Abouna, Sylvie (2009) Non-beta-cell progenitors in pregnant mice and the origin and functionality of beta-cells after diabetic recovery in a c-Myc ablation model. PhD thesis, University of Warwick.

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Abstract

The debate regarding the contribution of adult stem/progenitor cells during normal growth and beta-cell regeneration is far from being resolved. Therefore, we addressed in two distinct situations the origin of new beta-cells. We exploited a Cre/loxP lineage tracing system to efficiently label beta-cells in double transgenic mice (Z/AP; RIPCreERTAM) to address the origin of new beta-cell during the beta-cell mass expansion in response to one and two pregnancies. Similarly, we examined origin of new beta-cell after diabetic recovery in triple transgenic mouse (Z/AP; RIPCreERTAM; pIns-c-MycERTAM). Finally we evaluated the functionality of regenerated beta-cells after diabetic recovery in the single pIns-c-MycERTAM mouse model by microfluorimetry, in collaboration with Dr P. Squires. We showed that the beta-cell functionality in the pIns-c-MycERTAM line was abnormal. Second, we showed that the human placental alkaline phosphatase label (HPAP) in the double and triple transgenic mice was 1) specific to beta-cells, 2) irreversible and heritable and 3) tamoxifen dose-dependant. Third, the analysis of the proportion of beta-cells labelled for HPAP in one pregnancy, showed that the HPAP labelling index of the non-pregnant animals (0.44±0.05) was greater that in the pregnant group (0.33±0.06),(paired two-tailed t-test, P-value 0.021), indicating a dilution of the label in pregnant animal pancreata. Furthermore the combined results of the mean HPAP labelling index in non-pregnant animals (0.44±0.12) and pregnant animals (0.33±0.09) in one and two pregnancies reinforced our results above by indicating that the difference between the two groups was considered extremely significant (paired, two-sided student t-test, P-value 0.0007). Likewise, we showed that two to three months after the tamoxifen pulse, beta-cells do not fully lose differentiation or transdifferentiate into other lineages of either endocrine or exocrine compartment. In conclusion, we demonstrated for the first time that non-beta-cell progenitors contribute significantly to the increase of the beta-cell mass in response to pregnancy in combination with pre-existing beta-cell self-duplication.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history > QH426 Genetics
Library of Congress Subject Headings (LCSH):	Stem cells -- Research, Pancreatic beta cells -- Research, Diabetes -- Genetic aspects -- Research, Transgenic mice
Date:	September 2009
Institution:	University of Warwick
Theses Department:	Department of Biological Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Old, R. W. ; Khan, Michael
Format of File:	pdf
Extent:	202 leaves : ill., charts
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/3107

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