RESUMEN
Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.
Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Eliminación de Gen , Longevidad/genética , Neoplasias/genética , Células Madre/fisiología , Telómero/fisiología , Animales , Células Cultivadas , Cruzamientos Genéticos , Progresión de la Enfermedad , Intestinos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/patología , Telomerasa/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Stem cell transplantation is widely considered as a promising therapeutic approach for photoreceptor degeneration, one of the major causes of blindness. In this review, we focus on the biology of retinal stem cells (RSCs) and progenitor cells (RPCs) isolated from fetal, postnatal, and adult animals, with emphasis on those from rodents and humans. We discuss the origin of RSCs/RPCs, the markers expressed by these cells and the conditions for the isolation, culture, and differentiation of these cells in vitro or in vivo by induction with exogenous stimulation.
Asunto(s)
Retina/citología , Retina/trasplante , Células Madre/citología , Animales , Diferenciación Celular , Proliferación Celular , Separación Celular , Humanos , Nicho de Células Madre/citologíaAsunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Tolerancia a Medicamentos/genética , Etnicidad/genética , Frecuencia de los Genes/genética , Inactivación Metabólica/genética , Oxigenasas de Función Mixta/genética , Asia/etnología , Citocromo P-450 CYP2C19 , Variación Genética/genética , Genotipo , Geografía/estadística & datos numéricos , HumanosRESUMEN
Most cancer cells have an immortal growth capacity as a consequence of telomerase reactivation. Inhibition of this enzyme leads to increased telomere dysfunction, which limits the proliferative capacity of tumor cells; thus, telomerase inhibition represents a potentially safe and universal target for cancer treatment. We evaluated the potential of two thio-phosphoramidate oligonucleotide inhibitors of telomerase, GRN163 and GRN163L, as drug candidates for the treatment of human hepatoma. GRN163 and GRN163L were tested in preclinical studies using systemic administration to treat flank xenografts of different human hepatoma cell lines (Hep3B and Huh7) in nude mice. The studies showed that both GRN163 and GRN163L inhibited telomerase activity and tumor cell growth in a dose-dependent manner in vitro and in vivo. The potency and efficacy of the lipid-conjugated antagonist, GRN163L, was superior to the nonlipidated parent compound, GRN163. Impaired tumor growth in vivo was associated with critical telomere shortening, induction of telomere dysfunction, reduced rate of cell proliferation, and increased apoptosis in the treatment groups. In vitro, GRN163L administration led to higher prevalence of chromosomal telomere-free ends and DNA damage foci in both hepatoma cell lines. In addition, in vitro chemosensitivity assay showed that pretreatment with GRN163L increased doxorubicin sensitivity of Hep3B. In conclusion, our data support the development of GRN163L, a novel lipidated conjugate of the telomerase inhibitor GRN163, for systemic treatment of human hepatoma. In addition to limiting the proliferative capacity of hepatoma, GRN163L might also increase the sensitivity of this tumor type to conventional chemotherapy.