The second and last day of this CRG Symposium was focused on Cell Reprogramming, Aging and Cancer. Many results were shown on the link between Senescence and Cancer. Senescence has been shown to prevent and promote tumorigenesis. These results are not so paradoxical. Recent studies suggest that one of the outcomes of senescence is tissue re-organization, achieved via cell communication. To maintain homeostasis upon cellular stress organisms rely on cellular growth and cell division. During aging, cellular proliferation is blocked by senescence as an innate defense mechanism to prevent tumor formation. However, as organisms age, these processes are deregulated, leading to hyperplastic or degenerating diseases. In this context, new powerful tools were presented, which not only facilitate studies on the tumor progression in-vivo, but that strongly enhance the comprehension of the role of putative tumor-inducing factors through the regulation of their expression in an inducible and reversible manner.
A large and interesting part of this CRG Symposium was dedicated to the most promising results in the fields of Reprogramming of cellular identity. Many efforts have been made to define the culture conditions of embryonic stem cells that maintain the “naive” pluripotency of these cells in-vitro. However, the real “take home message” of this morning session was that reprogramming could be an in-vivo process. Groundbreaking results were presented suggesting that reprogramming to switch the identity of a cell is a process that could be achieved in a physiological context. Even if in principle, the differentiated state of a cell was thought to be locked and the differentiation process was thought to be an irreversible mechanism, cells could be forced to acquire a pluripotent phenotype within the tissue in which they reside. The evidence that liver regenerates not through the differentiation of existing stem cells but through the de-differentiation of mature hepatocytes that form a new pool of stem cells that in turn form new functional hepatic cells, give the message that the way back to a more immature state is a physiological process used within the body to regenerate tissues upon damages.
The epidermis is a multi-layered structure in which epigenetic factors are differentially expressed. The investigation of this dynamic expression using an in vitro differentiation system reveals a strong dynamic profile of unique genomic localization of genes that belong to the same chromatin modifier family, thus providing new insights into the function of key epigenetic players.
Despite the high interest in the reprogramming field due to the potential therapeutical applications, the possibility to change the cellular identity in vivo within the tissues will represent a potent tool to understand the mechanisms that control cell fate in a physiological context. Manuel Serrano’s group developed a transgenic mouse with inducible expression of the Yamanaka factors to dedifferentiate multiple tissues. Apart from the groundbreaking evidence that cells could be reprogrammed back to pluripotency in living mammals, thus definitively confirming that the differentiated state of a cell is not permanently locked within the body, his results suggest that the in vivo-generated iPSCs circulating in the blood of these mice represent a more primitive or plastic state than ESCs or in vitro-iPSCs.
Marius Wernig is the scientist who first directly converted fibroblast into Induced Neurons (iN) with the ectopic expression of only three factors. In this talk, he argumented that this process seems to be more fast and efficient than the canonical reprogramming to pluripotency. By investigating the functional role of the transcription factors involved at single cell resolution, he founds that there are discrepancy on the binding of the key reprogramming players to the target genes. Indeed, while Ascl1, the key player in iN formation, appears to bind its physiological target through the interaction with nucleosomal DNA, the main “reprogram to pluripotency” factors as Oct4 and Sox2 bind ectopic genomic regions that are typically not bound in ES cells. Thus, the dynamic and specificity of the interaction of the key factors with chromatin determine the efficiency of the reprogramming process.
During senescence, cells undergo a proliferative arrest that seems to induce a tumorigenic effect on the neighbouring cells through secretion of specific molecules. The identification of senescence-related genes reveals that some of these are also stem cell-related genes. In vivo transplantation of senescent cells suggests that their tumor formation role could be played by altering the endogenous stem cell fate.