Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure

Nat Med. 2020 Oct;26(10):1593-1601. doi: 10.1038/s41591-020-1024-z. Epub 2020 Sep 7.

Abstract

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Child
  • Enterocytes / pathology
  • Enterocytes / physiology
  • Enterocytes / transplantation
  • Extracellular Matrix / pathology
  • Female
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intestinal Diseases / congenital
  • Intestinal Diseases / pathology*
  • Intestinal Diseases / therapy
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / transplantation*
  • Jejunum / cytology
  • Jejunum / pathology
  • Jejunum / transplantation*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Organoids / pathology*
  • Precision Medicine / methods*
  • Primary Cell Culture / methods*
  • Proof of Concept Study
  • Swine
  • Tissue Engineering / methods*
  • Tissue Scaffolds