Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Tu, Jiajie; Wan, Chao; Zhang, Fengjie; Cao, Lianbao; Law, Patrick Wai Nok; Tian, Yuyao; Lü, Gang; Rennert, Owen M.; Chan, Wai‐Yee; Cheung, Hoi‐Hung

doi:10.1111/acel.13116

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…Our findings showed that WRN was expressed during the early stage of pluripotency and was specifically up-regulated during chondrocyte differentiation. Ablation of WRN did not affect the pluripotential status, which has been corroborated by the previous studies 37 . However, upon differentiation into multipotent MSCs, the differentiating ability was impaired by WRN loss somehow.…”

Section: Discussionsupporting

confidence: 88%

“…Together, these data suggest that the cells became a population enriched specifically for mesendodermal growth. It has been reported that the loss of WRN did not affect the pluripotency of induced stem cells (iPSCs); however, upon differentiation into the mesenchymal lineage, the differentiation ability of WRN −/− iPSCs was influenced 37 . We hereby continued to examine the differentiation at stage 3 where the CTR cell clusters were distributed throughout the culture and stained in dark blue, indicating the existence of an extracellular matrix, which is a necessary prerequisite for chondrocyte formation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

et al. 2022

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Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height. Zebrafish lacking wrn exhibit impairment of bone growth and have shorter body stature. We pinpoint the function of WRN to its helicase domain. We identify short-stature homeobox (SHOX) as a crucial and direct target of WRN and find that the WRN helicase core regulates the transcriptional expression of SHOX via unwinding G-quadruplexes. Consistent with this, shox −/− zebrafish exhibit impaired bone growth, while genetic overexpression of SHOX or shox expression rescues the bone developmental deficiency induced in WRN / wrn -null mutants both in vitro and in vivo. Collectively, we have identified a previously unknown function of WRN in regulating bone development and growth through the transcriptional regulation of SHOX via the WRN helicase domain, thus illuminating a possible approach for new therapeutic strategies.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

et al. 2022

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“…In the original publication of J. Tu et al, (2020), the Materials and Methods section was not included. The missing section is shown below.…”

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confidence: 99%

Corrigendum: Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Tu¹,

Chen²,

Zhang³

et al. 2020

Aging Cell

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“…We have previously characterized the transcriptomic difference between iPSC-derived, isogenic WRN +/+ and WRN −/− mesenchymal stem cells (MSC). Downregulation of paracrine factors such as HGF accounts for the impaired pro-angiogenic function in WRN −/− MSC [ 7 ]. Notably, we also found downregulation of short stature homeobox ( SHOX ) gene in the WRN-deficient cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells

et al. 2022

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Background Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually thin extremities. The reasons for these developmental defects are not completely understood and the underlying molecular mechanism remains to be elucidated. Results In this study, WRN was found to modulate transcription of short stature homeobox gene SHOX. Loss of WRN resulted in insufficient expression of SHOX, the gene dose of which is critical for driving chondrocyte differentiation. WRN could bind the G-quadruplex (G4) structures in the SHOX promoter and stimulate transcription. Aberrant formation of G4 structures in WRN-deficient cells impeded normal transcription of SHOX, thus resulting in impaired chondrogenesis. Chondrogenesis could be rescued by overexpression of WRN helicase or SHOX, suggesting that SHOX is a downstream target of WRN. Gene editing of the G4 structures in the SHOX promoter could increase SHOX expression, therefore rescuing the impaired chondrogenesis in WRN-deficient cells. Conclusions Our data suggest that dysgenesis of the developing bone in WS might be caused by SHOX insufficiency. Aberrant formation of G4 structures in SHOX promoter suppresses SHOX expression and impairs chondrogenesis. Targeted mutagenesis in the G4 structures enhances SHOX expression and thus providing an opportunity to rescue the chondrogenic defect.

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Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Cited by 10 publications

References 32 publications

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

Corrigendum: Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells

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