Telomere dysfunction and stem cell aging - Zhenyu Ju
Current evidence suggest that the functional decline of adult stem cells contributes to the impaired organ homeostasis and functionality during aging. The mechanisms of stem cell aging are still poorly understood. Telomere dysfunction represent one of the molecular mechanisms limiting adult stem cell function by triggering both cell intrinsic checkpoints and cell extrinsic alterations. Deletion of DNA damage checkpoints induced by telomere dysfunction can rejuvenate the aging stem cells and improve organ function in 3rd generation telomerase knockout mice (G3Terc-/-). However, the engrafted wild-type HSCs in G3Terc-/- mice showed abnormal hematopoiesis, which was associated with environmental defect induced by telomere dysfunctional in an age dependent manner. Further analysis revealed that telomere dysfunction induced alteration of systemic environmental factors contribute to the impaired lymphopoiesis and the decline stem cell functionality. By using a genetically modified mouse model, we tested the hypothesis that whether HSC transplantation could slow down the telomere-driven aging in the setting of ameliorate environmental defects. We found that wild-type HSC engrafted in G3Terc-/- knockout mouse showed impaired hematopoiesis, whereas HSC engrafted in Exo-1-/-, G3Terc-/- double knockout mouse showed normal hematopoiesis. Further analysis showed an increased survival in Exo-1-/-, G3Terc-/- double knockout mouse after wild-type HSC transplantation compared to those untreated mice, indicating that transplantation of wild-type HSC could rescue the survival of telomere dysfunctional mice in the setting of ameliorated environmental defects. We also utilized iPS and ntES approaches to rejuvenate the somatic cells from aged telomere dysfunctional mice. Our data showed that ntES cells exhibited remarkable elongation of telomere length and improved mitochondrial function, associated with a better self-renewal ability and developmental potential compared to iPS cells derived from G3Terc-/- somatic cells.