In vitro characterization of neonatal, juvenile, and adult porcine islet oxygen demand, β‐cell function, and transcriptomes

Background There is currently a shortage of human donor pancreata which limits the broad application of islet transplantation as a treatment for type 1 diabetes. Porcine islets have demonstrated potential as an alternative source, but a study evaluating islets from different donor ages under unified...

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Published in:	Xenotransplantation (Københaven) Vol. 25; no. 6; pp. e12432 - n/a
Main Authors:	Smith, Kate E., Purvis, William G., Davis, Melissa A., Min, Catherine G., Cooksey, Amanda M., Weber, Craig S., Jandova, Jana, Price, Nicholas D., Molano, Diana S., Stanton, James Brett, Kelly, Amy C., Steyn, Leah V., Lynch, Ronald M., Limesand, Sean W., Alexander, Michael, Lakey, Jonathan R. T., Seeberger, Karen, Korbutt, Gregory S., Mueller, Kate R., Hering, Bernhard J., McCarthy, Fiona M., Papas, Klearchos K.
Format:	Journal Article
Language:	English
Published:	Denmark Wiley Subscription Services, Inc 01-11-2018
Subjects:	Animals Animals, Newborn Cell growth Cell proliferation Deoxyribonucleic acid Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Experimental - therapy DNA DNA sequencing Gene expression Glucose Graft Rejection - immunology Graft Survival - immunology Insulin Insulin secretion Insulin-Secreting Cells - immunology Insulin-Secreting Cells - metabolism Islet cells islet transplantation Islets of Langerhans - metabolism Islets of Langerhans Transplantation - methods Neonates Oxygen consumption Oxygen Consumption - physiology Pancreas Pancreas - immunology Pancreas - metabolism Pancreatic islet transplantation Physiology porcine islets Ribonucleic acid RNA RNAseq Secretion Swine Transcriptome - immunology Transplantation, Heterologous - methods type 1 diabetes type 1 diabetes islet transplantation porcine islets RNAseq
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Summary:	Background There is currently a shortage of human donor pancreata which limits the broad application of islet transplantation as a treatment for type 1 diabetes. Porcine islets have demonstrated potential as an alternative source, but a study evaluating islets from different donor ages under unified protocols has yet to be conducted. Methods Neonatal porcine islets (NPI; 1‐3 days), juvenile porcine islets (JPI; 18‐21 days), and adult porcine islets (API; 2+ years) were compared in vitro, including assessments of oxygen consumption rate, membrane integrity determined by FDA/PI staining, β‐cell proliferation, dynamic glucose‐stimulated insulin secretion, and RNA sequencing. Results Oxygen consumption rate normalized to DNA was not significantly different between ages. Membrane integrity was age dependent, and API had the highest percentage of intact cells. API also had the highest glucose‐stimulated insulin secretion response during a dynamic insulin secretion assay and had 50‐fold higher total insulin content compared to NPI and JPI. NPI and JPI had similar glucose responsiveness, β‐cell percentage, and β‐cell proliferation rate. Transcriptome analysis was consistent with physiological assessments. API transcriptomes were enriched for cellular metabolic and insulin secretory pathways, while NPI exhibited higher expression of genes associated with proliferation. Conclusions The oxygen demand, membrane integrity, β‐cell function and proliferation, and transcriptomes of islets from API, JPI, and NPI provide a comprehensive physiological comparison for future studies. These assessments will inform the optimal application of each age of porcine islet to expand the availability of islet transplantation.
Bibliography:	Funding information This research was supported by JDRF grant #2‐SRA‐ 2014‐289‐ Q‐R and by the National Institutes of Health Interdisciplinary Training Grant in Cardiovascular Sciences (HL007249). JPI supply was supported by JDRF grant #17‐2013‐288. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0908-665X 1399-3089
DOI:	10.1111/xen.12432