Výsledky projektu Studium funkce chromatin remodelačního faktoru Smarca5 v myší krvetvorbě

In this publication we tackle the mechanisms underlying the loss of stem cell function in the transgenic Smarca5 model where deletion of this chromatin remodeling factor lead to complete loss of hematopoietic differentiation in fetal liver. We observe, that while definitive fetal liver hematopoiesis was timely initiated it failed to produce mature blood. FL stem and progenitor cell populations were greatly augmented such as Lin- c-Kit+ Sca1+ Cd34+, Flt3- Cd48+ Cd150+ myeloid-biased multipotent progenitors (MPPs). However, the Smarca5-null E13.5 fetal liver HSPCs completely failed to reconstitute hematopoiesis in adult sub-lethally irradiated hosts, pointing toward cell autonomous mechanism of stem cell failure. Furthermore, Smarca5-null progenitors failed to proliferate and differentiate in in vitro conditions. Importantly, we see up-regulation MAPK p38 pathway and its downstream targets leading to activation of p53 pathway and G2/M checkpoint activation in consequence of genotoxic stress, caused by dysregulation of chromatin structure.