Title:
Weaning gives β cells license to regenerate
Authors:
Meritxell Rovira1,2*,Jorge Ferrer1,2,3*
Affiliations:
1 Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
2 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
3 Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
*Correspondence should be addressed to M.R. (e-mail: ) or J.F. (e-mail: )
SUMMARY
Pancreatic beta cell proliferation is high at birth, thereby enabling postnatal growth, and then rapidly declines. Stolovich-Rain et al. show that the capacity for b cells to increase proliferation in response to injury is unexpectedly not acquired until after weaning, when nutritional changes trigger a metabolic and regenerative competence program.
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Although some tissues retain a robust capacity to regenerate throughout life, in many organs this capacity wanes with time and sometimes entirely disappears in adults. Notable examples include the mouse heart, which can transiently regenerate during the neonatal period, or human fingertips, which can regrow during young ages (Poss, 2010). In broad terms, pancreatic insulin-producing b cells also fall within this category: at very young ages β cells proliferate to sustain a physiological cellular expansion, and they can also mount a regenerative response to cellular damage (Kushner, 2013; Tschen et al., 2009; Wang et al., 2015). Lineage tracing experiments have shown that self-renewing β cells are the major source of new β cells during postnatal physiological growth and regeneration, although other sources have been shown in specific regenerative settings (Wang et al., 2015; Ziv et al., 2013). As mice and humans age, however, there is a rapid decline in β cell proliferation and regenerative capacity. This has been linked to the induction of p16, caused by loss of Polycomb-dependent transcriptional repression of the gene encoding this cell cycle inhibitor (Chen et al., 2009; Tschen et al., 2009). In fact, the proliferative rate and regenerative capacity of adult human β cells is truly modest, although probably not insignificant. Of note, obese adult humans have a higher demand for insulin that is paralleled by a higher number of β cells, which points to a capacity to adapt cellular mass over long timeframes (Saisho et al., 2013). Studies in mouse models have shown that β cells can trigger compensatory proliferation after induction of β cell-specific ablation and hyperglycemia (Nir et al., 2007). Interestingly, this dynamic proliferative response is mediated by signals derived from increased β cell aerobic glucose metabolism, the same process that promotes other glucose-dependent responses such as insulin secretion (Porat et al., 2011). A detailed understanding of these mechanisms can provide vital clues to develop novel therapies for correcting β cell deficiency in Type 1 and Type 2 diabetes.
Given the general tendency of β cell regenerative capacity to decline with age, one might infer that stimulus-induced regeneration is innate. In this issue of Developmental Cell, Stolovich-Rain and colleagues show that despite the fact that neonatal β cells have a high basal proliferative rate, they are paradoxically unable to increase cell cycle activity in response to cellular ablation. The capacity to mount a regenerative response is only gained during a maturation step that takes place when mice are weaned. This transition is associated with increased expression of numerous early cell cycle genes, which potentially contribute to the acquisition of competence for signal-responsive proliferation. The maturation step is further linked to increased expression of genes that regulate β cell glucose metabolism, including Pdk1 and mitochondrial electron transport chain genes, to increased glucose-dependent changes in β cell oxidative metabolism, as well as to enhanced effects of pharmacologic glycolytic activators on insulin secretion and cell proliferation. In short, weaning allows β cells to activate a new transcriptional program and to acquire a capacity for glucose-responsive insulin secretion and regeneration.
Using an elegant series of experiments in which the mice were prematurely weaned on different diets, Stolovich-Rain and colleagues show that this remarkable metabolic switch is triggered by nutritional cues. The data showed that it is the change from intake of fatty acid-rich maternal milk to a carbohydrate-rich diet that enables glucose-induced responsiveness. Changes in dietary nutrients therefore determine that β cells acquire full competence for dynamic regulation of secretion and regeneration.
The observations described by Stolovich-Rain et al. therefore make a fundamental distinction between basal growth, a property of newborn β cells, and a stimulus-induced cell growth program that is acquired later, in a previously unrecognized maturation step. The molecular mechanisms whereby nutrients control this maturation program remain elusive, but they are logical targets that could be harnessed to stimulate β cell regeneration for the treatment of diabetes. Equally interesting is the suggestion that dietary variation might influence regenerative capacities. The nutritional content of mouse and human milk is different, and developmental stages of different species do not necessarily occur during similar embryonic vs. postanatal periods. It is therefore important to clarify if such a maturation step occurs at any point of embryonic or postnatal development in humans. If this were the case, it could mean that maternal diet, or different infant feeding and weaning practices, could affect the timing and intensity of the maturation switch and thereby influence β cell mass. Given that fatty acids affect β cell compensation to insulin resistance, it is also pertinent to ask whether equivalents of maternal milk nutrients that are present in modern diets might affect β cell regeneration mechanisms in adults. The connection between dietary nutrients and regeneration competence thus opens exciting avenues for future research.
REFERENCES:
Chen, H., Gu, X., Su, I.H., Bottino, R., Contreras, J.L., Tarakhovsky, A., and Kim, S.K. (2009). Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes & development 23, 975-985.
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Wang, P., Fiaschi-Taesch, N.M., Vasavada, R.C., Scott, D.K., Garcia-Ocana, A., and Stewart, A.F. (2015). Diabetes mellitus-advances and challenges in human beta-cell proliferation. Nature reviews Endocrinology.
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