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Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery
Despite the βDTA (Ins2-rtTA; Tet-DTA) mice have been developed as a valuable tool to study β cell regeneration, their individual variation in therapeutic efficacy has not been characterized. Here, we demonstrated that the βDTA mice exhibited significant variations in both spontaneous and acquired β...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604075/ https://www.ncbi.nlm.nih.gov/pubmed/28959236 http://dx.doi.org/10.3389/fendo.2017.00242 |
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author | Lu, Song Li, Jiatao Lui, Kathy O. |
author_facet | Lu, Song Li, Jiatao Lui, Kathy O. |
author_sort | Lu, Song |
collection | PubMed |
description | Despite the βDTA (Ins2-rtTA; Tet-DTA) mice have been developed as a valuable tool to study β cell regeneration, their individual variation in therapeutic efficacy has not been characterized. Here, we demonstrated that the βDTA mice exhibited significant variations in both spontaneous and acquired β cell regeneration. We found that doxycycline (DOX)-induced β cell death was sufficient to cause polydipsia, translating even subtle difference in drinking habit into large variations in actual DOX intake among individuals within the same group. Accumulating evidence shows that transient expression of VEGF(A) enhances β cell functional recovery after injury. Therefore, we utilized the chemically modified mRNA (modRNA) technology to enable transient yet efficient VEGF(A) expression in the pancreas after DOX-induced β cell death. Surprisingly, under optimized DOX dose permissive of β cell regeneration, VEGF(A) modRNA only demonstrated marginal benefits on β cell functional recovery with large individual variations. We also revealed that the therapeutic efficacy of VEGF(A) modRNA on β cell regeneration was dependent on the degree of β cell loss induced by the accumulated DOX intake. Therefore, our results highlight a significant contribution of individual variation in the βDTA model and call for attention in evaluating potential efficacy of therapeutic agents in β cell regeneration studies. |
format | Online Article Text |
id | pubmed-5604075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-56040752017-09-28 Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery Lu, Song Li, Jiatao Lui, Kathy O. Front Endocrinol (Lausanne) Endocrinology Despite the βDTA (Ins2-rtTA; Tet-DTA) mice have been developed as a valuable tool to study β cell regeneration, their individual variation in therapeutic efficacy has not been characterized. Here, we demonstrated that the βDTA mice exhibited significant variations in both spontaneous and acquired β cell regeneration. We found that doxycycline (DOX)-induced β cell death was sufficient to cause polydipsia, translating even subtle difference in drinking habit into large variations in actual DOX intake among individuals within the same group. Accumulating evidence shows that transient expression of VEGF(A) enhances β cell functional recovery after injury. Therefore, we utilized the chemically modified mRNA (modRNA) technology to enable transient yet efficient VEGF(A) expression in the pancreas after DOX-induced β cell death. Surprisingly, under optimized DOX dose permissive of β cell regeneration, VEGF(A) modRNA only demonstrated marginal benefits on β cell functional recovery with large individual variations. We also revealed that the therapeutic efficacy of VEGF(A) modRNA on β cell regeneration was dependent on the degree of β cell loss induced by the accumulated DOX intake. Therefore, our results highlight a significant contribution of individual variation in the βDTA model and call for attention in evaluating potential efficacy of therapeutic agents in β cell regeneration studies. Frontiers Media S.A. 2017-09-14 /pmc/articles/PMC5604075/ /pubmed/28959236 http://dx.doi.org/10.3389/fendo.2017.00242 Text en Copyright © 2017 Lu, Li and Lui. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Lu, Song Li, Jiatao Lui, Kathy O. Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title | Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title_full | Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title_fullStr | Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title_full_unstemmed | Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title_short | Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery |
title_sort | individual variation in conditional β cell ablation mice contributes significant biases in evaluating β cell functional recovery |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604075/ https://www.ncbi.nlm.nih.gov/pubmed/28959236 http://dx.doi.org/10.3389/fendo.2017.00242 |
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