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Published Online: 15 May 2020

Microvessel Network Formation and Interactions with Pancreatic Islets in Three-Dimensional Chip Cultures

Publication: Tissue Engineering Part A
Volume 26, Issue Number 9-10

Abstract

The pancreatic islet is a highly vascularized micro-organ, and rapid revascularization postislet transplantation is important for islet survival and function. However, the various mechanisms involved in islet revascularization are not fully understood, and we currently lack good in vitro platforms to explore this. Our aim for this study was to generate perfusable microvascular networks in a microfluidic chip device, in which islets could be easily integrated, to establish an in vitro platform for investigations on islet–microvasculature interactions. We compared the ability of mesenchymal stem cells (MSCs) and fibroblasts to support microvascular network formation by human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial colony-forming cell in two-dimensional and three-dimensional models of angiogenesis, and tested the effect of different culture media on microvessel formation. HUVECs that were supported by MSCs formed patent and perfusable networks in a fibrin gel, whereas networks supported by fibroblasts rapidly regressed. Network morphology could be controlled by adjusting relative cell numbers and densities. Incorporation of isolated rat islets demonstrated that islets recruit local microvasculature in vitro, but that the microvessels did not invade islets, at least during the course of these studies. This in vitro microvascularization platform can provide a useful tool to study how various parameters affect islet integration with microvascular networks and could also be utilized for studies of vascularization of other organ systems.

Impact statement

To improve pancreatic islet graft survival and function posttransplantation, rapid and adequate revascularization is critical. Efforts to improve islet revascularization are demanding due to an insufficient understanding of the mechanisms involved in the process. We have applied a microfluidics platform to generate microvascular networks, and by incorporating pancreatic islets, we were able to study microvasculature–islet interactions in real time. This platform can provide a useful tool to study islet integration with microvascular networks, and could be utilized for studies of vascularization of other organ systems. Moreover, this work may be adapted toward developing a prevascularized islet construct for transplantation.

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cover image Tissue Engineering Part A
Tissue Engineering Part A
Volume 26Issue Number 9-10May 2020
Pages: 556 - 568
PubMed: 31724494

History

Published online: 15 May 2020
Published in print: May 2020
Published ahead of print: 20 January 2020
Published ahead of production: 14 November 2019
Accepted: 1 November 2019
Received: 17 July 2019

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Mia H. Rambøl [email protected]
Department of Molecular Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Edward Han
Department of Biomedical Engineering and Yale University, New Haven, Connecticut, USA.
Department of Anesthesiology, Yale University, New Haven, Connecticut, USA.
Laura E. Niklason
Department of Biomedical Engineering and Yale University, New Haven, Connecticut, USA.
Department of Anesthesiology, Yale University, New Haven, Connecticut, USA.

Notes

Address correspondence to: Mia H. Rambøl, MSc, Department of Molecular Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway [email protected]

Disclosure Statement

L.E.N. is a founder and shareholder in Humacyte, Inc., which is a regenerative medicine company. Humacyte, Inc. produces engineered blood vessels from allogeneic smooth muscle cells for vascular surgery. L.E.N.'s spouse has equity in Humacyte, Inc. and L.E.N. serves on Humacyte's Board of Directors. L.E.N. is an inventor on patents that are licensed to Humacyte, Inc. and that produce royalties for L.E.N. L.E.N. has received an unrestricted research gift to support research in her laboratory at Yale. Humacyte, Inc. did not influence the conduct, description, or interpretation of the findings in this report. The other authors report no conflicts.

Funding Information

This work was supported by Yale University, and by NIH R01 HL127386 and by an unrestricted research gift from Humacyte, Inc. (both to L.E.N). M.H.R was supported by a Fulbright grant and Gidske and Peter Jacob Soerensen's Research Fund.

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