Cell stem cell, Год журнала: 2023, Номер 30(11), С. 1452 - 1471.e10
Опубликована: Окт. 12, 2023
Язык: Английский
Molecular Cell, Год журнала: 2023, Номер 84(1), С. 34 - 54
Опубликована: Ноя. 13, 2023
Язык: Английский
Процитировано
55
Developmental Cell, Год журнала: 2024, Номер 59(8), С. 991 - 1009.e12
Опубликована: Март 13, 2024
Язык: Английский
Процитировано
19
PLoS Biology, Год журнала: 2019, Номер 17(4), С. e3000201 - e3000201
Опубликована: Апрель 1, 2019
Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified critical role for Yes-associated protein (YAP), major effector Hippo signaling, in maintaining younger state human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated 9 nuclease (Cas9)-mediated knockout (KO) YAP hMSCs resulted premature cellular senescence. Mechanistically, cooperated with TEA domain transcriptional factor (TEAD) to activate the expression forkhead box D1 (FOXD1), geroprotective protein. deficiency led down-regulation FOXD1. In turn, overexpression or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration lentiviral vector encoding attenuated development Collectively, our findings reveal YAP–FOXD1, novel regulatory axis, as potential target gene therapy alleviate
Язык: Английский
Процитировано
139
Protein & Cell, Год журнала: 2020, Номер 11(7), С. 483 - 504
Опубликована: Июнь 6, 2020
Abstract SIRT7, a sirtuin family member implicated in aging and disease, is regulator of metabolism stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during mesenchymal (hMSC) deficiency accelerates senescence. Mechanistically, forms complex with nuclear lamina proteins heterochromatin proteins, thus maintaining the repressive state at periphery. Accordingly, results loss heterochromatin, de-repression LINE1 retrotransposon (LINE1), activation innate immune signaling via cGAS-STING pathway. These aging-associated cellular defects were reversed overexpression or treatment targeted reverse-transcriptase inhibitor. Together, these findings highlight safeguards chromatin architecture to control regulation ensure geroprotection aging.
Язык: Английский
Процитировано
126
Protein & Cell, Год журнала: 2018, Номер 10(6), С. 417 - 435
Опубликована: Авг. 1, 2018
Aging increases the risk of various diseases. The main goal aging research is to find therapies that attenuate and alleviate aging-related In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), premature model recently established. Ten candidate were identified quercetin was investigated in detail due its leading effects. Mechanistic studies revealed alleviated senescence via enhancement cell proliferation restoration heterochromatin architecture WS hMSCs. RNA-sequencing analysis transcriptional commonalities differences effects by Vitamin C. Besides hMSCs, also attenuated cellular Hutchinson-Gilford progeria (HGPS) physiological-aging Taken together, our study identifies as agent against accelerated providing potential therapeutic intervention treating age-associated disorders.
Язык: Английский
Процитировано
109
Nature Communications, Год журнала: 2019, Номер 10(1)
Опубликована: Июль 26, 2019
Abstract DiGeorge syndrome critical region 8 (DGCR8) is a component of the canonical microprocessor complex for microRNA biogenesis. However, non-canonical functions DGCR8 have not been studied. Here, we demonstrate that plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version (DR8 dex2 ) accelerated senescence human mesenchymal stem cells (hMSCs) independent its microRNA-processing activity. Further studies revealed maintained by interacting with nuclear envelope protein Lamin B1, heterochromatin-associated proteins, KAP1 HP1γ. Overexpression any these including DGCR8, reversed premature senescent phenotypes DR8 hMSCs. Finally, was downregulated pathologically naturally aged hMSCs, whereas overexpression alleviated hMSC aging mouse osteoarthritis. Taken together, analyses uncovered novel, processing-independent thus representing new therapeutic target alleviating aging-related disorders.
Язык: Английский
Процитировано
106
Light Science & Applications, Год журнала: 2020, Номер 9(1)
Опубликована: Янв. 28, 2020
Abstract The emergence of super-resolution (SR) fluorescence microscopy has rejuvenated the search for new cellular sub-structures. However, SR achieves high contrast at expense a holistic view interacting partners and surrounding environment. Thus, we developed fluorescence-assisted diffraction computational tomography (SR-FACT), which combines label-free three-dimensional optical (ODT) with two-dimensional Hessian structured illumination microscopy. ODT module is capable resolving mitochondria, lipid droplets, nuclear membrane, chromosomes, tubular endoplasmic reticulum, lysosomes. Using dual-mode correlated live-cell imaging prolonged period time, observed novel subcellular structures named dark-vacuole bodies, majority originate from densely populated perinuclear regions, intensively interact organelles such as mitochondria membrane before ultimately collapsing into plasma membrane. This work demonstrates unique capabilities SR-FACT, suggests its wide applicability in cell biology general.
Язык: Английский
Процитировано
106
Cell Reports, Год журнала: 2019, Номер 26(13), С. 3643 - 3656.e7
Опубликована: Март 1, 2019
Highlights•CBX4 is downregulated in physiologically and pathologically aged hMSCs•CBX4 deficiency leads to premature cellular senescence counteracts hMSC by maintaining nucleolar homeostasis•CBX4 overexpression alleviates osteoarthritisSummaryCBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles the maintenance cell identity organ development through gene silencing. However, whether CBX4 regulates human stem homeostasis remains unclear. Here, we demonstrate that mesenchymal (hMSC) aging via homeostasis. protein hMSCs, whereas knockout hMSCs results destabilized heterochromatin, enhanced ribosome biogenesis, increased translation, accelerated senescence. maintains recruiting fibrillarin (FBL) heterochromatin KRAB-associated (KAP1) at rDNA, limiting excessive expression rRNAs. Overexpression physiological attenuates osteoarthritis mice. Altogether, our findings reveal critical role counteracting homeostasis, providing potential therapeutic target for aging-associated disorders.Graphical abstract
Язык: Английский
Процитировано
104
Cell stem cell, Год журнала: 2019, Номер 24(3), С. 447 - 461.e8
Опубликована: Янв. 17, 2019
Язык: Английский
Процитировано
94
Cell Research, Год журнала: 2020, Номер 31(2), С. 187 - 205
Опубликована: Июль 31, 2020
Abstract Accumulating evidence indicates an association between the circadian clock and aging process. However, it remains elusive whether deregulation of proteins underlies stem cell they are targetable for alleviation aging-associated syndromes. Here, we identified a transcription factor-independent role CLOCK, core component molecular machinery, in counteracting human mesenchymal (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, deficiency accelerated senescence, whereas overexpression even as transcriptionally inactive form, rejuvenated physiologically pathologically aged hMSCs. Mechanistic studies revealed that formed complexes with nuclear lamina KAP1, thus maintaining heterochromatin architecture stabilizing repetitive genomic sequences. Finally, gene therapy lentiviral vectors encoding promoted cartilage regeneration attenuated age-related articular degeneration mice. These findings demonstrate noncanonical heterochromatin, promoting tissue regeneration, mitigating chronic diseases.
Язык: Английский
Процитировано
87