Engineering human islet organoids from iPSCs using an organ-on-chip platform

• Published in: Lab on a chip Vol. 19; no. 6; pp. 948 - 958
• Main Authors: Tao, Tingting, Wang, Yaqing, Chen, Wenwen, Li, Zhongyu, Su, Wentao, Guo, Yaqiong, Deng, Pengwei, Qin, Jianhua
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 13.03.2019
• Subjects: Biomimetics; Calcium ions; Culture; Diabetes mellitus; Differentiation (biology); Gene expression; Insulin; Medicine; Microfluidic devices; Modelling; Multilayers; Organic chemistry; Proteins; Stem cells
• ISSN: 1473-0197; 1473-0189; 1473-0189
• DOI: 10.1039/c8lc01298a

Human pluripotent stem cell (hPSC)-derived islet cells provide promising resources for diabetes studies, cell replacement treatment and drug screening. Recently, hPSC-derived organoids have represented a new class of in vitro organ models for disease modeling and regenerative medicine. However, rebuilding biomimetic human islet organoids from hPSCs remains challenging. Here, we present a new strategy to engineer human islet organoids derived from human induced pluripotent stem cells (hiPSCs) using an organ-on-a-chip platform combined with stem cell developmental principles. The microsystem contains a multi-layer microfluidic device that allows controllable aggregation of embryoid bodies (EBs), in situ pancreatic differentiation and generation of heterogeneous islet organoids in parallel under perfused 3D culture in a single device. The generated islet organoids contain heterogeneous islet-specific α and β-like cells that exhibit favorable growth and cell viability. They also show enhanced expression of pancreatic β-cell specific genes and proteins (PDX1 and NKX6.1) and increased β-cell hormone specific INS gene and C-peptide protein expressions under perfused 3D culture conditions compared to static cultures. In addition, the islet organoids exhibit more sensitive glucose-stimulated insulin secretion (GSIS) and higher Ca 2+ flux, indicating the role of biomimetic mechanical flow in promoting endocrine cell differentiation and maturation of islet organoids. This islet-on-a-chip system is robust and amenable to real-time imaging and in situ tracking of islet organoid growth, which may provide a promising platform for organoid engineering, disease modeling, drug testing and regenerative medicine. This work presents a new strategy to engineer functional human islet organoids from iPSCs in a perfusable organ-on-a-chip device.