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Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell
Song Lu1,2, Jiatao Li1,2, Kathy O Lui1,2
1Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong.
Abstract:
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 VEGFA enhances β cell functional recovery after injury. Therefore, we utilized the chemically modified mRNA (modRNA) technology to enable transient yet efficient VEGFA expression in the pancreas after DOX-induced β cell death. Surprisingly, under optimized DOX dose permissive of β cell regeneration, VEGFA modRNA only demonstrated marginal benefits on β cell functional recovery with large individual variations. We also revealed that the therapeutic efficacy of VEGFA 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.
Insights
Individual variations in beta-cell regeneration were significant in betaDTA mice, impacting therapeutic efficacy. VEGF-A modRNA showed limited benefits due to these variations and the degree of beta-cell loss.
Area of Science:
- Endocrinology
- Regenerative Medicine
- Molecular Biology
Background:
- Beta-cell regeneration is crucial for diabetes treatment.
- BetaDTA mice are used to study beta-cell regeneration.
- Individual variability in therapeutic response is a challenge.
Purpose of the Study:
- To characterize individual variations in betaDTA mice for beta-cell regeneration.
- To evaluate the efficacy of VEGF-A modRNA in enhancing beta-cell regeneration.
- To investigate the impact of doxycycline-induced beta-cell loss on therapeutic outcomes.
Main Methods:
- Utilized betaDTA mouse model with doxycycline-induced beta-cell death.
- Administered chemically modified mRNA (modRNA) for transient VEGF-A expression.
- Assessed beta-cell regeneration and functional recovery.
Main Results:
- Significant individual variations observed in spontaneous and acquired beta-cell regeneration.
- Doxycycline intake varied due to polydipsia, leading to inconsistent beta-cell loss.
- VEGF-A modRNA showed marginal benefits with substantial individual variability.
- Therapeutic efficacy was dependent on the extent of beta-cell loss.
Conclusions:
- Individual variation is a critical factor in the betaDTA model for beta-cell regeneration studies.
- VEGF-A modRNA efficacy is influenced by individual differences and the degree of beta-cell loss.
- Further attention is needed to account for individual variability when evaluating therapeutic agents for beta-cell regeneration.
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