Oral Presentation ESA-SRB-APEG-NZSE 2022

Human foetal reproductive organoids and their potential clinical applications (#56)

Varshini Devarapalli Venkata 1 2 3 , Muhammad F.B Jamaluddin 1 2 3 , Rachel O'Sullivan 4 , Yvette Ius 4 , Ken Jaaback 4 , Pravin Nahar 5 , Pradeep S Tanwar 1 2 3
  1. Global Centre for Gynaecological Diseases, The University of Newcastle, Newcastle, NSW, Australia
  2. School of Biomedical Sciences and Pharmacy, The university of Newcastle, Newcastle, NSW, Australia
  3. Hunter Medical Research Institute, Newcastle, NSW, Australia
  4. Hunter New England Centre for Gynecological Cancer, Newcastle, NSW, Australia
  5. Department of Maternity and Gynaecology, John Hunter Hospital, Newcastle, NSW, Australia

Background and Aims

Müllerian duct anomalies (MDAs) are developmental disorders of the female reproductive tract organs, and their prevalence is 5% in fertile women and ~ 6-15% in patients with infertility worldwide [1-3]. Studies using mouse models and human genome sequencing has revealed that the WNT signalling pathway is altered in patients with MDAs [4]. However, due to restricted access to foetal tissues, there is very little understood about human reproductive development and diseases. Therefore, we aimed to establish human fetal female reproductive organoids that represent a unique platform for understanding human female reproductive tract development and diseases.

Methods

In this study, we first performed a comparative histopathology analysis to differentiate between human fetal and adult female reproductive tract epithelium. We then developed human fetal female reproductive tract organoids and compared them to their adult counterparts using proteomic analysis and histology validation. Further, we established an in vitro transplantation model to regenerate adult tissues using fetal organoids to assess the differentiation potential of the fetal organoids. Finally, the transplanted tissue scaffolds were treated with Wnt inhibitors to understand the functional consequences of Wnt signalling suppression.

Results

The histopathological and proteomic analysis of the epithelial cell types revealed significant differences in protein expression and signalling pathways between fetal and adult tissues. We showed the successful establishment of culture conditions for fetal organoid growth and long-term maintenance. Our transplantation model provided evidence that fetal organoids represent a transplantable source of cells and have the capacity to regenerate adult organs. We further highlight the requirement of Wnt signalling in the self-renewal and differentiation of the fetal epithelium.

Conclusion

To conclude, we developed an organoid-scaffold model from the fetal female reproductive tissue to understand the basis of human female reproductive tract development and associated disorders.

  1. Acién, P., Incidence of Müllerian defects in fertile and infertile women. Hum Reprod, 1997. 12(7): p. 1372-6.
  2. Raga, F., et al., Reproductive impact of congenital Müllerian anomalies. Hum Reprod, 1997. 12(10): p. 2277-81.
  3. Mullen, R.D. and R.R. Behringer, Molecular genetics of Müllerian duct formation, regression and differentiation. Sex Dev, 2014. 8(5): p. 281-96.
  4. Ledig, S. and P. Wieacker, Clinical and genetic aspects of Mayer–Rokitansky–Küster–Hauser syndrome. medizinische genetik, 2018. 30(1): p. 3-11.