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STAMCELLER-Stamcelleforskning

STEM CELL DNA INTEGRITY AND PLURIPOTENCY

Tildelt: kr 3,0 mill.

Stem cell metabolism is characterized by low respiratory activity and high glycolytic flux, which maintain cells in a reductive state. This is important to prevent damage to cellular genomes (nuclear and mitochondrial DNA). In addition and like differenti ated cells and other somatic cells, stem cells perform repair of DNA damage, which is important to preserve stem cell potential. DNA repair involves many distinct repair pathways, but the base excision repair pathway is postulated as the major pathway for removal of endogenously induced DNA damage. The DNA glycosylases initiate the base excision repair. This pathway has been the focus of our research for more than two decades, and we have identified several proteins involved in the pathway. Still there a re examples of repair homologues with unknown functions, and some of the characterized proteins may have other functions that remain to be explored. Our laboratory is currently breeding seven different knockout strains defective in DNA glycosylases removi ng oxidized DNA base lesions. These animals provide excellent models to investigate the impact of stem cell DNA integrity for differentiation capacity. By example, neural progenitor cells (neurospheres) derived from brain of two DNA glycosylase knockout m ouse models, ogg1-/- and neil3-/-, showed different properties. ogg1-/- neurospheres were more prone to differentiation towards astrocytic lineage as compared to wild type cells. Whereas proliferation of neurospheres from ogg1-/- brain was normal we foun d that the pool of neural stem/progenitor cells in neil3 knock-out animals was strongly impaired. These observations demonstrate the importance of DNA base repair activity for stem cell proliferation and differentiation, in which genome integrity is dec isive for the fate of stem/progenitor cells. In this project, we will characterize the pluripotency of stem/progenitor cells in DNA glycosylases deficient mouse models.

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STAMCELLER-Stamcelleforskning