive tract.
This project is a collaborative program among federal agencies within the National Institutes of Health (NIH) including the National Center for Advancing Translational Sciences (NCATS), the National Institute of Environmental Health Sciences (NIEHS), the Office of Research on Women’s Health (ORWH) together with, the Defense Advanced Research Projects Agency (DARPA), and the United States Food and Drug Administration (FDA). These federal agencies are working together to catalyze a microphysiologic platform to model the human body. The hope is that the resultant platform can better predict drug safety and efficacy than current in vitro and animal models (http://www.ncats.nih.gov/research/reengineering/tissue-chip/funding/funding.html.) Our research on the female reproductive tract allows sex specific biology to be included in the program. An on-going problem with drug development is that reproductive aged females are excluded from clinical trials and much of basic research is conducted using male animals or ignores sex completely. In addition, females experience more adverse drug effects than men. We view the program, with its goal of modeling human physiology and our expertise in female reproductive biology, as an excellent opportunity to begin alleviating some of these problems. Furthermore, the program allows us to bring reproductive biology to the forefront of cutting edge scientific research.
During the first two years of funding, we have established 3D cultures of female reproductive tissues that respond physiologically to female sex steroids, estrogen and progesterone. Importantly, we add estrogen and progesterone in a pattern that mimics the human menstrual cycle over 28 days. In addition to supplementing estrogen and progesterone, we have the ability to trigger ovarian follicles to produce hormones in a pattern that mimics the menstrual cycle. These accomplishments are major successes for reproductive biology research, since an in vitro assessment of the female reproductive tract across the menstrual cycle has never been completed. Our culture models allow us to assess changes across the cycle and in the presence of potentially disruptive compounds, such as chemotherapy and environmental toxins. We have also designed and implemented the first microfluidic culture system for ovarian follicles. Ovarian follicles in this system produce an in vitro menstrual cycle over 28 days. This achievement is the first step to establishing a fully microfluidic culture system for the female reproductive tract.
The current phase of funding will focus on establishing an engineered microfluidic platform for the female reproductive tract. The goal is to culture tissues on a single platform that pumps media from one tissue to the other. More specifically, ovarian follicles will secrete hormones into cell culture media that will flow to the fallopian tube, uterus, endocervix, and ectocervix. We hope that this will mimic tissue-tissue interactions that occur during the menstrual cycle. Additional goals are to validate the system using a set of test compounds and to develop renewable cell sources for female reproductive tissues, using cryopreservation and induced pluripotent stem cells (iPSC).
Project Activities:
Graduate Student Kelly McKinnon and postdoctoral researcher Shuo Xiao, PhD received awards for their presentations at the 2015 Center for Reproductive Science Minisymposium. Kelly presented a poster titled “Engineering a three-dimensional human ectocervical tissue model to study hormonal regulation and immune response of the female reproductive tract”. Shuo gave an oral presentation titled “Personalized Follicle Monitoring Improves Oocyte Reproductive Outcomes During Encapsulated In Vitro Follicle Growth (eIVFG) in Mouse And Human”.
Postdoctoral researcher Sevim Yildiz Arslan, PhD served on the 2015 Center for Reproductive Science Minisymposium organizing committee.
Dr. Spiro Getsios (Co-I, ectocervix) was invited to participate in a National Institute of Arthritis and Musculoskeletal and Skin Disease roundtable on “Opportunities and Challenges in Developing 3-Dimensional Human Tissue Models to Study Musculoskeletal and Skin Physiology and Pathophysiology”. A summary of the roundtable is here: http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/2014/3-D_models.asp.
Media:
On December 4, 2014, Dr. Teresa Woodruff gave a guest lecture on FemKUBE at the National Institute of Environmental Health Sciences. Dr. Woodruff’s lecture was highlighted in the Institute’s newsletter: http://www.niehs.nih.gov/news/newsletter/2015/1/science-woodruff/
Northwestern Medicine showcases FemKUBE and the Tissue Chip Program: http://www.feinberg.northwestern.edu/news/2014/10/Woodruff-tissue-chip-grant.html
Publications:
1) Laronda MM, Jakus AE, Whelan KA, Wertheim JA, Shah RN, Woodruff TK. Initiation of puberty in mice following decellularized ovary transplant. Biomaterials. 2015 May; 50:20-9
2) Arslan SY, Yu Y, Burdette JE, Pavone ME, Hope TJ, Woodruff TK, Kim JJ. Novel three dimensional human endocervix cultures respond to 28-day hormone treatment. Endocrinology. 2015 Apr;156(4):1602-9.
3) Xu U, Duncan FE, Woodruff TK. Use of an organotypic mammalian in vitro follicle growth assay to facilitate female reproductive toxicity screening. Reprod Fertil Dev. 2015 Feb 18. [Epub ahead of print]
4) Eddie SL, Quartuccio SM, Zhu J, Shepherd JA, Kothari R, Kim JJ, Woodruff TK, Burdette JE. Three-dimensional modeling of the human fallopian tube fimbriae. Gynecol Oncol. 2015 Feb;136(2):348-54.
5) Eddie SL, Kim JJ, Woodruff TK, Burdette JE. Microphysiological modeling of the reproductive tract: A fertile endeavor. Exp Biol Med (Maywood). 2014 Sep;239(9):1192-202
6) Laronda MM, Burdette JE, Kim J, Woodruff TK. Recreating the female reproductive tract in vitro using iPSC technology in a linked microfluidics environment. Stem Cell Res Ther. 2013;4 Suppl 1:S13. Epub 2013 Dec 20.
FemKUBE Biology Teams:
PI: Teresa K. Woodruff1*
EstroKUBE: Shuo Xiao1 , Alexandra Rashedi1
TubeKUBE: Joanna Burdette2* (http://tigger.uic.edu/~joannab/Burdette_Lab/Welcome.html), Jie Zhu1
UteroKUBE/EndocerixKUBE: J.Julie Kim1* (http://labs.feinberg.northwestern.edu/kim/index.html), Sevim Yildiz Arslan1, Susan Olalekan1, Thomas Hope (http://www.hopelab.northwestern.edu/index.shtml)1
EctocervixKUBE: Spiro Getsios3* (https://fsmweb.northwestern.edu/faculty/facultyProfile.cfm?xid=17633), Kelly McKinnon1, Paul Hoover3
iPSC Development: Monica M. Laronda1, Hanna Valli1
Gynecology Tissue Core: Mary Ellen Pavone1* (https://fsmweb.northwestern.edu/faculty/facultyprofile.cfm?xid=19888), Saurabh Malpani1
Bioengineering Support: Peter Chen1, Mingyang Jiang1
Pharmacokinetics: Michael Avram4 (https://fsmweb.northwestern.edu/faculty/FacultyProfile.cfm?xid=14060)
Project Management: Elizabeth C. Sefton1
FemKUBE Technology Team: Jonathan Coppeta5 , Brett Isenberg5 , Jeffrey T. Borenstein5 (http://www.draper.com)
1Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago IL, 60611;2Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607; 3Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago IL, 60611; 4Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago IL, 60611; 5The Charles Stark Draper Laboratory, Cambridge, MA, 02139;* sub-project leader
Funding Agencies: NCATS, ORWH, NICHD, NIEHS, NIH Common Fund
Grant Numbers: UH2ES022920 and UH3TR001207
Project Contact: Beth Sefton, e-sefton@northwestern.edu