Accumulating Mitochondrial DNA Mutations Drive Premature Hematopoietic Aging Phenotypes Distinct from Physiological Stem Cell Aging
| Autor: | Amol Ugale, Gudmundur L. Norddahl, David Bryder, Gerd Sten, Martin Wahlestedt, Mikael Sigvardsson, Jens M. Nygren, Cornelis J.H. Pronk |
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| Rok vydání: | 2011 |
| Předmět: |
Somatic cell
Cellular differentiation Stem cell theory of aging DNA-Directed DNA Polymerase Biology DNA Mitochondrial Mice Lymphopenia medicine Genetics Animals Regeneration Progenitor cell Cells Cultured Cellular Senescence Membrane Potential Mitochondrial Chimera Gene Expression Profiling Hematopoietic stem cell Aging Premature Anemia Cell Biology Hematopoietic Stem Cells Mice Mutant Strains Cell biology DNA Polymerase gamma Hematopoiesis Mitochondria Mice Inbred C57BL Adult Stem Cells medicine.anatomical_structure Mutation Molecular Medicine Stem cell Cell aging Adult stem cell |
| Zdroj: | Cell Stem Cell. 8(5):499-510 |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2011.03.009 |
| Popis: | SummarySomatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging. |
| Databáze: | OpenAIRE |
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