Pancreatic Progenitors and Organoids as a Prerequisite to Model Pancreatic Diseases and Cancer

Abstract

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their unique capacity to stepwise differentiate towards any particular cell type in an adult organism. Pluripotent stem cells provide a beneficial platform to model hereditary diseases and even cancer development. While the incidence of pancreatic diseases such as diabetes and pancreatitis is increasing, the understanding of the underlying pathogenesis of particular diseases remains limited. Only a few recent publications have contributed to the characterization of human pancreatic development in the fetal stage. Hence, most knowledge of pancreatic specification is based on murine embryology. Optimizing and understanding current in vitro protocols for pancreatic differentiation of ESCs and iPSCs constitutes a prerequisite to generate functional pancreatic cells for better disease modeling and drug discovery. Moreover, human pancreatic organoids derived from pluripotent stem cells, organ-restricted stem cells, and tumor samples provide a powerful technology to model carcinogenesis and hereditary diseases independent of genetically engineered mouse models. Herein, we summarize recent advances in directed differentiation of pancreatic organoids comprising endocrine cell types. Beyond that, we illustrate up-and-coming applications for organoid-based platforms.

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment

“…Additionally, organoids harboring Cdh1 loss and Kras mutation were transplanted back into nude mice, which induced the growth of tumors that represented poorly differentiated adenocarcinoma in contrast to mice transplanted with organoids containing either mutation alone. This highlights the versatility of organoids in their ability to be transplanted into mouse models to induce fibrosis and tumor formation, and other studies have also demonstrated success transplanting PDAC primary and metastatic murine organoids into nude mice [7,10]. Overall, these studies demonstrate the utility of murine-derived organoids to elucidate the role of molecular changes inherent in the progression from normal pancreatic tissues to PanIN to PDAC.…”

“…Pancreatitis is a condition characterized by inflammation and fibrosis. Patients with chronic pancreatitis have a significantly increased likelihood of developing pancreatic intraepithelial neoplasia (PanIN) and subsequently, PDAC [10]. The sequence of tumorigenesis from normal phenotype to malignancy has been shown in organoids derived from murine tissues.…”

“…Further, organoids created from patient tumor tissues are useful for drug sensitivity testing as biobanks for novel drug development or as individualized models of personalized medicine [9]. They are more clinically relevant than traditional models of human cancers such as 2D cell cultures, which are immortalized, grown in monolayers, and fail to represent tumor heterogeneity and the surrounding microenvironment, including stromal and immune components [7,9,10]. Additionally, components [7,9,10].…”

“…They are more clinically relevant than traditional models of human cancers such as 2D cell cultures, which are immortalized, grown in monolayers, and fail to represent tumor heterogeneity and the surrounding microenvironment, including stromal and immune components [7,9,10]. Additionally, components [7,9,10]. Additionally, patient-derived xenografts, which mimic in vivo interactions, require 4-8 months to develop before sufficient material is generated for drug sensitivity testing [9][10][11].…”

“…Additionally, components [7,9,10]. Additionally, patient-derived xenografts, which mimic in vivo interactions, require 4-8 months to develop before sufficient material is generated for drug sensitivity testing [9][10][11]. Organoids are rapid growing and less costly than in vivo models; therefore, they present an attractive alternative for the rapid study of molecular interactions and drug response.…”