A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival

Ting Zhou, Tae Wan Kim, Chi Nok Chong, Lei Tan, Sadaf Amin, Zohreh Sadat Badieyan, Suranjit Mukherjee, Zaniar Ghazizadeh, Hui Zeng, Min Guo, Miguel Crespo, Tuo Zhang, Reyn Kenyon, Christopher L. Robinson, Effie Apostolou, Hui Wang, Jenny Zhaoying Xiang, Todd Evans, Lorenz Studer () and Shuibing Chen ()
Additional contact information
Ting Zhou: Weill Cornell Medical College
Tae Wan Kim: Sloan-Kettering Institute for Cancer Research
Chi Nok Chong: Weill Cornell Medical College
Lei Tan: Weill Cornell Medical College
Sadaf Amin: Weill Cornell Medical College
Zohreh Sadat Badieyan: Weill Cornell Medical College
Suranjit Mukherjee: Weill Cornell Medical College
Zaniar Ghazizadeh: Weill Cornell Medical College
Hui Zeng: Weill Cornell Medical College
Min Guo: Weill Cornell Medical College
Miguel Crespo: Weill Cornell Medical College
Tuo Zhang: Weill Cornell Medical College
Reyn Kenyon: Weill Cornell Medical College
Christopher L. Robinson: Weill Cornell Medical College
Effie Apostolou: Weill Cornell Medical College
Hui Wang: Shanghai Jiao Tong University, School of Medicine
Jenny Zhaoying Xiang: Weill Cornell Medical College
Todd Evans: Weill Cornell Medical College
Lorenz Studer: Sloan-Kettering Institute for Cancer Research
Shuibing Chen: Weill Cornell Medical College

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Common disorders, including diabetes and Parkinson’s disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic β-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson’s disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson’s disease. We found GSTT1−/− pancreatic β-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human β-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions.

Date: 2018
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DOI: 10.1038/s41467-018-07201-1

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