Abstract
There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immunedeficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.
| Original language | English |
|---|---|
| Article number | e0156053 |
| Journal | PLoS One |
| Volume | 11 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2016 |
| Externally published | Yes |
Bibliographical note
Funding Information:NA is supported through the Canadian National Transplantation Research Program (CNTRP) and Saudi Arabian Cultural Bureau. AP is supported primarily through a JDRF Canadian Clinical Trial Network Fellowship, and further supplemented through an AIHS CRIO Team Award (No. 201201154) and the CNTRP. AB is supported through scholarships from the University of Alberta, the Alberta Diabetes Institute (ADI) and the Alberta Diabetes Foundation. Other funding includes: the Diabetes Research Institute Foundation of Canada (DRIFCan). BGL is supported through an Alberta Innovates Health Solutions (AIHS) Clinician Fellowship, and also receives support from the CNTRP. EM is supported by Betalin Therapeutics Ltd. (2015) Israel. AMJS is supported through a Canada Research Chair in Transplantation Surgery and Regenerative Medicine and through Alberta Innovates Healthcare Solutions as a Senior Scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the Health Sciences Laboratory Animal Services (HSLAS) for their assistance with animal housing and care. The microscaffold technology is covered by a patent granted to EM.
Publisher Copyright:
© 2016 Abualhassan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ASJC Scopus Subject Areas
- General Biochemistry,Genetics and Molecular Biology
- General Agricultural and Biological Sciences
- General
