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The Human Pancreas as a Source of Protolerogenic Extracellular Matrix Scaffold for a New-generation Bioartificial Endocrine Pancreas

Peloso, Andrea MD, PhD; Urbani, Luca PhD; Cravedi, Paolo MD, PhD; Katari, Ravi BS; Maghsoudlou, Panagiotis BS; Fallas, Mario Enrique Alvarez BS; Sordi, Valeria PhD; Citro, Antonio PhD; Purroy, Carolina MD, PhD; Niu, Guoguang PhD; McQuilling, John P. PhD; Sittadjody, Sivanandane PhD; Farney, Alan C. MD, PhD; Iskandar, Samy S. MBBCh, PhD; Zambon, Joao P. MD, PhD; Rogers, Jeffrey MD; Stratta, Robert J. MD; Opara, Emmanuel C. PhD; Piemonti, Lorenzo MD, PhD; Furdui, Cristina M. PhD; Soker, Shay PhD; De Coppi, Paolo MD, PhD; Orlando, Giuseppe MD, PhD

doi: 10.1097/SLA.0000000000001364
ORIGINAL ARTICLES

Objectives: Our study aims at producing acellular extracellular matrix scaffolds from the human pancreas (hpaECMs) as a first critical step toward the production of a new-generation, fully human-derived bioartificial endocrine pancreas. In this bioartificial endocrine pancreas, the hardware will be represented by hpaECMs, whereas the software will consist in the cellular compartment generated from patient's own cells.

Background: Extracellular matrix (ECM)-based scaffolds obtained through the decellularization of native organs have become the favored platform in the field of complex organ bioengineering. However, the paradigm is now switching from the porcine to the human model.

Methods: To achieve our goal, human pancreata were decellularized with Triton-based solution and thoroughly characterized. Primary endpoints were complete cell and DNA clearance, preservation of ECM components, growth factors and stiffness, ability to induce angiogenesis, conservation of the framework of the innate vasculature, and immunogenicity. Secondary endpoint was hpaECMs’ ability to sustain growth and function of human islet and human primary pancreatic endothelial cells.

Results: Results show that hpaECMs can be successfully and consistently produced from human pancreata and maintain their innate molecular and spatial framework and stiffness, and vital growth factors. Importantly, hpaECMs inhibit human naïve CD4+ T-cell expansion in response to polyclonal stimuli by inducing their apoptosis and promoting their conversion into regulatory T cells. hpaECMs are cytocompatible and supportive of representative pancreatic cell types.

Discussion: We, therefore, conclude that hpaECMs has the potential to become an ideal platform for investigations aiming at the manufacturing of a regenerative medicine-inspired bioartificial endocrine pancreas.

Supplemental Digital Content is available in the text

*Wake Forest School of Medicine, Winston-Salem, NC

Surgery Unit, Stem Cells and Regenerative Medicine Section, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom

Department of Medicine, Recanati Miller Transplant Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY

§Stem Cells and Regenerative Medicine Lab, Fondazione Instituto di Ricerca Pediatrica Città della Speranza, Padova, Italy

Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Reprints: Giuseppe Orlando, MD, PhD, Marie Curie Fellow, Department of Surgery, Section of Transplantation, Wake Forest School of Medicine, Wake Forest Baptist Hospital, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: gorlando@wakehealth.edu.

Disclosure: Supported by a grant from the Fondazione Banca del Monte di Lombardia—Progetto Professionalità Ivano Becchi to Andrea Peloso. Also supported by unrestricted funds from Liberitutti Foundation (http://www.liberituttionlus.org/ricerca-medicina-rigenerativa.html) to Giuseppe Orlando's research. Paolo De Coppi is Supported by NIHR, UK. No conflict of interest to declare by any of the coauthors.

¶Currently at General Surgery, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy

|| Affiliated to General Surgery, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy

** On behalf of the Carolina Donor Service.

†† On behalf of LifeShare of The Carolinas.

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