Neonatal beta cell neogenesis evidenced by lineage tracing

Onderzoeksoutput: Meeting abstract (Book)

Samenvatting

Background and aims: Stimulation of beta cell formation and beta cell transplantation offer hope as diabetes therapies. Yet, lack of knowledge in the mechanisms of postnatal islet growth hampers their implementation. In the last decade, self-duplication of beta cells has been put forward as the principal mechanism of beta cell maintenance in adults. However, beta cell neogenesis i.e. the formation of new beta cells from other cells than beta cells might take place under other conditions e.g. during the dynamic neonatal development. Previously, indirect evidence was reported for beta cell neogenesis in this early period of life. More recently, a tracing study suggested generation of beta cells from non-beta cells neonatally. However, uncovering the source and quantity of the newly formed beta cells is requisite. Methods: To quantify neonatal beta cell neogenesis we used transgenic RIPCreER Rosa26LoxSTOPLoxYFP mice. Pups received tamoxifen on the day of birth and were followed during the next four weeks. To uncover the origin of the neonatal beta cell neogenesis we studied Hnf1bCreER R26LacZ mice, ElastaseCreER R26YFP mice and Glucagon-rtTA TetO-Cre R26YFP mice to specifically track the fate of duct, acinar and alpha cells, respectively. Results and discussion: In tamoxifen-treated RIP YFP mice, beta cells are labelled with a high efficiency and specificity. 82.2 ± 1.7% beta cells express YFP at postnatal day 7 (P7). Without tamoxifen, there is only limited ‘leaky’ expression. From week 1 to week 4, there is a 3- to 4-fold increase in the beta cell mass both in tamoxifen and non-tamoxifen animals. The islet size distribution shows a decrease in the fraction of small islets (1-5 beta cells) and an increase in the fraction of larger islets (11-50 beta cells and >50 beta cells). To quantify beta cell neogenesis, we assessed the beta cell labelling index. The percentage of labelled beta cells remains unchanged between week 1 and week 2, but starts to decrease from week 3 on and falls significantly to 70.8 ± 2.6% at week 4. The YFP+ fraction of beta cells are beta cells which were already present at birth or originate from self-duplication of beta cells. This decrease indicates that between 2 and 4 weeks of age new beta cells (about 16-17%) arise from non-beta cells (progenitor cells or stem cells). Both in small and large beta cell clusters (islets) a decrease in YFP+ beta cells is observed. No further reduction in the beta cell labelling is observed from week 4 to week 6 (70.4 ± 0.9% YFP+ beta cells at P42) indicating that the period during which beta cell neogenesis occurs under physiological growth is restricted to the neonatal period between 2- and 4-weeks of age. Lineage tracing experiments revealed that nor duct cells nor acinar cells nor alpha cells contribute to the neonatal beta cell neogenesis. Conclusion: We have obtained direct evidence (via genetic lineage tracing) which confirms that new formation of beta cells from non-beta cells occurs in young mice. Grant Acknowledgement: IH is a research fellow of the Research Foundation - Flanders (FWO)
Originele taal-2English
TitelPoster presentation at Islet Cell Plasticity in Diabetes Therapy conference, Copenhagen, Denmark
Pagina's62-62
Aantal pagina's1
StatusPublished - 8 okt 2015
EvenementIslet Cell Plasticity in Diabetes Therapy 2nd BBDC-JOSLIN-UNCPH Conference 2015 - Copenhagen, Denmark
Duur: 8 okt 20159 okt 2015

Conference

ConferenceIslet Cell Plasticity in Diabetes Therapy 2nd BBDC-JOSLIN-UNCPH Conference 2015
LandDenmark
StadCopenhagen
Periode8/10/159/10/15

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