Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

Abstract

The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models that mimic in vivo tissues and organs at the three-dimensional (3D) level. Recent bioengineering approaches have begun to combine different 3D organoid types into a single '4D multi-organ system'. We summarize the advantages of this approach and speculate on the future role of 4D multi-organ systems in human disease modeling.

Keywords: Disease modeling; Induced pluripotent stem cells; Organ-on-chip; Organoid.

Fig. 1.

Schematic overview of current iPSC disease modeling in 2D and 3D systems. iPSCs exhibit the capability to self-renew and differentiate into multiple cells (e.g. cardiomyocytes, neurons and hepatocytes), similar to ESCs that are derived from the inner cell mass (ICM) of the early embryo. Patient-specific iPSC-derived cells have been widely used to study various human diseases using a 2D monolayer platform, but this approach cannot recapitulate complex tissue architecture and organ functions seen in vivo. Various 3D systems have been developed to model human diseases under conditions that mimic more closely the bona fide physiological environment, including engineered tissues, organoids and organs-on-chip. In the future, converging these 3D systems and linking multi-organs together with engineered vasculature will enable modeling of the temporal dynamic processes in the living body and disease pathogenesis, adding a fourth dimension.