Search

Induction of pluripotency in somatic cells with defined genetic factors has been successfully used to investigate the mechanisms of disease initiation and progression. Cellular reprogramming and oncogenic transformation share common features; both involve undergoing a dramatic change in cell identity, and immortalization is a key step for cancer progression that enhances reprogramming. However, there are very few examples of complete successful reprogramming of tumor cells. Here we address the effect of expressing an active oncogene, RAS, on the process of reprogramming and found that, while combined expression with reprogramming factors enhanced dedifferentiation, expression within the context of neoplastic transformation impaired reprogramming. RAS induces expression changes that promote loss of cell identity and acquisition of stemness in a paracrine manner and these changes result in reprogramming when combined with reprogramming factors. When cells carry cooperating oncogenic defects, RAS drives cells into an incompatible cellular fate of malignancy.

Aging is characterized by a gradual functional decline of tissues with age. Adult stem and progenitor cells are responsible for tissue maintenance, repair, and regeneration, but during aging, this population of cells is decreased or its activity is reduced, compromising tissue integrity and causing pathologies that increase vulnerability, and ultimately lead to death. The causes of stem cell exhaustion during aging are not clear, and whether a reduction in stem cell function is a cause or a consequence of aging remains unresolved. Here, we took advantage of a mouse model of induced adult Sox2+ stem cell depletion to address whether accelerated stem cell depletion can promote premature aging. After a short period of partial repetitive depletion of this adult stem cell population in mice, we observed increased kyphosis and hair graying, and reduced fat mass, all of them signs of premature aging. It is interesting that cellular senescence was identified in kidney after this partial repetitive Sox2+ cell depletion. To confirm these observations, we performed a prolonged protocol of partial repetitive depletion of Sox2+ cells, forcing regeneration from the remaining Sox2+ cells, thereby causing their exhaustion. Senescence specific staining and the analysis of the expression of genetic markers clearly corroborated that adult stem cell exhaustion can lead to cellular senescence induction and premature aging.