Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders

Kyu Shik Mun,Balamurugan N Appakalai,Joseph J Palermo,Yunjie Huang,Maisam Abu-El-Haija,Fanmuyi Yang,Jaimie D Nathan,Yashaswini Ramananda,Anjaparavanda P Naren,Kavisha Arora,Sunitha Yarlagadda

doi:10.1038/s41467-019-11178-w

Abstract

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.

Highlights

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function
CFTR is highly expressed in the pancreatic ductal epithelial cells (PDECs)[1,11,12,13], which are located in close proximity to pancreatic islets14;,. the functional relationship between these two cell types in CF-related diabetes (CFRD) remains unclear
The pancreatic remnant cell pellet was obtained after islet cell isolation (Fig. 1b) and shown to contain pancreatic islets, acinar cells, and PDECs) (Fig. 1c)

Summary

Introduction

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. To investigate the role of CFTR in CFRD and functional correlation between PDECs and islet cells, we isolated PDECs and pancreatic islets from pancreatitis patients, who underwent total pancreatectomy with islet autotransplantation (TPIAT)[15] We cultured these cell types in a microfluidic device to develop pancreas-on-achip, an in vitro model system to mimic the functional interface between PDECs and pancreatic islets. We have successfully co-cultured patient-derived PDECs and islet cells in the same chip and observed that attenuating CFTR function in PDECs reduces insulin secretion in islet cells by 54% This pancreas-on-a-chip is an innovative approach of developing personalized medicine to address heterogeneity in CFRDs

Methods

Results

Conclusion