Open Access Revascularization of Pancreatic Islet Allografts Is Enhanced by α-1-Antitrypsin Under Anti-Inflammatory Conditions

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Abstract:

Pancreatic islets are a highly vascularized entity, and their transplantation into diabetic individuals requires optimal revascularization. In addition, β-cells in islets are extremely sensitive to inflammation. α-1-Antitrypsin (AAT), a circulating serine-protease inhibitor that is available for clinical use as an affinity-purified human product, has been shown to protect islets from graft failure in mouse transplantation models and to achieve readily vascularized islet grafts. AAT is known to induce vascular endothelial growth factor (VEGF) expression and release, as well as protect from proteolytic cleavage of VEGF by elastase, promote viability of endothelial cells, and enhance migration of myocytes. Our aim was to examine whether AAT enhances vasculogenesis toward islet grafts. We employed Matrigel-islet plugs as means to introduce islets in an explantable isolated compartment and examined vessel formation, vessel maturation, and inflammatory profile of explants 9 days after implantation. Also, we examined primary epithelial cell grafts that were prepared from lungs of mice that are transgenic for human AAT. In addition, aortic ring sprouting assay was performed, and HUVEC tube formation assays were studied in the presence of AAT. Our findings indicate that islet grafts exhibit mature vessels in the presence of AAT, as demonstrated by morphology, as well as expression of endothelial CD31, smooth muscle actin (SMA), and von Willebrand factor (vWF). Epithelial cells that express human AAT achieved a similar positive outcome. Aortic ring sprouting was enhanced in AAT-treated cultures and also in cultures that contained primary epithelial cells from human AAT transgenic animals in the absence of added AAT. According to the tube formation assay, HUVECs exhibited superior responses in the presence of AAT. We conclude that vasculogenesis toward islet grafts is enhanced in the presence of AAT. Together with the remarkable safety profile of AAT, the study supports its use in the relevant clinical setups.

Keywords: Angiogenesis; Diabetes; Inflammation; Transgenic; Transplantation

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368912X657701

Publication date: November 5, 2013

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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