title: Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids.
abstract: Short bowel syndrome (SBS) is characterized by poor nutrient absorption due to a deficit of healthy intestine. Current treatment practices rely on providing supportive medical therapy with parenteral nutrition; while life saving, such interventions are not curative and are still associated with significant co-morbidities. As approaches to lengthen remaining intestinal tissue have been met with only limited success and intestinal transplants have poor survival outcomes, new approaches to treating SBS are necessary. Human intestine derived from embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs), called human intestinal organoids (HIOs), have the potential to offer a personalized and scalable source of intestine for regenerative therapies. However, given that HIOs are small three-dimensional structures grown in vitro, methods to generate usable HIO-derived constructs are needed. We investigated the ability of hESCs or HIOs to populate acellular porcine intestinal matrices and artificial polyglycolic/poly L lactic acid (PGA/PLLA) scaffolds, and examined the ability of matrix/scaffolds to thrive when transplanted in vivo. Our results demonstrate that the acellular matrix alone is not sufficient to instruct hESC differentiation towards an endodermal or intestinal fate. We observed that while HIOs reseed acellular porcine matrices in vitro, the HIO-reseeded matrices do not thrive when transplanted in vivo. In contrast, HIO-seeded PGA/PLLA scaffolds thrive in vivo and develop into tissue that looks nearly identical to adult human intestinal tissue. Our results suggest that HIO-seeded PGA/PLLA scaffolds are a promising avenue for developing the mucosal component of tissue engineered human small intestine, which need to be explored further to develop them into fully functional tissue.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Stacy R
authors.initials: SR
authors.lastname: Finkbeiner
authors.affiliation: Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Freeman
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.
authors.forename: Minna M
authors.initials: MM
authors.lastname: Wieck
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Nachef
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Altheim
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yu-Hwai
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, Section of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dyal
authors.affiliation: Department of Internal Medicine, Section of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Grikscheit
authors.affiliation: Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Teitelbaum
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA spencejr@umich.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Spence
keywords: Human intestinal organoids; Matrix; Scaffold; Tissue-engineered intestine