A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects

Geetika Sahni; Shu-Yung Chang; Jeremy Teo Choon Meng; Jerome Zu Yao Tan; Jean Jacques Clement Fatien; Carine Bonnard; Kagistia Hana Utami; Puck Wee Chan; Thong Teck Tan; Umut Altunoglu; Hülya Kayserili; Mahmoud Pouladi; Bruno Reversade; Yi-Chin Toh

doi:10.1002/advs.202001100

A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects

Adv Sci (Weinh). 2021 Jan 6;8(5):2001100. doi: 10.1002/advs.202001100. eCollection 2021 Mar.

Authors

Geetika Sahni^{1

2}, Shu-Yung Chang^{1

3}, Jeremy Teo Choon Meng^{4

5}, Jerome Zu Yao Tan^{1

2}, Jean Jacques Clement Fatien^{1

2}, Carine Bonnard⁶, Kagistia Hana Utami⁷, Puck Wee Chan⁸, Thong Teck Tan⁶, Umut Altunoglu⁸, Hülya Kayserili^{8

9}, Mahmoud Pouladi^{7

10}, Bruno Reversade^{6

9

11

12

13}, Yi-Chin Toh^{1

2

3

14

15

16}

Affiliations

¹ Department of Biomedical Engineering National University of Singapore Singapore 117583 Singapore.
² NUS Tissue Engineering Program National University of Singapore Singapore 119077 Singapore.
³ Institute for Health Innovation & Technology (iHealthTech) National University of Singapore Singapore 117599 Singapore.
⁴ Divison of Engineering New York University Abu Dhabi 129188 United Arab Emirates.
⁵ Department of Mechanical Engineering New York University New York NY 11201 USA.
⁶ Institute of Medical Biology Human Genetics and Embryology Laboratory ASTAR Singapore 138648 Singapore.
⁷ Translational Laboratory in Genetic Medicine (TLGM) Agency for Science, Technology, and Research (ASTAR) Singapore 138648 Singapore.
⁸ Istanbul Medical Faculty Medical Genetics Department Istanbul 34093 Turkey.
⁹ Koç University School of Medicine Medical Genetics Department Istanbul 34010 Turkey.
¹⁰ Department of Medicine National University of Singapore Singapore 119228 Singapore.
¹¹ Institute of Molecular and Cellular Biology ASTAR Singapore 138673 Singapore.
¹² Amsterdam Reproduction and Development Academic Medical Centre and VU University Medical Center Amsterdam 1105 the Netherlands.
¹³ National University of Singapore Department of Pediatrics Singapore 119228 Singapore.
¹⁴ The N.1 Institute for Health National University of Singapore Singapore 117456 Singapore.
¹⁵ School of Mechanical Medical and Process Engineering Queensland University of Technology Brisbane Queensland 4000 Australia.
¹⁶ Institute of Health and Biomedical Innovation Queensland University of Technology Kelvin Grove Queensland 4059 Australia.

Abstract

The generation of structurally standardized human pluripotent stem cell (hPSC)-derived neural embryonic tissues has the potential to model genetic and environmental mediators of early neurodevelopmental defects. Current neural patterning systems have so far focused on directing cell fate specification spatio-temporally but not morphogenetic processes. Here, the formation of a structurally reproducible and highly-organized neuroepithelium (NE) tissue is directed from hPSCs, which recapitulates morphogenetic cellular processes relevant to early neurulation. These include having a continuous, polarized epithelium and a distinct invagination-like folding, where primitive ectodermal cells undergo E-to-N-cadherin switching and apical constriction as they acquire a NE fate. This is accomplished by spatio-temporal patterning of the mesoendoderm, which guides the development and self-organization of the adjacent primitive ectoderm into the NE. It is uncovered that TGFβ signaling emanating from endodermal cells support tissue folding of the prospective NE. Evaluation of NE tissue structural dysmorphia, which is uniquely achievable in the model, enables the detection of apical constriction and cell adhesion dysfunctions in patient-derived hPSCs as well as differentiating between different classes of neural tube defect-inducing drugs.

Keywords: human pluripotent stem cells; micropatterning; morphogenesis; neurodevelopmental defects; neuroepithelium.