Amelioration of experimental tendinopathy by lentiviral CD44 gene therapy targeting senescence-associated secretory phenotypes

Chen, Shih-Yao; Jou, I‐Ming; Ko, Po‐Jen; Hsu, Kai-Lan; Su, Wei-Ren; Kuo, Li-Chieh; Lee, Pei-Yuan; Wu, Chao‐Liang; Wu, Po‐Ting

doi:10.1016/j.omtm.2022.06.006

Cited by 9 publications

(26 citation statements)

References 41 publications

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“…Senolysis has been showed to ameliorate various age-associated disorders [ 48 ]. Integration of our previous study [ 6 ] and the current work, senolysis of tenocyte can improve tendinopathic characteristics. Taken together, we proposed that the specific cHA + DEX combination might be an ideal therapeutic agent for tendinopathy via the senolytic effect.…”

Section: Discussionsupporting

confidence: 56%

“…Jeon et al reported that selective removal of senescent chondrocytes attenuated the development of post-traumatic OA, reduced pain and decreased expression of inflammatory markers as well as increased expression of cartilage tissue extracellular matrix proteins [ 27 ]. Our recent study reveals that senescence is positively correlated with disease severity of tendinopathy [ 6 ]. Decreased senescence and SASP via overexpression of CD44 can ameliorate rat experimental tendinopathy [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study reveals that senescence is positively correlated with disease severity of tendinopathy [ 6 ]. Decreased senescence and SASP via overexpression of CD44 can ameliorate rat experimental tendinopathy [ 6 ]. In this study, senescent markers and SASP induced by IL-1β, DEX, and IL-1β + DEX in human tenocytes can be reduced by the cHA (50:50) + DEX and cHA (20:80) + DEX treatments ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…The tenodesis or tenotomy of LHB were performed, and the pathological area of LHB was collected for the primary culture. The preparation of tendon samples and tenocyte culture methods were performed according to our previous study [ 6 , 49 ]. Well-characterized second-to-fourth passage cells were used in this experiment, and they showed no phenotypic drift of major tenocyte markers such as cell shape (elongated and spindle-shaped with apposition) and tenomodulin expression identified using anti-tenomodulin antibody (Santa Cruz) as described previously [ 6 , 49 ].…”

Section: Methodsmentioning

confidence: 99%

“…It is widely accepted that inflammation and degeneration may mutually affect disease progression [ 2 ]. Furthermore, emerging evidence shows that excess apoptosis and senescence play important roles in the pathogenesis of tendinopathy [ 3 , 4 , 5 , 6 ]. Therefore, ameliorating apoptosis [ 7 ] and senescence [ 6 , 8 ] in the translation studies would be the targeted therapeutic approach for tendinopathy.…”

Section: Introductionmentioning

confidence: 99%

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Cross-Linked Hyaluronate and Corticosteroid Combination Ameliorate the Rat Experimental Tendinopathy through Anti-Senescent and -Apoptotic Effects

Hsu

Chen

et al. 2022

IJMS

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The combination of cross-linked hyaluronate (cHA) and corticosteroid showed more rapid pain or functional improvement in knee osteoarthritis and adhesive capsulitis. However, rare evidence of this combination in treating tendinopathy has been reported. We hypothesized that the specific formulations of cHA and dexamethasone (DEX) conferred amelioration of tendinopathy via anti-apoptosis and anti-senescence. In this controlled laboratory study, primary tenocytes from the human tendinopathic long head of biceps were treated with three cHA formulations (cHA:linealized HA = 80:20, 50:50, and 20:80) + DEX with or without IL-1β stimulation. Cell viability, inflammatory cytokines, tendon-related proliferation markers, matrix metalloproteinases (MMPs), senescent markers, and apoptosis were examined. The in vivo therapeutic effects of the selected cHA + DEX combinations were evaluated in a collagenase-induced rat patellar tendinopathy model. The expression levels of inflammatory mediators, including IL-1β, IL-6, COX-2, MMP-1, and MMP-3 were significantly reduced in all cHA + DEX-treated tenocytes (p < 0.05, all). The cHA (50:50) + DEX and cHA (20:80) + DEX combinations protected tenocytes from cytotoxicity, senescence, and apoptosis induced by DEX in either IL-1β stimulation or none. Furthermore, the two combinations significantly improved the rat experimental tendinopathy by reducing ultrasound feature scores and histological scores as well as the levels of apoptosis, senescence, and senescence-associated secretory phenotypes (p < 0.05, all). We identified two specific cHA formulations (cHA (50:50) and cHA (20:80)) + DEX that could ameliorate tendinopathy through anti-senescence and -apoptosis without cytotoxicity. This study provides a possible approach to treating tendinopathy using the combination of two well-known agents.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cross-Linked Hyaluronate and Corticosteroid Combination Ameliorate the Rat Experimental Tendinopathy through Anti-Senescent and -Apoptotic Effects

Hsu

Chen

et al. 2022

IJMS

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Young Exosome Bio‐Nanoparticles Restore Aging‐Impaired Tendon Stem/Progenitor Cell Function and Reparative Capacity

Jin¹,

Wang²,

Wu³

et al. 2023

Advanced Materials

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Tendon aging is frequently accompanied by extrinsic inflammation-aging harassment and intrinsic TSPC senescence, resulting in impaired reparative and regenerative capacities. [2] Although the functional decline of senescent TSPCs is accepted well, an efficient and precise method to rejuvenate aged TSPC (AT-SC) function and recover aging-impaired tendon reparative capacity remains to be further explored.Extracellular vesicles (EVs) are membrane-enclosed structures mainly that are classified into two main groups: exosomes and microvesicles. Among them, exosomes range from 40 to 150 nm in diameter and are mainly derived from the endosomal system, [3] whereas microvesicles range from 100 to 1000 nm in diameter and are generated by shedding of the plasma membrane. EVs could facilitate intercellular communication by transferring mRNA, microRNA, proteins, and organelle cargoes into recipient cells; [4] therefore, EVs have been suggested as excellent candidates for therapeutic methods for tissue regeneration and repair. Recently, EVs have been proven to be beneficial components of young blood in extending the life span of mice, suggesting that some specific EVs may possess an anti-senescent function. [5] Aging impairs tendon stem/progenitor cell function and tendon homeostasis, however, effective treatments for aging-induced tendon diseases are lacking. Exosomes are naturally derived nanoparticles that contain bioactive molecules, and therefore, have attracted great interest in tissue engineering and regenerative medicine. In this study, it is shown that young exosomes secreted by stem cells from human exfoliated deciduous teeth (SHED-Exos) possess abundant anti-aging signals. These young bio-nanoparticles can alleviate the aging phenotypes of aged tendon stem/progenitor cells (AT-SCs) and maintain their tenogenic capacity. Mechanistically, SHED-Exos modulate histone methylation and inhibit nuclear factor-κB to reverse AT-SC aging. In a naturally aging mouse model, systemic administration of SHED-Exo bio-nanoparticles retards tendon degeneration. Interestingly, local delivery of SHED-Exos-loaded microspheres confers anti-aging phenotypes, including reduced senescent cells and decreased ectopic bone formation, thereby functionally and structurally rescuing endogenous tendon regeneration and repair capacity in aged rats. Overall, SHED-Exos, as natural bioactive nanoparticles, have promising translational and therapeutic potential for aging-related diseases.

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A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super‐enhancers in maintaining EBV latency

Yan

Wang

Chakravorty

et al. 2022

Journal of Medical Virology

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We probed the lifecycle of Epstein‐Barr virus (EBV) on a cell‐by‐cell basis using single cell RNA sequencing (scRNA‐seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350–LMP1hi cells, expressed high levels of HIF1A and was transcriptionally regulated by HIF1‐α. Treatment of LCLs with Pevonedistat, a drug that enhances HIF1‐α signaling, markedly induced this cluster. The second cluster, containing GP350+LMP1hi cells, expressed EBV lytic genes. Host genes that are controlled by super‐enhancers (SEs), such as transcription factors MYC and IRF4, had the lowest expression in this cluster. Functionally, the expression of genes regulated by MYC and IRF4 in GP350+LMP1hi cells were lower compared to other cells. Indeed, induction of EBV lytic reactivation in EBV+ AKATA reduced the expression of these SE‐regulated genes. Furthermore, CRISPR‐mediated perturbation of the MYC or IRF4 SEs in LCLs induced the lytic EBV gene expression, suggesting that host SEs and/or SE target genes are required for maintenance of EBV latency. Collectively, our study revealed EBV‐associated heterogeneity among LCLs that may have functional consequence on host and viral biology.

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Amelioration of experimental tendinopathy by lentiviral CD44 gene therapy targeting senescence-associated secretory phenotypes

Cited by 9 publications

References 41 publications

Cross-Linked Hyaluronate and Corticosteroid Combination Ameliorate the Rat Experimental Tendinopathy through Anti-Senescent and -Apoptotic Effects

Cross-Linked Hyaluronate and Corticosteroid Combination Ameliorate the Rat Experimental Tendinopathy through Anti-Senescent and -Apoptotic Effects

Young Exosome Bio‐Nanoparticles Restore Aging‐Impaired Tendon Stem/Progenitor Cell Function and Reparative Capacity

A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super‐enhancers in maintaining EBV latency

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