Wnt/β‐catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration

Bastakoty, Dikshya; Young, Pampee P.

doi:10.1096/fj.201600502r

Cited by 105 publications

(89 citation statements)

References 178 publications

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“…Several pathways regulate skeletal muscle fibrosis . Of these, TGF‐β and Wnt‐signaling mechanisms are considered as the key players in fibrosis . Canonical Wnt signaling is upregulated during aging as well as after tissue injury and is recognized as a key player in kidney, liver, myocardial, and pulmonary fibrosis .…”

Section: Discussionmentioning

confidence: 99%

Age and multiparity related urethral sphincter muscle dysfunction in a rabbit model: Potential roles of TGF‐β and Wnt‐β catenin signaling pathways

Rajasekaran

Nguyen

et al. 2018

Neurourology and Urodynamics

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Aims Prior studies demonstrate increased incidence of urinary incontinence (UI) in the geriatric population which affects their quality of life. Pathophysiology of UI in the geriatric population and the underlying molecular mechanisms are still unclear. To elucidate these mechanisms, we performed a pre‐clinical study in a rabbit model and the objectives were to (i) determine the effect of aging as well as multiparity on urethral sphincter muscle thickness and urethral closing pressure (UCP); (ii) examine the role of fibrosis and atrophy; and (iii) elucidate the molecular pathways that mediate fibrosis and atrophy in the urethral tissue. Methods New Zealand White female rabbits (n = 6 each; young 6‐12 months and old over 30 months of age) were anesthetized and urethral muscle thickness and sphincter closure function were measured. Rabbits were then sacrificed and urethral tissues (bladder neck and mid‐urethra) were collected to process for immunostaining as well as for molecular studies for markers for fibrosis (β‐catenin which is an important mediator of Wnt signaling, Collagen‐1, and TGF‐β) and atrophy (MuRF‐1). Results Our studies showed a significant decrease in the urethral sphincter muscle thickness and closure function with age. Age‐related increase in protein and mRNA expression levels of fibrosis, as well as atrophy markers were observed in the bladder neck and mid‐urethral tissues. Conclusions Age and multiparity related increase in fibrosis and atrophy of urethral sphincter muscles may contribute to impaired urethral closure function seen in old animals.

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Section: Discussionmentioning

confidence: 99%

Age and multiparity related urethral sphincter muscle dysfunction in a rabbit model: Potential roles of TGF‐β and Wnt‐β catenin signaling pathways

Rajasekaran

Nguyen

et al. 2018

Neurourology and Urodynamics

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“…Consistent with the present findings, a previous transcriptomic study of Val66Met mice found the Wnt signaling pathway dysregulated in BDNF Met/Met mice (Wang et al, ). Wnt/β‐catenin canonical pathway regulates many cellular processes such as development during embryogenesis, maintenance of tissue homeostasis, and regeneration in the adult (Bastakoty & Young, ; Grigoryan et al, ). In the adult hippocampus, Wnt signaling regulates synaptic plasticity, dendritic morphogenesis, synaptogenesis, long‐term potentiation, and learning and memory (Dickins & Salinas, ; Fortress & Frick, ; Rosso & Inestrosa, ).…”

Section: Discussionmentioning

confidence: 99%

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes

et al. 2018

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Brain-derived neurotrophic factor (BDNF), a neurotrophin highly expressed in the hippocampus, plays crucial roles in cognition, neuroplasticity, synaptic function, and dendritic remodeling. The common human Val66Met polymorphism of BDNF has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders, and in the outcome of pro-adaptive and therapeutic treatments. Altered gene-expression profile has been previously shown in BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmarks of individuals carrying the BDNF Met allele. The aim of this study was to investigate the impact of the BDNF Val66Met polymorphism in the knock-in mouse model on two hippocampal epigenetic marks for transcriptional repression and activation, respectively: trimethylation of lysine 27 on histone H3 (H3K27me3) and acetylation of histone H3 (AcH3), using a genome-wide approach. Chromatin immunoprecipitation followed by deep sequencing of immunoprecipitated DNA (ChIP-Seq) was carried out with specific antibodies for H3K27me3 and AcH3. Our results revealed broad alteration of H3K27me3 and AcH3 marks association profiles in BDNF , compared to BDNF mice. Bioinformatics analysis showed changes in several biological functions and related pathways, affected by the presence of the polymorphism. In particular, a number of networks of functional interaction contained BDNF as central node. Quantitative PCR analysis confirmed epigenetically related significant changes in the expression of five genes: Dvl1, Nos3, Reln, Lypd6, and Sh3gl2. The first three are involved in dendrite and spine remodeling, morphological features altered in BDNF mice. This work in homozygous knock-in mice shows that the human BDNF Val66Met polymorphism induces an array of histone H3 epigenetic modifications, in turn altering the expression of select genes crucial for structural and functional neuronal features.

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“…) and our findings confirm a role for periostin as a novel marker in penile fibrosis. Targeted antifibrotic therapy has been shown to reduce fibrosis and improve organ function (Bastakoty and Young ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of age‐related penile microvascular hemodynamic impairment using laser speckle contrast imaging: possible role of increased fibrogenesis

Lee

Kim

You

et al. 2017

Physiological Reports

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Current technology for penile hemodynamic evaluations in small animals is invasive and has limitations. We evaluated a novel laser speckle contrast imaging (LSCI) technique to determine age‐related changes in penile microvascular perfusion (PMP) and tested the role of cavernosal muscle (CC) fibrosis mediated by Wnt‐TGF β1 signaling pathways in a mouse model. Ten young (2–3 months) and old (24–28 months) wild‐type C57BL6 male mice were subjected to PMP measured using a LSCI system. Penile blood flow (PBF, peak systolic velocity, PSV) was also measured using a color Doppler ultrasound for comparison. Measurements were made before and after injection of vasoactive drugs: prostaglandin E1 (PGE 1) and acetylcholine (ACh). CC was processed for immunohistochemical studies for markers of endothelium and fibrosis. Protein levels were quantified by Western blot.PMP and PBF increased significantly from baseline after injection of vasoactive drugs. Peak PMP after PGE 1 and ACh was higher in young mice (225.0 ± 12.0 and 211.3 ± 12.1 AU) compared to old (155.9 ± 7.1 and 162.6 ± 5.1 AU, respectively). PSV after PGE 1 was higher in young than old mice (112.7 ± 8.5 vs. 78.2 ± 4.6 mm/sec). PSV after ACh was also higher in young (112.7 ± 5.6 mm/sec) than older mice (69.2 ± 7.1 mm/sec). PMP positively correlated with PSV (r = 0.867, P = 0.001). Immunostaining and Western blot showed increased protein expression of all fibrosis markers with aging. LSCI is a viable technique for evaluating penile hemodynamics. Increased cavernosal fibrosis may cause impaired penile hemodynamics and increased incidence of erectile dysfunction in older men.

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Wnt/β‐catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration

Cited by 105 publications

References 178 publications

Age and multiparity related urethral sphincter muscle dysfunction in a rabbit model: Potential roles of TGF‐β and Wnt‐β catenin signaling pathways

Age and multiparity related urethral sphincter muscle dysfunction in a rabbit model: Potential roles of TGF‐β and Wnt‐β catenin signaling pathways

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes

Characterization of age‐related penile microvascular hemodynamic impairment using laser speckle contrast imaging: possible role of increased fibrogenesis

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