Molecular mechanisms of stress response in planarian stem cells

In adult organisms, stem cells are crucial to homeostasis and regeneration of damaged tissues over the life span of an individual. Understanding the biology of adult stem cells has become one of the most challenges in many fields of science, particularly in medical areas, in which stem cells can be used for the treatment of degenerative diseases associated with ageing. To prevent senescence and prolong proliferative capacity, stem cells must have evolved cytoprotective mechanisms to defend themselves against environmental and physiological stresses. Planarians (Platyhelminthes) represent a versatile and powerful model system well known for regenerative potential, high body plasticity and continuous cell turnover. These characteristics depend on a population of adult stem cells, the neoblasts. Damage or reduction in number of neoblasts deeply affects planarian regeneration and survival. Heat shock proteins (HSPs) perform essential cytoprotective functions in all organisms and their expression may be induced in response to a wide variety of stresses. To investigate the potential role of hsp-related genes on the dynamics of planarian stem cells, representative hsp-related genes were characterized in normal conditions and after different stress stimuli. The experimental data obtained in my PhD work provide the first evidence of an involvement of hsp genes in the adaptive response of planarian cells to stress conditions. Diverse genes are expressed in different cell types. For example, Djhsp90 is a gene with a distribution in a well defined cell type, i.e. gastrodermal cells, while Djhsp60 and Djhsp70-related members are specifically expressed in stem cells. In particular my interest was focused on the analysis of Djmot, a gene coding for a protein with high similarity with the mammalian Mortalin (HSP70 family). Functional studies by RNA interference (RNAi) demonstrate that Djmot expression is essential for planarian survival, as planarians become unable to regenerate and die within 1-2 months. Both dramatic reduction of the number of mitotic divisions and reduction of the expression level of different neoblast specific molecular markers demonstrate that the lethal phenotypes are a consequence of growth arrest and induction of senescence in neoblasts. The possibility that DjMot plays an essential role in a conserved mechanism of cytoplasmic sequestration of p53, thus antagonizing its nuclear entry, is discussed