Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

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Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24 -null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24 -/- Lmna+/- mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24-/- mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.
This work was supported by grants from Ministerio de Educacion y Ciencia (Spain), Fundación Lilly, Fundación La Caixa, Fundación M. Botín, and the European Union. I. Flores is a Ramón y Cajal senior scientist. M.A. Blasco´s laboratory is funded by the Ministerio de Ciencia y Tecnologia (Spain), the regional government of Madrid, the European Union, and Josef Steiner Cancer Research Award 2003. The Instituto Universitario de Oncología is supported by Obra Social Cajastur.