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Creation of Human Intestine from Human Pluripotent Stem Cells

Review of “An in vivo model of human small intestine using pluripotent stem cells” from Nature Medicine by Stuart P. Atkinson

Modelling the human intestine has proven to be a difficult task; currently used models have severe limitations leaving them unsuitable for detailed studies [1, 2]. This is not helped by the cellular complexity of the tissue, the requirement for primary cells, and, up until recently, our lack of knowledge of the stem cell compartment in the intestine [3]. Recent studies have described the generation of human intestinal organoids (HIOs) from pluripotent stem cell sources [4, 5] composed of an epithelial layer accompanied by a supportive mesenchymal layer. These organoids lacked some aspects of the mature intestine, and so the authors of these previous studies have now gone one further, and have developed an in vivo engraftment model which generates mature, functional human intestinal tissues [6].

Following the generation of HIOs (in vitro HIOs) from both human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the researchers transplanted these immature organoids under the kidney capsule of immunodeficient mice to mature and grow for 6 weeks (in vivo or engrafted HIOs). This induced a 50-100 fold increase in volume, prominent vascularization, and a morphology and histology similar to that of native human intestine. Epithelial and mesenchymal cells were nearly all of human origin, while blood and lymphatic vessels were generally all of mouse origin. In comparison with in vitro HIOs, in vivo HIOs were more mature and differentiated, displayed all major intestinal cell lineages, displayed mature goblet and enteroendocrine cells in the epithelium, and showed strong evidence of an intestinal stem cell pool. An accompanying mesenchymal layer is important to gastrointestinal development [7], and while in vitro HIOs presented with an immature mesenchymal component, in vivo HIOs displayed a more mature mesenchyme, including more mature smooth muscle layers, a pericryptal sheath of intestinal subepithelial myofibroblasts (ISEMFs) known to support small intestinal epithelial stem cells growth [1], alongside many other similarities to adult intestine. mRNA and protein comparisons demonstrated that in vivo HIOs expressed higher levels of mature epithelium markers, brush border enzymes and secretory cell markers, confirming the mature nature of the in vivo HIOs.

Does this mature phenotype of in vivo HIOs translate to mature physiological responses? Well, mature organoids displayed excellent absorptive functions and humeral factors released following resection of the mouse intestine [8] stimulated the in vivo HIOs. These positive outcomes strongly suggest that the in vivo organoids have the functionality of a mature organ.

This represents an important first; the generation of a functional model for the human intestine from pluripotent stem cell types. The successful use of iPSCs may allow for the further modelling of specific gastrointestinal disorders and the generation of immunologically matched transplantable tissue. The implantation of the organ into the mouse and the integration of mouse cells into the organoid do represent a hurdle to the clinical translation of this work, although further analysis of this model system may allow researchers to identify factors which can recapitulate in vivo organoid maturation.

References

  1. Lahar N, Lei NY, Wang J, et al. Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium. PLoS One 2011;6:e26898.
  2. Levin DE, Barthel ER, Speer AL, et al. Human tissue-engineered small intestine forms from postnatal progenitor cells. Journal of pediatric surgery 2013;48:129-137.
  3. Jung P, Sato T, Merlos-Suarez A, et al. Isolation and in vitro expansion of human colonic stem cells. Nature medicine 2011;17:1225-1227.
  4. Spence JR, Mayhew CN, Rankin SA, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 2011;470:105-109.
  5. McCracken KW, Howell JC, Wells JM, et al. Generating human intestinal tissue from pluripotent stem cells in vitro. Nature protocols 2011;6:1920-1928.
  6. Watson CL, Mahe MM, Munera J, et al. An in vivo model of human small intestine using pluripotent stem cells. Nature medicine 2014;
  7. Kosinski C, Stange DE, Xu C, et al. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 2010;139:893-903.
  8. Dekaney CM, Fong JJ, Rigby RJ, et al. Expansion of intestinal stem cells associated with long-term adaptation following ileocecal resection in mice. Am J Physiol Gastrointest Liver Physiol 2007;293:G1013-1022.