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Building gut from scratch — progress and update of intestinal tissue engineering

Abstract

Short bowel syndrome (SBS), a condition defined by insufficient absorptive intestinal epithelium, is a rare disease, with an estimated prevalence up to 0.4 in 10,000 people. However, it has substantial morbidity and mortality for affected patients. The mainstay of treatment in SBS is supportive, in the form of intravenous parenteral nutrition, with the aim of achieving intestinal autonomy. The lack of a definitive curative therapy has led to attempts to harness innate developmental and regenerative mechanisms to engineer neo-intestine as an alternative approach to addressing this unmet clinical need. Exciting advances have been made in the field of intestinal tissue engineering (ITE) over the past decade, making a review in this field timely. In this Review, we discuss the latest advances in the components required to engineer intestinal grafts and summarize the progress of ITE. We also explore some key factors to consider and challenges to overcome when transitioning tissue-engineered intestine towards clinical translation, and provide the future outlook of ITE in therapeutic applications and beyond.

Key points

  • Intestinal tissue engineering has the potential to offer curative therapy in patients with short bowel syndrome.

  • Multiple components, including an absorptive mucosa, smooth muscle, enteric nerves and vasculature are required to generate a functional full-thickness intestinal graft.

  • Advances in intestinal tissue engineering include endothelial cell reprogramming and vascular engineering, generation of mucosal grafts using patient-derived materials and colon mucosal repurposing using small intestinal organoids.

  • Vascularization and lymphatic engineering, generation of multilayered personalized intestinal grafts and scaling-up of graft size present some of the future challenges in intestinal tissue engineering.

  • A collaborative approach, combining expertise in stem cell biology, engineering and biotechnology, is fundamental to advance engineered intestine towards clinical translation.

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Fig. 1: Intestinal structure and components of engineered intestinal grafts.
Fig. 2: Timeline highlighting significant advances in the field of intestinal tissue engineering.
Fig. 3: Cellular and scaffold sources used to generate TESI and summary of engineering strategies to date.

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Acknowledgements

This Review is a snapshot of the current state of intestinal tissue engineering and we apologize to the many colleagues whose work could not be cited here due to space limitations. The authors (V.S.W.L., P.De C. and L.T.) were funded by Horizon 2020 grant INTENS 668294 on the project ‘Intestinal Tissue Engineering Solution for Children with Short Bowel Syndrome’. The laboratory of V.S.W.L. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001105), the UK Medical Research Council (FC001105) and the Wellcome Trust (FC001105). P.De C. is supported by an NIHR Professorship, NIHR UCL BRC-GOSH, the Great Ormond Street Hospital Children’s Charity and the Oak Foundation. L.T. is funded by NIHR UCL BRC-GOSH Crick Clinical Research Training Fellowship. B.C.J. is supported by the General Sir John Monash Foundation, Australia and University College London.

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L.T. and B.C.J. researched data for the article. L.T., B.C.J. and V.S.W.L. contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Paolo De Coppi or Vivian S. W. Li.

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Nature Reviews Gastroenterology & Hepatology thanks Hans Clevers; Hjalte Larsen, who co-reviewed with Kim Jensen; Simon Vales, who co-reviewed with Maxime Mahe; and Toshiro Sato for their contribution to the peer review of this work.

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Glossary

Stem cells

Cells with the ability to divide and produce further stem cells (self-renewal) and cells that can differentiate into specialized cell types (potency).

Organoid units

Aggregates of intestinal epithelial cells with a core of mesenchyme obtained by mechanical and enzymatic digestion of small intestinal mucosa.

Pluripotent stem cells

(PSCs). Cells with the ability to be cultured indefinitely in an undifferentiated state, whilst retaining the ability to differentiate into endoderm, mesoderm and ectoderm

Organoids

Cluster of cells growing in 3D containing stem, progenitor and differentiated cells that self-organize to resemble aspects of native tissue.

Epithelial organoids

Organoids containing stem, progenitor and differentiated cells from epithelium only (single germ layer).

Multi-tissue organoids

Organoids containing cells of multiple germ layers, established through the co-culture of different cell types or differentiation of pluripotent stem cells. Induced pluripotent stem cell-derived intestinal organoids are an example.

Neural crest cells

(NCCs). Neural progenitor cells derived from the cranial and sacral neural crest which migrate to the gut and give rise to the submucosal and myenteric plexuses of the enteric nervous system.

Progenitor cells

A transitional cell type between stem and fully differentiated cell types, that has lost the ability for self-renewal but retains the capacity for differentiation.

Mesangioblasts

Blood vessel-associated multipotent progenitor cells with the capacity to differentiate into a variety of mesodermal cell types.

Hydrogels

3D structural networks composed of natural (for example, Matrigel) or synthetic (for example, polyglycolic acid) polymer units that can absorb large amounts of water relative to the dry weight of the component polymers.

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Tullie, L., Jones, B.C., De Coppi, P. et al. Building gut from scratch — progress and update of intestinal tissue engineering. Nat Rev Gastroenterol Hepatol 19, 417–431 (2022). https://doi.org/10.1038/s41575-022-00586-x

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