The present study investigated a promising strategy for scaling up the expansion of high-quality human limbal stem cells (LSCs) in vitro. The LSCs isolated from human cornea biopsies were cultured with Mitomycin-C (MMC)-treated Swiss-3T3 feeder layers using three different methods: LSCs with MMC-treated Swiss-3T3 (L with MS), LSCs on MMC-treated Swiss-3T3 (L on MS), and LSCs on reverse MMC-treated Swiss-3T3 (L on RMS). Cell morphology, purity, and differentiation during culture were examined through light microscopy, flow cytometry, immunofluorescence staining, and reverse transcription-polymerase chain reaction (RT-PCR). Results showed that the LSCs continued to grow and exhibited the highest expression of p63 + cells (99.5 ± 0.5 %) in the L on RMS method. After 7 days of culture, the L on RMS method exhibited a significantly higher cell expansion rate than the L with MS method (**p < 0.01). Moreover, RT-PCR demonstrated that the cultured LSCs could naturally differentiate into epithelial cells, indicated by K3 expression. The cells could also efficiently form colonies while maintaining their stem cell markers. Therefore, the L on RMS method is promising for rapidly expanding high-quality LSCs and preserving their growth and stemness for corneal tissue engineering and reconstructive surgery.
本研究探讨了一种在体外扩大高质量人角膜缘干细胞（LSCs）的有希望的策略。将从人角膜活检中分离的LSCs用丝裂霉素c （MMC）处理过的Swiss-3T3饲养层进行培养，采用三种不同的方法：MMC处理过的Swiss-3T3 （L与MS结合）、MMC处理过的Swiss-3T3 （L与MS结合）和反向MMC处理过的Swiss-3T3 （L与RMS结合）的LSCs。通过光镜、流式细胞术、免疫荧光染色和逆转录聚合酶链反应（RT-PCR）检测细胞形态、纯度和培养过程中的分化情况。结果显示，LSCs继续生长，在L on RMS法中p63 + 细胞的表达量最高（99.5 ± 0.5 %）。培养7 d后，RMS法的细胞扩增率显著高于MS法（**p <； 0.01）。RT-PCR结果表明，培养的LSCs可以自然分化为上皮细胞，K3表达表明。这些细胞还可以有效地形成集落，同时保持它们的干细胞标记。因此，L on RMS方法有望快速扩增高质量的LSCs，并保持其生长和干性，用于角膜组织工程和重建手术。
{"title":"A promising strategy to rapidly expand high-quality human limbal stem cells for tissue engineering and cornea reconstruction","authors":"Keng-Liang Ou , Hsieh-Tsung Shen , Chi-Hsun Tsai , Takashi Saito , Chia-Yu Wu","doi":"10.1016/j.tice.2026.103343","DOIUrl":"10.1016/j.tice.2026.103343","url":null,"abstract":"<div><div>The present study investigated a promising strategy for scaling up the expansion of high-quality human limbal stem cells (LSCs) <em>in vitro</em>. The LSCs isolated from human cornea biopsies were cultured with Mitomycin-C (MMC)-treated Swiss-3T3 feeder layers using three different methods: LSCs with MMC-treated Swiss-3T3 (L with MS), LSCs on MMC-treated Swiss-3T3 (L on MS), and LSCs on reverse MMC-treated Swiss-3T3 (L on RMS). Cell morphology, purity, and differentiation during culture were examined through light microscopy, flow cytometry, immunofluorescence staining, and reverse transcription-polymerase chain reaction (RT-PCR). Results showed that the LSCs continued to grow and exhibited the highest expression of p63 + cells (99.5 ± 0.5 %) in the L on RMS method. After 7 days of culture, the L on RMS method exhibited a significantly higher cell expansion rate than the L with MS method (**<em>p</em> < 0.01). Moreover, RT-PCR demonstrated that the cultured LSCs could naturally differentiate into epithelial cells, indicated by K3 expression. The cells could also efficiently form colonies while maintaining their stem cell markers. Therefore, the L on RMS method is promising for rapidly expanding high-quality LSCs and preserving their growth and stemness for corneal tissue engineering and reconstructive surgery.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103343"},"PeriodicalIF":2.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.tice.2026.103340
Mohammed Alissa , Suad A. Alghamdi , Abdulkarim S. Binshaya , Tawfiq N. Juraybi , Awaji Y. Safhi , Amal A. Albati , Adil Abalkhail , Adel M. Alqarni
Brexpiprazole (BPZ) is a third-generation atypical antipsychotic drug that is reported to induce various organ toxicity in non-target organisms. The current investigation was conducted to explore the dose-dependent toxicity of BPZ on cardiac tissues. Thirty-six rats were divided into four groups including control, BPZ (3 mg/kg), BPZ (10 mg/kg), and BPZ (30 mg/kg) treated group. BPZ intoxication compromised mRNA expressions of Calcineurin/NFAT and Calcium Signaling Pathway as evidenced by increased expression of protein phosphatase 3 catalytic subunit alpha (PPP3CA), nuclear factor of activated T cells, cytoplasmic 3 (NFATC3), regulator of calcineurin 1 (RCAN1), and phospholamban (PLN) while downregulating the expression of Ryanodine receptor 2 (RYR2), calcium voltage-gated channel subunit alpha c (CACNA1C), ATPase sarcoplasmic/endoplasmic reticulum Ca2 + transporting 2 (SERCA2). Oxidative stress was clearly observed given the level of reactive oxygen species (ROS) and malondialdehyde (MDA) was markedly elevated coupled with significant inhibition of endogenous antioxidant enzymes including, heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR), reduced glutathione (GSH) and glutathione S-transferase (GST) after BPZ intoxication. Functional cardiac impairment was further corroborated by significant changes occurring in echocardiographic parameters of myocardial impairment and ventricular dysfunction following the exposure of BPZ. Consistently, BPZ administration provoked the levels of creatine phosphokinase (CPK), B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI) and cardiac troponin T (cTnT). Higher BPZ doses (10 and 30 mg/kg) triggered apoptotic imbalance, i.e., an increase in Cysteine-aspartic acid protease-3 (Caspase-3), Cysteine-aspartic acid protease-9 (Caspase-9), Bcl-2–associated X protein (Bax), while a significant reduction in the levels of B cell lymphoma-2 (Bcl-2). Histopathological evaluation showed severe myocardial damage in cardiac morphology following the intoxication of BPZ. In silico analyses supported these results showing binding affinity of BPZ with important key regulatory proteins. Collectively, the obtained data suggest that long-term exposure to BPZ results in cardiotoxicity mediated by oxidative stress, inflammation, apoptosis, and functional cardiac dysfunction.
{"title":"Brexpiprazole induces acute cardiotoxicity via disrupting calcineurin/NFAT and calcium signaling pathway: A validation from biochemical, echocardiographic, histological, and computational analysis","authors":"Mohammed Alissa , Suad A. Alghamdi , Abdulkarim S. Binshaya , Tawfiq N. Juraybi , Awaji Y. Safhi , Amal A. Albati , Adil Abalkhail , Adel M. Alqarni","doi":"10.1016/j.tice.2026.103340","DOIUrl":"10.1016/j.tice.2026.103340","url":null,"abstract":"<div><div>Brexpiprazole (BPZ) is a third-generation atypical antipsychotic drug that is reported to induce various organ toxicity in non-target organisms. The current investigation was conducted to explore the dose-dependent toxicity of BPZ on cardiac tissues. Thirty-six rats were divided into four groups including control, BPZ (3 mg/kg), BPZ (10 mg/kg), and BPZ (30 mg/kg) treated group. BPZ intoxication compromised mRNA expressions of Calcineurin/NFAT and Calcium Signaling Pathway as evidenced by increased expression of protein phosphatase 3 catalytic subunit alpha (PPP3CA), nuclear factor of activated T cells, cytoplasmic 3 (NFATC3), regulator of calcineurin 1 (RCAN1), and phospholamban (PLN) while downregulating the expression of Ryanodine receptor 2 (RYR2), calcium voltage-gated channel subunit alpha c (CACNA1C), ATPase sarcoplasmic/endoplasmic reticulum Ca<sup>2 +</sup> transporting 2 (SERCA2). Oxidative stress was clearly observed given the level of reactive oxygen species (ROS) and malondialdehyde (MDA) was markedly elevated coupled with significant inhibition of endogenous antioxidant enzymes including, heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR), reduced glutathione (GSH) and glutathione S-transferase (GST) after BPZ intoxication. Functional cardiac impairment was further corroborated by significant changes occurring in echocardiographic parameters of myocardial impairment and ventricular dysfunction following the exposure of BPZ. Consistently, BPZ administration provoked the levels of creatine phosphokinase (CPK), B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI) and cardiac troponin T (cTnT). Higher BPZ doses (10 and 30 mg/kg) triggered apoptotic imbalance, i.e., an increase in Cysteine-aspartic acid protease-3 (Caspase-3), Cysteine-aspartic acid protease-9 (Caspase-9), Bcl-2–associated X protein (Bax), while a significant reduction in the levels of B cell lymphoma-2 (Bcl-2). Histopathological evaluation showed severe myocardial damage in cardiac morphology following the intoxication of BPZ. In silico analyses supported these results showing binding affinity of BPZ with important key regulatory proteins. Collectively, the obtained data suggest that long-term exposure to BPZ results in cardiotoxicity mediated by oxidative stress, inflammation, apoptosis, and functional cardiac dysfunction.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103340"},"PeriodicalIF":2.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.tice.2026.103345
Yagang Ding , Bangde Xue , Mingkui Gao , Sibin Guan , Qinchuan Li , Jun Liu
Adipose-derived stem cells are widely used in aging field because of their extensive sources, low immunogenicity and strong secretory function. In particular, the exosomes of adipose-derived stem cells are rich in small molecules of RNA and protein. Studies have shown that exosomes also play a role in regulation of ER stress. Therefore, we hypothesized that exosomes of adipose-derived stem cells could regulate ER stress and delay fibroblasts senescence. In this study, we use H2O2 to promote cellular senescence and treat with adipose-derived stem cell exosomes. The function of cell proliferation and apoptosis were compared, and the levels of validating factor and collagen were detected. Then we explored the mechanism of action of exosomes derived from adipose-derived stem cells. We found adipose-derived stem cell exosomes could inhibit fibroblast senescence, including promoting cell proliferation, inhibiting apoptosis and regulating collagen secretion, by regulating ER stress through SIRT1. To further validate the relevance of this mechanism at the population level, public human skin transcriptomic data were analyzed, revealing coordinated downregulation of SIRT1 expression and unfolded protein response (UPR) signaling during physiological skin aging, with a strong positive correlation between SIRT1 expression and UPR pathway activity. This study suggests that adipose-derived stem cell exosomes attenuate stress-induced senescence-like changes in fibroblasts, highlighting their potential relevance in the modulation of cellular aging.
{"title":"Adipose-derived stem cell exosomes attenuated fibroblast senescence by regulating endoplasmic reticulum stress through SIRT1","authors":"Yagang Ding , Bangde Xue , Mingkui Gao , Sibin Guan , Qinchuan Li , Jun Liu","doi":"10.1016/j.tice.2026.103345","DOIUrl":"10.1016/j.tice.2026.103345","url":null,"abstract":"<div><div>Adipose-derived stem cells are widely used in aging field because of their extensive sources, low immunogenicity and strong secretory function. In particular, the exosomes of adipose-derived stem cells are rich in small molecules of RNA and protein. Studies have shown that exosomes also play a role in regulation of ER stress. Therefore, we hypothesized that exosomes of adipose-derived stem cells could regulate ER stress and delay fibroblasts senescence. In this study, we use H<sub>2</sub>O<sub>2</sub> to promote cellular senescence and treat with adipose-derived stem cell exosomes. The function of cell proliferation and apoptosis were compared, and the levels of validating factor and collagen were detected. Then we explored the mechanism of action of exosomes derived from adipose-derived stem cells. We found adipose-derived stem cell exosomes could inhibit fibroblast senescence, including promoting cell proliferation, inhibiting apoptosis and regulating collagen secretion, by regulating ER stress through SIRT1. To further validate the relevance of this mechanism at the population level, public human skin transcriptomic data were analyzed, revealing coordinated downregulation of SIRT1 expression and unfolded protein response (UPR) signaling during physiological skin aging, with a strong positive correlation between SIRT1 expression and UPR pathway activity. This study suggests that adipose-derived stem cell exosomes attenuate stress-induced senescence-like changes in fibroblasts, highlighting their potential relevance in the modulation of cellular aging.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103345"},"PeriodicalIF":2.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.tice.2026.103332
Ahmad A. Obaid , Mazen M. Ghaith , Ahmad Najem Alshammari , Ekramy M. Elmorsy , Manal S. Fawzy , Neven A. Ebrahim , Hamada S. Salem , Nashwa Mostafa Hussein
Background
Chlorpyrifos was shown to cause oxidative, inflammatory, and apoptotic renal damage. The natural Astaxanthin (ASX) exhibits nephroprotective effects, however its limited bioavailability hinders its therapeutic potential. Chitosan nanoparticles were shown to enhance bioavailability and therapeutic delivery of the natural compounds.
Objective
This study investigated the renoprotective effects of astaxanthin-loaded chitosan nanoparticles (ASX-CNPs) compared with crude astaxanthin (ASX) against chlorpyrifos (CPF)-induced nephrotoxicity in male Wistar rats.
Methods
Ninety rats (235 g) were randomly assigned into six groups (n = 15) and orally treated for 60 days with saline, ASX (40 mg/kg), ASX-CNPs (40 mg/kg), CPF (10 mg/kg), or combinations of CPF with ASX or ASX-CNPs. ASX-CNPs were characterized by transmission electron microscopy and dynamic light scattering, revealing uniform spherical nanoparticles with high stability and an encapsulation efficiency of 84.72 %. Oxidative, inflammatory, and apoptotic pathways were evaluated via different assays
Results
CPF exposure significantly impaired renal function, elevating blood urea, creatinine, uric acid, cystatin C, and NGAL levels, while promoting oxidative stress, lipid peroxidation, and DNA damage. CPF also suppressed the Nrf2/HO-1 antioxidant pathway, triggered inflammation and nitrosative stress, and disrupted apoptotic balance by increasing Bax and Caspase-3 while decreasing Bcl-2 expression. Histopathological and ultra-structural analysis confirmed severe renal alterations, including glomerular contraction, structurally disrupted mitochondria, vascular congestion, and tubular degeneration. Co-treatment with ASX-CNPs markedly ameliorated biochemical, oxidative, inflammatory, nitrosative, and apoptotic disturbances, restoring renal morphology close to normal. In contrast, crude ASX provided partial protection, with less pronounced effects on antioxidant enzyme activities, cytokine levels, and tissue architecture. The superior efficacy of ASX-CNPs highlights the advantages of nanoparticle delivery in enhancing bioavailability, stability, and cellular uptake compared with the conventional form.
Conclusion
These findings indicate that ASX-CNPs represent a promising nanotherapeutic strategy for preventing CPF-induced kidney injury and demonstrate the enhanced protective potential of nanoformulations over their crude counterparts
{"title":"Astaxanthin-loaded chitosan nanoparticles attenuate chlorpyrifos-induced nephrotoxicity via activation of the Nrf2/HO-1 axis and suppression of oxidative, inflammatory, and apoptotic pathways","authors":"Ahmad A. Obaid , Mazen M. Ghaith , Ahmad Najem Alshammari , Ekramy M. Elmorsy , Manal S. Fawzy , Neven A. Ebrahim , Hamada S. Salem , Nashwa Mostafa Hussein","doi":"10.1016/j.tice.2026.103332","DOIUrl":"10.1016/j.tice.2026.103332","url":null,"abstract":"<div><h3>Background</h3><div>Chlorpyrifos was shown to cause oxidative, inflammatory, and apoptotic renal damage. The natural Astaxanthin (ASX) exhibits nephroprotective effects, however its limited bioavailability hinders its therapeutic potential. Chitosan nanoparticles were shown to enhance bioavailability and therapeutic delivery of the natural compounds.</div></div><div><h3>Objective</h3><div>This study investigated the renoprotective effects of astaxanthin-loaded chitosan nanoparticles (ASX-CNPs) compared with crude astaxanthin (ASX) against chlorpyrifos (CPF)-induced nephrotoxicity in male Wistar rats.</div></div><div><h3>Methods</h3><div>Ninety rats (235 g) were randomly assigned into six groups (n = 15) and orally treated for 60 days with saline, ASX (40 mg/kg), ASX-CNPs (40 mg/kg), CPF (10 mg/kg), or combinations of CPF with ASX or ASX-CNPs. ASX-CNPs were characterized by transmission electron microscopy and dynamic light scattering, revealing uniform spherical nanoparticles with high stability and an encapsulation efficiency of 84.72 %. Oxidative, inflammatory, and apoptotic pathways were evaluated via different assays</div></div><div><h3>Results</h3><div>CPF exposure significantly impaired renal function, elevating blood urea, creatinine, uric acid, cystatin C, and NGAL levels, while promoting oxidative stress, lipid peroxidation, and DNA damage. CPF also suppressed the Nrf2/HO-1 antioxidant pathway, triggered inflammation and nitrosative stress, and disrupted apoptotic balance by increasing Bax and Caspase-3 while decreasing Bcl-2 expression. Histopathological and ultra-structural analysis confirmed severe renal alterations, including glomerular contraction, structurally disrupted mitochondria, vascular congestion, and tubular degeneration. Co-treatment with ASX-CNPs markedly ameliorated biochemical, oxidative, inflammatory, nitrosative, and apoptotic disturbances, restoring renal morphology close to normal. In contrast, crude ASX provided partial protection, with less pronounced effects on antioxidant enzyme activities, cytokine levels, and tissue architecture. The superior efficacy of ASX-CNPs highlights the advantages of nanoparticle delivery in enhancing bioavailability, stability, and cellular uptake compared with the conventional form.</div></div><div><h3>Conclusion</h3><div>These findings indicate that ASX-CNPs represent a promising nanotherapeutic strategy for preventing CPF-induced kidney injury and demonstrate the enhanced protective potential of nanoformulations over their crude counterparts</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103332"},"PeriodicalIF":2.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.tice.2026.103331
Peng Yi, Bo Peng, Ying Cao, Xianghong Fu
Background
Male infertility represents a major global health challenge. Heat shock protein A1A (HSPA1A), a stress-inducible molecular chaperone, shows potential importance in spermatogenesis, though its precise mechanistic role remains undefined.
Methods
Analysis of human sperm transcriptome data (GSE6969) revealed HSPA1A expression in fertile versus infertile samples. Functional characterization involved the overexpression of HSPA1A in spermatogonia (GC-1 spg) and its knockdown in spermatocytes (GC-2 spd(ts)), assessing apoptosis, proliferation, and cell cycle progression. HSPA1A-interacting proteins were identified through immunoprecipitation-mass spectrometry and validated by co-immunoprecipitation. Downstream targets were investigated via bioinformatic analysis and proteomics. In vivo validation employed a mouse model of chronic HSP70 inhibition (VER-155008).
Results
HSPA1A is highly expressed in fertile sperm, and its overexpression significantly inhibited apoptosis, enhanced proliferation, and induced S/G2 phase arrest, while HSPA1A knockdown produced opposite effects. BAG5 was identified as a primary HSPA1A interactor. Mechanistically, the HSPA1A-BAG5 complex promoted ubiquitination-mediated degradation of ATF2, subsequently downregulating apoptotic signaling. In vivo HSPA1A inhibition induced testicular atrophy, reduced sperm count, impaired sperm morphology and acrosome reaction, disrupted seminiferous tubule architecture, and elevated germ cell apoptosis. Concurrent upregulation of ATF2, p53, and reduced testosterone levels were observed.
Conclusion
The HSPA1A-BAG5 complex maintains spermatogenic cell survival and proliferation through ubiquitination-dependent ATF2 degradation. These findings elucidate a novel regulatory axis essential for spermatogenesis and position HSPA1A as a promising therapeutic target for male infertility.
{"title":"HSPA1A-BAG5 chaperone complex promotes spermatogenesis by driving ubiquitination-mediated degradation of ATF2","authors":"Peng Yi, Bo Peng, Ying Cao, Xianghong Fu","doi":"10.1016/j.tice.2026.103331","DOIUrl":"10.1016/j.tice.2026.103331","url":null,"abstract":"<div><h3>Background</h3><div>Male infertility represents a major global health challenge. Heat shock protein A1A (HSPA1A), a stress-inducible molecular chaperone, shows potential importance in spermatogenesis, though its precise mechanistic role remains undefined.</div></div><div><h3>Methods</h3><div>Analysis of human sperm transcriptome data (GSE6969) revealed HSPA1A expression in fertile versus infertile samples. Functional characterization involved the overexpression of HSPA1A in spermatogonia (GC-1 spg) and its knockdown in spermatocytes (GC-2 spd(ts)), assessing apoptosis, proliferation, and cell cycle progression. HSPA1A-interacting proteins were identified through immunoprecipitation-mass spectrometry and validated by co-immunoprecipitation. Downstream targets were investigated via bioinformatic analysis and proteomics. <em>In vivo</em> validation employed a mouse model of chronic HSP70 inhibition (VER-155008).</div></div><div><h3>Results</h3><div>HSPA1A is highly expressed in fertile sperm, and its overexpression significantly inhibited apoptosis, enhanced proliferation, and induced S/G2 phase arrest, while HSPA1A knockdown produced opposite effects. BAG5 was identified as a primary HSPA1A interactor. Mechanistically, the HSPA1A-BAG5 complex promoted ubiquitination-mediated degradation of ATF2, subsequently downregulating apoptotic signaling. <em>In vivo</em> HSPA1A inhibition induced testicular atrophy, reduced sperm count, impaired sperm morphology and acrosome reaction, disrupted seminiferous tubule architecture, and elevated germ cell apoptosis. Concurrent upregulation of ATF2, p53, and reduced testosterone levels were observed.</div></div><div><h3>Conclusion</h3><div>The HSPA1A-BAG5 complex maintains spermatogenic cell survival and proliferation through ubiquitination-dependent ATF2 degradation. These findings elucidate a novel regulatory axis essential for spermatogenesis and position HSPA1A as a promising therapeutic target for male infertility.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103331"},"PeriodicalIF":2.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.tice.2026.103330
Jun Qiu , Xinpan Li , Yi Fang , Qiaoyuan Wu , Shixiong Liang
Background
Thoracic radiotherapy commonly causes radiation-induced lung injury (RILI); however, its mechanisms remain poorly defined, and no FDA-approved therapies are available.
Methods
To identify key pathways and regulators, we analyzed metabolic and transcriptomic alterations in a murine model of RILI. Following a 15 Gy thoracic irradiation, lung tissues were assessed by histopathology (H&E and Masson staining), LC-MS-based metabolomics, and transcriptomics.
Results
Irradiated lungs showed erythrocyte exudation, inflammatory infiltration, fibrosis, and epithelial damage, whereas control tissues showed no pathological changes. Metabolomic profiling identified 186 differentially abundant metabolites, primarily enriched in purine and glycine/serine/threonine metabolism. Transcriptomics revealed 180 differentially expressed genes. Integrative analysis demonstrated that both metabolites and genes converged on the PI3K–Akt and phospholipase D signaling pathways, suggesting their potential as early RILI biomarkers. Analyses also revealed a consistent association between RILI and lung microbiota dysbiosis, pointing to novel mechanistic insights.
Conclusions
Our integrative multi-omics analysis reveals that RILI progression is characterized by dysregulated purine metabolism and transcriptomic changes that converge on the PI3K-Akt and phospholipase D signaling pathways. These pathway alterations were associated with lung microbiota dysbiosis, providing new avenues for early biomarker discovery and therapeutic intervention.
{"title":"Integrative multi-omics profiling implicates purine metabolism and the PI3K-Akt pathway in radiation-induced lung injury","authors":"Jun Qiu , Xinpan Li , Yi Fang , Qiaoyuan Wu , Shixiong Liang","doi":"10.1016/j.tice.2026.103330","DOIUrl":"10.1016/j.tice.2026.103330","url":null,"abstract":"<div><h3>Background</h3><div>Thoracic radiotherapy commonly causes radiation-induced lung injury (RILI); however, its mechanisms remain poorly defined, and no FDA-approved therapies are available.</div></div><div><h3>Methods</h3><div>To identify key pathways and regulators, we analyzed metabolic and transcriptomic alterations in a murine model of RILI. Following a 15 Gy thoracic irradiation, lung tissues were assessed by histopathology (H&E and Masson staining), LC-MS-based metabolomics, and transcriptomics.</div></div><div><h3>Results</h3><div>Irradiated lungs showed erythrocyte exudation, inflammatory infiltration, fibrosis, and epithelial damage, whereas control tissues showed no pathological changes. Metabolomic profiling identified 186 differentially abundant metabolites, primarily enriched in purine and glycine/serine/threonine metabolism. Transcriptomics revealed 180 differentially expressed genes. Integrative analysis demonstrated that both metabolites and genes converged on the PI3K–Akt and phospholipase D signaling pathways, suggesting their potential as early RILI biomarkers. Analyses also revealed a consistent association between RILI and lung microbiota dysbiosis, pointing to novel mechanistic insights.</div></div><div><h3>Conclusions</h3><div>Our integrative multi-omics analysis reveals that RILI progression is characterized by dysregulated purine metabolism and transcriptomic changes that converge on the PI3K-Akt and phospholipase D signaling pathways. These pathway alterations were associated with lung microbiota dysbiosis, providing new avenues for early biomarker discovery and therapeutic intervention.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103330"},"PeriodicalIF":2.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.tice.2026.103328
Wenze Zhang , Yanjuan Jia , Anqi Wang , Rui Guo , Zhuomin Fu , Wanxia Wang
{"title":"Corrigendum to “Targeting YBX1: A novel therapeutic strategy for gastric cancer through regulation of cellular senescence and mTOR signaling” [Tissue and Cell, 97 (2025) 103089]","authors":"Wenze Zhang , Yanjuan Jia , Anqi Wang , Rui Guo , Zhuomin Fu , Wanxia Wang","doi":"10.1016/j.tice.2026.103328","DOIUrl":"10.1016/j.tice.2026.103328","url":null,"abstract":"","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"99 ","pages":"Article 103328"},"PeriodicalIF":2.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.tice.2026.103326
Ana Carolina Bontempi , Letícia Faustino Adolpho , Anne Caroline Teles Campos de Carvalho , Natália Bispo de Sousa , Taís Browne de Miranda , Matheus Kury , Denise Carleto Andia
Periodontal ligament-derived mesenchymal stem cells (PDLCs) are accessible and multipotent, with potential in regenerative therapies. However, their limited replicative capacity restricts long-term in vitro studies and hinders deeper understanding of mineralization mechanisms. To overcome this, we established an immortalized PDLC line (iPDLCs) by introducing the human telomerase reverse transcriptase (hTERT) gene via lentiviral transduction. We compared iPDLCs to primary PDLCs in terms of phenotype, proliferation, and osteogenic differentiation. Surface markers (CD105, CD166, CD34) were assessed by flow cytometry, while gene expression of hTERT, OCT4, NANOG, MAPK14, YAP1, CREB1, RUNX2, SP7, and ALPL was analyzed by RT-qPCR. ALPL activity and Alizarin Red staining were used to evaluate mineralization. iPDLCs showed a 2,300-fold increase in hTERT expression and maintained mesenchymal features, with high CD105/CD166 and low CD34 expression, as well as elevated OCT4 and NANOG levels. Upon osteogenic induction, iPDLCs upregulated proliferation-related genes (MAPK14, YAP1, CREB1) and showed early and enhanced expression of osteogenic markers (RUNX2, SP7, ALPL), particularly on day 7 (p ≤ 0.05 vs. PDLCs). Strong correlations were found between YAP1, RUNX2, and SP7 expression on days 7 and 10. Despite this early gene activation in iPDLCs, mineral deposition was greater in PDLCs at day 28 (p ≤ 0.05), confirmed by ALPL activity. These findings suggest that iPDLCs retain their undifferentiated state, proliferation capacity, and mineralization potential, while offering a reliable and long-lasting model for studying the molecular mechanisms involved in osteogenic differentiation of PDLCs.
{"title":"Immortalized periodontal ligament mesenchymal cells retain undifferentiation, proliferation and osteogenic characteristics","authors":"Ana Carolina Bontempi , Letícia Faustino Adolpho , Anne Caroline Teles Campos de Carvalho , Natália Bispo de Sousa , Taís Browne de Miranda , Matheus Kury , Denise Carleto Andia","doi":"10.1016/j.tice.2026.103326","DOIUrl":"10.1016/j.tice.2026.103326","url":null,"abstract":"<div><div>Periodontal ligament-derived mesenchymal stem cells (PDLCs) are accessible and multipotent, with potential in regenerative therapies. However, their limited replicative capacity restricts long-term <em>in vitro</em> studies and hinders deeper understanding of mineralization mechanisms. To overcome this, we established an immortalized PDLC line (iPDLCs) by introducing the human telomerase reverse transcriptase (<em>hTERT</em>) gene via lentiviral transduction. We compared iPDLCs to primary PDLCs in terms of phenotype, proliferation, and osteogenic differentiation. Surface markers (CD105, CD166, CD34) were assessed by flow cytometry, while gene expression of <em>hTERT</em>, <em>OCT4</em>, <em>NANOG</em>, <em>MAPK14</em>, <em>YAP1</em>, <em>CREB1</em>, <em>RUNX2</em>, <em>SP7</em>, and <em>ALPL</em> was analyzed by RT-qPCR. ALPL activity and Alizarin Red staining were used to evaluate mineralization. iPDLCs showed a 2,300-fold increase in <em>hTERT</em> expression and maintained mesenchymal features, with high CD105/CD166 and low CD34 expression, as well as elevated <em>OCT4</em> and <em>NANOG</em> levels. Upon osteogenic induction, iPDLCs upregulated proliferation-related genes (<em>MAPK14</em>, <em>YAP1</em>, <em>CREB1</em>) and showed early and enhanced expression of osteogenic markers (<em>RUNX2</em>, <em>SP7</em>, <em>ALPL</em>), particularly on day 7 (p ≤ 0.05 vs. PDLCs). Strong correlations were found between <em>YAP1</em>, <em>RUNX2</em>, and <em>SP7</em> expression on days 7 and 10. Despite this early gene activation in iPDLCs, mineral deposition was greater in PDLCs at day 28 (p ≤ 0.05), confirmed by ALPL activity. These findings suggest that iPDLCs retain their undifferentiated state, proliferation capacity, and mineralization potential, while offering a reliable and long-lasting model for studying the molecular mechanisms involved in osteogenic differentiation of PDLCs.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"100 ","pages":"Article 103326"},"PeriodicalIF":2.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145969315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.tice.2026.103325
Qingzhu Yang , Shuo Sun , Shuwei Dang , Zeyan Li , Lixue Feng , Qiaoyi Yang , Yanyan Sun , Xin Huang , Weiwei Zhang , Zhicheng Zhang , Guodong Li
Background
Nuclear transcription factor Y subunit α (NFYA) has been reported to play functional roles in a range of malignancies, while its precise mechanistic function in the context of colorectal cancerer (CRC) progression has yet to be established.
Methods
TIMER2, UALCAN, and Kaplan-Meier Plotter databases were leveraged to evaluate the expression of NFYA and to gauge its prognostic relevance in CRC. Determine NFYA and glutathione peroxidase 4 (GPX4) expression in cell lines (NCM460, DLD1 and HCT116) and clinical samples using Quantitative Real-time PCR (qPCR) and western immunoblotting assay. Assessment of cell viability, proliferation, and migration involved MTT, EdU staining assay, colony formation, and flow cytometry. Malondialdehyde (MDA) content and lipid reactive oxygen species (ROS) levels were assessed using specialized kits. Mitochondrial ultrastructural changes were observed using transmission electron microscopy (TEM). The transcriptional regulation of GPX4 by NFYA was investigated through Luciferase reporter assays and Chromatin Immunoprecipitation Assay (ChIP) experiments.
Results
Higher levels of NFYA were expressed in CRC cells and clinical samples, and the upregulation of this target was associated with a worse prognostic outcome for patients with CRC. In vitro,the inhibition of NFYA expression impaired CRC cell proliferative and migratory activity. NFYA was found to function in part by binding to the GPX4 promoter and activating transcription, leading to an increase in GPX4 levels and consequent reductions in lipid peroxide levels and ferroptosis. NFYA binds to the promoter region of GPX4, regulating the transcription of GPX4. In the recovery experiment, inhibition of NFYA-induced ferroptosis in cells was reversed by GPX4. Correspondingly, the ferroptosis caused by GPX4 suppression can be reversed by NFYA.
Conclusion
NFYA is thus a promising target for therapies aimed at treating CRC. NFYA is a key regulator of ferroptosis resistance in CRC while also providing direct mechanistic insights into the oncogenic function that this protein plays in these tumor cells. NFYA/GPX4 may be one of the underlying reasons for malignant growth of CRC cells.
{"title":"NFYA transcriptionally activates GPX4 inhibiting ferroptosis in colorectal cancer","authors":"Qingzhu Yang , Shuo Sun , Shuwei Dang , Zeyan Li , Lixue Feng , Qiaoyi Yang , Yanyan Sun , Xin Huang , Weiwei Zhang , Zhicheng Zhang , Guodong Li","doi":"10.1016/j.tice.2026.103325","DOIUrl":"10.1016/j.tice.2026.103325","url":null,"abstract":"<div><h3>Background</h3><div>Nuclear transcription factor Y subunit α (NFYA) has been reported to play functional roles in a range of malignancies, while its precise mechanistic function in the context of colorectal cancerer (CRC) progression has yet to be established.</div></div><div><h3>Methods</h3><div>TIMER2, UALCAN, and Kaplan-Meier Plotter databases were leveraged to evaluate the expression of NFYA and to gauge its prognostic relevance in CRC. Determine NFYA and glutathione peroxidase 4 (GPX4) expression in cell lines (NCM460, DLD1 and HCT116) and clinical samples using Quantitative Real-time PCR (qPCR) and western immunoblotting assay. Assessment of cell viability, proliferation, and migration involved MTT, EdU staining assay, colony formation, and flow cytometry. Malondialdehyde (MDA) content and lipid reactive oxygen species (ROS) levels were assessed using specialized kits. Mitochondrial ultrastructural changes were observed using transmission electron microscopy (TEM). The transcriptional regulation of GPX4 by NFYA was investigated through Luciferase reporter assays and Chromatin Immunoprecipitation Assay (ChIP) experiments.</div></div><div><h3>Results</h3><div>Higher levels of NFYA were expressed in CRC cells and clinical samples, and the upregulation of this target was associated with a worse prognostic outcome for patients with CRC. <em>In vitro</em>,the inhibition of NFYA expression impaired CRC cell proliferative and migratory activity. NFYA was found to function in part by binding to the GPX4 promoter and activating transcription, leading to an increase in GPX4 levels and consequent reductions in lipid peroxide levels and ferroptosis. NFYA binds to the promoter region of GPX4, regulating the transcription of GPX4. In the recovery experiment, inhibition of NFYA-induced ferroptosis in cells was reversed by GPX4. Correspondingly, the ferroptosis caused by GPX4 suppression can be reversed by NFYA.</div></div><div><h3>Conclusion</h3><div>NFYA is thus a promising target for therapies aimed at treating CRC. NFYA is a key regulator of ferroptosis resistance in CRC while also providing direct mechanistic insights into the oncogenic function that this protein plays in these tumor cells. NFYA/GPX4 may be one of the underlying reasons for malignant growth of CRC cells.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"99 ","pages":"Article 103325"},"PeriodicalIF":2.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.tice.2026.103316
Ye Qiu , Zhenkun Lv , Xingying Zhu , Xiaoqian Yang , Jiaming Wan
Background
Mechanical forces play a crucial role in regulating cellular communication during tissue repair; however, it remains unclear how mechanical stimulation modulates endothelial exosome secretion and its effects on fibroblast activation.
Methods
In this study, endothelial cells were incorporated into 3D bioprinted tissue-engineered dermal constructs and cultured under static or mechanically stretched conditions. Exosomes were isolated from these cells, characterised, and applied to human dermal fibroblasts to assess their influence on proliferation, migration, and extracellular matrix formation. Data-independent acquisition proteomics was performed to analyse exosomal protein cargo and associated signalling pathways.
Results
Mechanical loading increased exosome secretion by approximately 2.5-fold without altering vesicle morphology. Functionally, mechanically stimulated exosomes enhanced fibroblast migration and type I collagen synthesis more significantly than controls. Proteomics profiling identified 4476 proteins in the exosomes, of which 677 were differentially expressed. Enrichment analysis revealed activation of the VEGF, HIF-1, Relaxin, and AGE–RAGE pathways, implicating roles in angiogenesis, metabolic regulation, and extracellular matrix remodelling.
Conclusion
These findings demonstrate that 3D mechanical stimulation not only augments the quantity of endothelial exosomes but also reshapes their molecular cargo, thereby enhancing biomechanical communication between endothelial cells and fibroblasts. Building on prior evidence that fibroblast-derived exosomes promote endothelial angiogenesis, we propose a bidirectional ‘mechanical stimulation–exosome–communication–tissue reconstruction’ loop, providing a theoretical foundation for optimising exosome-based strategies in skin tissue engineering.
{"title":"3D mechanical stimulation modulates endothelial exosomes to promote fibroblast activation","authors":"Ye Qiu , Zhenkun Lv , Xingying Zhu , Xiaoqian Yang , Jiaming Wan","doi":"10.1016/j.tice.2026.103316","DOIUrl":"10.1016/j.tice.2026.103316","url":null,"abstract":"<div><h3>Background</h3><div>Mechanical forces play a crucial role in regulating cellular communication during tissue repair; however, it remains unclear how mechanical stimulation modulates endothelial exosome secretion and its effects on fibroblast activation.</div></div><div><h3>Methods</h3><div>In this study, endothelial cells were incorporated into 3D bioprinted tissue-engineered dermal constructs and cultured under static or mechanically stretched conditions. Exosomes were isolated from these cells, characterised, and applied to human dermal fibroblasts to assess their influence on proliferation, migration, and extracellular matrix formation. Data-independent acquisition proteomics was performed to analyse exosomal protein cargo and associated signalling pathways.</div></div><div><h3>Results</h3><div>Mechanical loading increased exosome secretion by approximately 2.5-fold without altering vesicle morphology. Functionally, mechanically stimulated exosomes enhanced fibroblast migration and type I collagen synthesis more significantly than controls. Proteomics profiling identified 4476 proteins in the exosomes, of which 677 were differentially expressed. Enrichment analysis revealed activation of the VEGF, HIF-1, Relaxin, and AGE–RAGE pathways, implicating roles in angiogenesis, metabolic regulation, and extracellular matrix remodelling.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that 3D mechanical stimulation not only augments the quantity of endothelial exosomes but also reshapes their molecular cargo, thereby enhancing biomechanical communication between endothelial cells and fibroblasts. Building on prior evidence that fibroblast-derived exosomes promote endothelial angiogenesis, we propose a bidirectional ‘mechanical stimulation–exosome–communication–tissue reconstruction’ loop, providing a theoretical foundation for optimising exosome-based strategies in skin tissue engineering.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"99 ","pages":"Article 103316"},"PeriodicalIF":2.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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