Engraftment of human induced pluripotent stem cell-derived hepatocytes in immunocompetent mice via 3D co-aggregation and encapsulation

Abstract

Cellular therapies for liver diseases and in vitro models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum-H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in immunocompromised animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in immunocompetent mice by pre-engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and α1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H, and may be applicable to many stem cell-based therapies.

Liver tissue engineering: From implantable tissue to whole organ engineering

“…This promoted an evident hepatic differentiation of iPSCs when compared to single‐cell culture conditions. In addition, human cocultured encapsulated cells were transplanted in immunocompetent mice without causing immune rejection for at least 24 days 21. However, the actual applicability of the encapsulated coculture system approach needs to be further explored in specific disease models where additional parallel strategies aimed at reducing potential foreign body fibrotic reactions22, 23 and improving neovascularization24, 25 should be considered.…”

Visit to intensive care of 2050

“…These data are used to generate a replacement scaffold for organ construction using either a 3-D printer [29] or an individually-modified decellularized organ scaffold. Either ex vivo tissue engineering with nanotechnology [30] or in vivo directed pleuripotent stem cell transplantation are used to recreate the organ in its entirety [31,32].…”

Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals

“…Immunodeficient chimeric mice with human hepatocytes have been widely used in pharmaceutical ADMET research (Kakuni et al, 2012;Schulz-Utermoehl et al, 2012). The transplantation study of hiPSC-derived hepatocytes to immunodeficient mice has been reported very recently, but their drug metabolizing activities remained to be determined (Song et al, 2015).…”