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Regenerative medicine and cell-based approaches to restore pancreatic function

Key Points

  • Both exocrine and endocrine pancreatic pathologies bear tremendous costs to health-care systems and patients alike; identifying cell-based therapies for restoring exocrine pancreatic insufficiency or replacing inadequate β cells in patients with diabetes are important targets

  • Two strategies for restoring pancreatic function are through differentiation of stem cells and reprogramming of cells through gene therapy

  • Beyond functional assessments, considerations for delivery of stem-cell-derived β cells include implant site and decreasing immunosuppression requirements

  • In situ reprogramming strategies must consider different risks than cell delivery approaches, including lack of specificity and unpredictable off-target effects

  • Neither approach is ready to supersede enzyme replacement therapy or exogenous insulin delivery, but with continued progress cell replacement strategies could become the standard of care

Abstract

The pancreas is a complex organ with exocrine and endocrine components. Many pathologies impair exocrine function, including chronic pancreatitis, cystic fibrosis and pancreatic ductal adenocarcinoma. Conversely, when the endocrine pancreas fails to secrete sufficient insulin, patients develop diabetes mellitus. Pathology in either the endocrine or exocrine pancreas results in devastating economic and personal consequences. The current standard therapy for treating patients with type 1 diabetes mellitus is daily exogenous insulin injections, but cell sources of insulin provide superior glycaemic regulation and research is now focused on the goal of regenerating or replacing β cells. Stem-cell-based models might be useful to study exocrine pancreatic disorders, and mesenchymal stem cells or secreted factors might delay disease progression. Although the standards that bioengineered cells must meet before being considered as a viable therapy are not yet established, any potential therapy must be acceptably safe and functionally superior to current therapies. Here, we describe progress and challenges in cell-based methods to restore pancreatic function, with a focus on optimizing the site for cell delivery and decreasing requirements for immunosuppression through encapsulation. We also discuss the tools and strategies being used to generate exocrine pancreas and insulin-producing β-cell surrogates in situ and highlight obstacles to clinical application.

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Figure 1: The healthy human pancreas contains both an endocrine and an exocrine compartment.
Figure 2: Examples of endocrine and exocrine pancreatic pathologies.

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Authors

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The authors contributed equally to the review.

Corresponding author

Correspondence to Timothy J. Kieffer.

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Competing interests

T.J.K. has patents related to the material covered in this Review and is a co-founder and shareholder of enGene, a biotechnology company developing gene therapy approaches for metabolic diseases, including diabetes. He has also collaborated with scientists at BetaLogics and ViaCyte on stem-cell-based therapies for diabetes and received funding from Janssen R&D for this research.

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Glossary

Exocrine

Pertaining to the secretion of products from glands into ducts.

Endocrine

Pertaining to the secretion of hormones directly into the bloodstream.

Pancreatic insufficiency

A state of inadequate exocrine secretions by the pancreas leading to incomplete digestion of food.

Reprogramming

The directed conversion of one cell type to another artificially through the introduction of exogenous factors.

Islets

The endocrine micro-organs of the pancreas, containing cells that secrete insulin, glucagon, or other hormones.

Acinar cell

The primary exocrine cell of the pancreas that secretes digestive enzymes.

Regeneration

The renewal, regrowth or restoration of cells or tissues.

Shwachman–Diamond syndrome

A rare congenital disorder presenting with many abnormalities including pancreatic insufficiency.

Pancreatectomy

The surgical removal of the pancreas.

Ductal cells

Duct-lining cells that carry exocrine secretions, such as the digestive enzymes of the pancreas.

Xenotransplantation

A type of transplantation in which the recipient and donor tissues are from different species.

Endoderm

One of the three germ layers that mainly gives rise to the gastrointestinal tract, including the stomach, intestine, pancreas and liver.

Macroencapsulation

The enclosure and containment of a large quantity of cells or tissue in a device for implantation.

Transdifferentiation

The process in which a mature cell converts to another cell type without returning to a stem-cell state.

Omentum

A folded layer of peritoneum that hangs in front of the abdominal viscera.

Microencapsulation

The enclosure and containment of small cell clusters or dispersed cells for implantation.

Gene therapy

A therapeutic approach involving the delivery of genes into cells to repair, replace or alter expression of abnormal, insufficient or targeted genes.

Gastrin

A peptide hormone secreted predominantly by G cells of the stomach that stimulates the production of acid by parietal cells.

Cell differentiation

The process whereby a cell becomes specialized to perform a specific function.

K cells

An intestinal endocrine cell that secretes glucose-dependent insulinotropic polypeptide.

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Ellis, C., Ramzy, A. & Kieffer, T. Regenerative medicine and cell-based approaches to restore pancreatic function. Nat Rev Gastroenterol Hepatol 14, 612–628 (2017). https://doi.org/10.1038/nrgastro.2017.93

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