An in vivo model of human small intestine using pluripotent stem cells

Abstract

Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant1,2. To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds3,4. Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)5,6 that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the cryptvillus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response7–9. This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies.

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

“…Spence et al have shown that a sequential differentiation program can guide both mice ES cells and iPS cells to endoderm progenitors, and subsequently to IECs [125]. Such an in vivo induction of pluripotent cells towards intestinal tissues is also possible in human ES cells or iPS cells, and those engineered intestinal tissues are validated to have a satisfying level of intestine-specific functions [126]. A comprehensive search for transcription factors that are required for endodermal differentiation has revealed that so-called ''iHep cells'' are able to form intestinal organoids, and can be transplanted onto the damaged colonic epithelium [127].…”

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

“…Growth, in response to massive small bowel resection, was noted in the kidney capsule in an in vivo implant model. There was no evidence presented for an ENS (Watson et al 2014).…”

“…Pluripotent stem cells have been developed into many of the components of functional intestine, although development of an innervated smooth muscle layer is missing and immunosuppression would be required (Watson et al 2014).…”

Intestinal Organoids—Current and Future Applications

“…Transplanted human intestinal organoids have displayed mature intestine characteristics such as peptide uptake, but therapeutic application would require additional functions, such as the ability to perform the peristaltic movements essential for food bolus transition along the digestive tract [48].…”