Novel 3D embryo implantation model within macroporous alginate scaffolds

Dganit Stern-Tal; Hanna Achache; Liora Jacobs Catane; Reuven Reich; Tali Tavor Re'em

doi:10.1186/s13036-020-00240-7

Novel 3D embryo implantation model within macroporous alginate scaffolds

J Biol Eng. 2020 Jun 30:14:18. doi: 10.1186/s13036-020-00240-7. eCollection 2020.

Authors

Dganit Stern-Tal¹, Hanna Achache¹, Liora Jacobs Catane¹, Reuven Reich¹, Tali Tavor Re'em²

Affiliations

¹ School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel.
² Department of Pharmaceutical Engineering, Azrieli College of Engineering Jerusalem, 26 Yaakov Shreibom Street, 9103501 Jerusalem, Israel.

Abstract

Background: Implantation failure remains an unsolved obstacle in reproductive medicine. Previous studies have indicated that estrogen responsiveness, specifically by estrogen receptor alpha (ERα), is crucial for proper implantation. There is an utmost need for a reliable in vitro model that mimics the events in the uterine wall during the implantation process for studying the regulatory mechanisms governing the process. The current two-dimensional and hydrogel-based in vitro models provide only short-term endometrial cell culture with partial functionality.

Results: Endometrial biopsies showed an increase in E-cadherin expression on the typical window of implantation of fertile women, compared to negligible expression in recurrent implantation failure (RIF) patients. These clinical results indicated E-cadherin as a marker for receptivity. Three-dimensional (3D) macroporous alginate scaffolds were the base for epithelial endometrial cell-seeding and long-term culture under hormone treatment that mimicked a typical menstrual cycle. The RL95-2 epithelial cell culture in macroporous scaffolds was viable for 3 weeks and showed increased E-cadherin levels in response to estrogen. Human choriocarcinoma (JAR) spheroids were used as embryo models, seeded onto cell constructs and successfully adhered to the RL95-2 cell culture. Moreover, a second model of HEC-1A with low ERα levels, showed lower E-cadherin expression and no JAR attachment. E-cadherin expression and JAR attachment were recovered in HEC-1A cells that were transfected with ERα plasmid.

Conclusions: We present a novel model that enables culturing endometrial cells on a 3D matrix for 3 weeks under hormonal treatment. It confirmed the importance of ERα function and E-cadherin for proper implantation. This platform may serve to elucidate the regulatory mechanisms controlling the implantation process, and for screening and evaluating potential novel therapeutic strategies for RIF.

Keywords: 3D in vitro model; Alginate; Embryo implantation; Endometrium; Epithelial endometrial cells; Hormone treatment; Menstrual cycle; Porous scaffold; RIF; Recurrent implantation failure.