progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated...progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.展开更多
Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatricdiseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development ...Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatricdiseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development ofcardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become thefocus in aging research. Natural aging is not regarded as a programmed process. However, accelerated agingdue to inherited genetic defects in patients of progeria is programmed and resembles many aspects ofnatural aging. Among several premature aging syndromes, Werner syndrome (WS) and Hutchinson–Gilfordprogeria syndrome (HGPS) are two broadly investigated diseases. In this review, we discuss how stem cellaging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigeneticlandscape in aged cells can be reversed to a “juvenile” state. Lastly, we explore the potential application ofthe latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.展开更多
文摘progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
基金This work was partly supported by the Lo Kwee-Seong Biomedical Research Fund and the Chinese University of Hong Kong(CUHK)Vice Chancellor(VC)Discretionary Fund.
文摘Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatricdiseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development ofcardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become thefocus in aging research. Natural aging is not regarded as a programmed process. However, accelerated agingdue to inherited genetic defects in patients of progeria is programmed and resembles many aspects ofnatural aging. Among several premature aging syndromes, Werner syndrome (WS) and Hutchinson–Gilfordprogeria syndrome (HGPS) are two broadly investigated diseases. In this review, we discuss how stem cellaging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigeneticlandscape in aged cells can be reversed to a “juvenile” state. Lastly, we explore the potential application ofthe latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.
