Advanced Technologies for Studying Microbiome-Female Reproductive Tract Interactions: Organoids, Organoids-on-a-Chip, and Beyond

Overview

Journal Semin Reprod Med

Specialty Reproductive Medicine

Date 2024 Jan 23

PMID 38262440

Authors

Yosun A Kaya

Marcel R de Zoete

Gaby S Steba

Affiliations

Soon will be listed here.

Abstract

The female reproductive tract (FRT) is home to diverse microbial communities that play a pivotal role in reproductive health and disorders such as infertility, endometriosis, and cervical cancer. To understand the complex host-microbiota interactions within the FRT, models that authentically replicate the FRT's environment, including the interplay between the microbiota, mucus layer, immune system, and hormonal cycle, are key. Recent strides in organoid and microfluidic technologies are propelling research in this domain, offering insights into FRT-microbiota interactions and potential therapeutic avenues. This review delves into the current state of FRT organoid models and microbe integration techniques, evaluating their merits and challenges for specific research objectives. Emphasis is placed on innovative approaches and applications, including integrating organoids with microfluidics, and using patient-derived biobanks, as this offers potential for deeper mechanistic insights and personalized therapeutic strategies. Modeling various FRT properties in organoids is explored, from encompassing age-related epithelial features, oxygen levels, and hormonal effects to mucus layers, immune responses, and microbial interactions, highlighting their potential to transform reproductive health research and predict possible outcomes.

References

Westrom L, Joesoef R, Reynolds G, Hagdu A, THOMPSON S . Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results. Sex Transm Dis. 1992; 19(4):185-92. View

Kutteh W, Moldoveanu Z, Mestecky J . Mucosal immunity in the female reproductive tract: correlation of immunoglobulins, cytokines, and reproductive hormones in human cervical mucus around the time of ovulation. AIDS Res Hum Retroviruses. 1998; 14 Suppl 1:S51-5. View

Karzbrun E, Kshirsagar A, Cohen S, Hanna J, Reiner O . Human Brain Organoids on a Chip Reveal the Physics of Folding. Nat Phys. 2018; 14(5):515-522. PMC: 5947782. DOI: 10.1038/s41567-018-0046-7. View

Boretto M, Cox B, Noben M, Hendriks N, Fassbender A, Roose H . Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development. 2017; 144(10):1775-1786. DOI: 10.1242/dev.148478. View

Alzamil L, Nikolakopoulou K, Turco M . Organoid systems to study the human female reproductive tract and pregnancy. Cell Death Differ. 2020; 28(1):35-51. PMC: 7852529. DOI: 10.1038/s41418-020-0565-5. View

Leslie J, Huang S, Opp J, Nagy M, Kobayashi M, Young V . Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun. 2014; 83(1):138-45. PMC: 4288864. DOI: 10.1128/IAI.02561-14. View

Zhang Y, Aleman J, Shin S, Kilic T, Kim D, Mousavi Shaegh S . Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci U S A. 2017; 114(12):E2293-E2302. PMC: 5373350. DOI: 10.1073/pnas.1612906114. View

Cazanave C, Manhart L, Bebear C . Mycoplasma genitalium, an emerging sexually transmitted pathogen. Med Mal Infect. 2012; 42(9):381-92. DOI: 10.1016/j.medmal.2012.05.006. View

Venneri M, Franceschini E, Sciarra F, Rosato E, DEttorre G, Lenzi A . Human genital tracts microbiota: dysbiosis crucial for infertility. J Endocrinol Invest. 2022; 45(6):1151-1160. PMC: 9098539. DOI: 10.1007/s40618-022-01752-3. View

10.

Mahajan G, Doherty E, To T, Sutherland A, Grant J, Junaid A . Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip. Microbiome. 2022; 10(1):201. PMC: 9701078. DOI: 10.1186/s40168-022-01400-1. View

11.

Liptakova A, curova K, Zahumensky J, Visnyaiova K, Varga I . Microbiota of female genital tract - functional overview of microbial flora from vagina to uterine tubes and placenta. Physiol Res. 2023; 71(Suppl 1):S21-S33. PMC: 9853993. View

12.

Li H, Zang Y, Wang C, Li H, Fan A, Han C . The Interaction Between Microorganisms, Metabolites, and Immune System in the Female Genital Tract Microenvironment. Front Cell Infect Microbiol. 2021; 10:609488. PMC: 7785791. DOI: 10.3389/fcimb.2020.609488. View

13.

Sozzi E, Kajtez J, Bruzelius A, Wesseler M, Nilsson F, Birtele M . Silk scaffolding drives self-assembly of functional and mature human brain organoids. Front Cell Dev Biol. 2022; 10:1023279. PMC: 9614032. DOI: 10.3389/fcell.2022.1023279. View

14.

Kessler M, Hoffmann K, Brinkmann V, Thieck O, Jackisch S, Toelle B . The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat Commun. 2015; 6:8989. PMC: 4686873. DOI: 10.1038/ncomms9989. View

15.

Kutteh W, Prince S, HAMMOND K, Kutteh C, Mestecky J . Variations in immunoglobulins and IgA subclasses of human uterine cervical secretions around the time of ovulation. Clin Exp Immunol. 1996; 104(3):538-42. PMC: 2200440. DOI: 10.1046/j.1365-2249.1996.36742.x. View

16.

Zhang F, Dai J, Chen T . Role of in Female Infertility Modulating Sperm Agglutination and Immobilization. Front Cell Infect Microbiol. 2021; 10:620529. PMC: 7868545. DOI: 10.3389/fcimb.2020.620529. View

17.

Rajan A, Robertson M, Carter H, Poole N, Clark J, Green S . Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection. PLoS Pathog. 2020; 16(9):e1008851. PMC: 7553275. DOI: 10.1371/journal.ppat.1008851. View

18.

Nanki Y, Chiyoda T, Hirasawa A, Ookubo A, Itoh M, Ueno M . Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. Sci Rep. 2020; 10(1):12581. PMC: 7387538. DOI: 10.1038/s41598-020-69488-9. View

19.

Pierson Smela M, Kramme C, Fortuna P, Adams J, Su R, Dong E . Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. Elife. 2023; 12. PMC: 9943069. DOI: 10.7554/eLife.83291. View

20.

Yao Y, Cai X, Chen C, Fang H, Zhao Y, Fei W . The Role of Microbiomes in Pregnant Women and Offspring: Research Progress of Recent Years. Front Pharmacol. 2020; 11:643. PMC: 7225329. DOI: 10.3389/fphar.2020.00643. View