Vascularized Liver Organoids Generated Using Induced Hepatic Tissue and Dynamic Liver‐Specific Microenvironment as a Drug Testing Platform

Abstract

Induced hepatic (iHep) cells generated by direct reprogramming have been proposed as cell sources for drug screening and regenerative medicine. However, the practical use of a 3D hepatic tissue culture comprised of iHep cells for drug screening and toxicology testing has not been demonstrated. In this study, a 3D vascularized liver organoid composed of iHep cells and a decellularized liver extracellular matrix (LEM) cultured in a microfluidic system is demonstrated. iHep cells are generated by transfection with polymer nanoparticles and plasmids expressing hepatic transcription factors. The iHep cells are cocultured with endothelial cells in the 3D LEM hydrogel in a microfluidic-based cell culture device with a continuous dynamic flow of media. The resultant 3D vascularized liver organoids maintained under this physiologically relevant culture microenvironment exhibit improved hepatic functionalities, metabolic activity, biosynthetic activity, and drug responses. Finally, the feasibility of using the iHep-based 3D liver organoid as a highthroughput drug screening platform, as well as its use in a multiorgan model comprised of multiple internal organoids is confirmed. The study suggests that a combined strategy of direct reprogramming, matrix engineering, and microfluidics can be used to develop a highly functional, standardized, drug screening, and toxicological analysis platform.

Gastrointestinal tract modeling using organoids engineered with cellular and microbiota niches

“…Methods employing the fusion of organoids and coculture of multiple organoids have recently emerged ( Fig. 3) [112][113][114] . A multiorgan integrated system fusing three different types of digestive system organoids on a microfluidic device has been used to identify crosstalk between organoids 113 .…”

Human Microphysiological Models of Intestinal Tissue and Gut Microbiome

“…Another study developed a microfluidic platform connecting the liver, stomach, and intestinal cells in a multi-organ-on-a-chip, with the goal of using this as an in vitro drugs screening platform, given that not only the liver, but the intestine and stomach play roles in drug metabolism (Jin et al, 2018).…”

Next-Generation Liver Medicine Using Organoid Models

“…Underhill and Khetani (2018) have recently reviewed the advances in bioengineered liver models with utility in drug screening and the microenvironmental determinants of liver cell differentiation/function (Massa et al, 2017;Zhang et al, 2017a). Jin et al (2018) developed a vascularized 3D liver organoid model derived from induced hepatocytes (iHep) that were directly differentiated from fibroblasts. They achieved this by co-culturing the iHeps with endothelial cells in a decellularized 3D liver extracellular matrix (LEM) hydrogel in a microfluidicbased cell culture device with a continuous dynamic flow of media.…”

“…They achieved this by co-culturing the iHeps with endothelial cells in a decellularized 3D liver extracellular matrix (LEM) hydrogel in a microfluidicbased cell culture device with a continuous dynamic flow of media. By taking advantage of this platform, iHep-based 3D liver organoids were able to establish a multiorgan system comprised of multiple organoids derived from different internal organs and demonstrated great feasibility for functional and standardized high-throughput drug screening (HTS) (Jin et al, 2018).…”