Pub Date : 2024-10-11DOI: 10.1038/s12276-024-01329-5
Sungryul Park, Jin Hwa Cho, Jeong-Hoon Kim, Jung-Ae Kim
Histone lysine methylation is pivotal in shaping the epigenetic landscape and is linked to cell physiology. Coordination of the activities of multiple histone lysine methylation modifiers, namely, methyltransferases and demethylases, modulates chromatin structure and dynamically alters the epigenetic landscape, orchestrating almost all DNA-templated processes, such as transcription, DNA replication, and DNA repair. The stability of modifier proteins, which is regulated by protein degradation, is crucial for their activity. Here, we review the current knowledge of modifier-protein degradation via specific pathways and its subsequent impact on cell physiology through epigenetic changes. By summarizing the functional links between the aberrant stability of modifier proteins and human diseases and highlighting efforts to target protein stability for therapeutic purposes, we aim to promote interest in defining novel pathways that regulate the degradation of modifiers and ultimately increase the potential for the development of novel therapeutic strategies. Histone modifications, such as methylation, are key in controlling gene expression by changing the structure of chromatin, the DNA and protein mix in our cells’ nucleus. This study investigates how the stability of histone lysine methylation modifiers—enzymes that add or remove methyl groups from histones—is managed. It’s a study aimed at understanding the delicate balance of these modifiers in the cell. The researchers studied various cell processes, including the ubiquitin-proteasome system, and post-translational modifications, that affect the stability of these enzymes. The results show changing the stability of these modifiers can alter histone methylation patterns, suggesting new ways to target diseases like cancer. Researchers conclude that understanding the control of enzyme stability offers a promising path for developing therapies that can correct abnormal gene expression by targeting the enzymes responsible for histone modifications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
组蛋白赖氨酸甲基化在形成表观遗传景观方面起着关键作用，并与细胞生理有关。多种组蛋白赖氨酸甲基化修饰因子（即甲基转移酶和去甲基化酶）的活动相互协调，可调节染色质结构，动态改变表观遗传学景观，协调几乎所有由 DNA 引发的过程，如转录、DNA 复制和 DNA 修复。修饰蛋白的稳定性受蛋白降解的调控，这对其活性至关重要。在这里，我们回顾了目前关于修饰蛋白通过特定途径降解及其随后通过表观遗传变化对细胞生理产生影响的知识。通过总结修饰蛋白稳定性异常与人类疾病之间的功能性联系，并重点介绍为治疗目的而针对蛋白稳定性所做的努力，我们希望提高人们对定义调节修饰蛋白降解的新途径的兴趣，并最终提高开发新型治疗策略的潜力。
{"title":"Histone lysine methylation modifiers controlled by protein stability","authors":"Sungryul Park, Jin Hwa Cho, Jeong-Hoon Kim, Jung-Ae Kim","doi":"10.1038/s12276-024-01329-5","DOIUrl":"10.1038/s12276-024-01329-5","url":null,"abstract":"Histone lysine methylation is pivotal in shaping the epigenetic landscape and is linked to cell physiology. Coordination of the activities of multiple histone lysine methylation modifiers, namely, methyltransferases and demethylases, modulates chromatin structure and dynamically alters the epigenetic landscape, orchestrating almost all DNA-templated processes, such as transcription, DNA replication, and DNA repair. The stability of modifier proteins, which is regulated by protein degradation, is crucial for their activity. Here, we review the current knowledge of modifier-protein degradation via specific pathways and its subsequent impact on cell physiology through epigenetic changes. By summarizing the functional links between the aberrant stability of modifier proteins and human diseases and highlighting efforts to target protein stability for therapeutic purposes, we aim to promote interest in defining novel pathways that regulate the degradation of modifiers and ultimately increase the potential for the development of novel therapeutic strategies. Histone modifications, such as methylation, are key in controlling gene expression by changing the structure of chromatin, the DNA and protein mix in our cells’ nucleus. This study investigates how the stability of histone lysine methylation modifiers—enzymes that add or remove methyl groups from histones—is managed. It’s a study aimed at understanding the delicate balance of these modifiers in the cell. The researchers studied various cell processes, including the ubiquitin-proteasome system, and post-translational modifications, that affect the stability of these enzymes. The results show changing the stability of these modifiers can alter histone methylation patterns, suggesting new ways to target diseases like cancer. Researchers conclude that understanding the control of enzyme stability offers a promising path for developing therapies that can correct abnormal gene expression by targeting the enzymes responsible for histone modifications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2127-2144"},"PeriodicalIF":9.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01329-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-07DOI: 10.1038/s12276-024-01319-7
Soie Kwon, Seongmin Cheon, Kyu-Hong Kim, Areum Seo, Eunjin Bae, Jae Wook Lee, Ran-Hui Cha, Jin Ho Hwang, Yong Chul Kim, Dong Ki Kim, Yon Su Kim, Dohyun Han, Seung-Hee Yang
Chronic kidney disease (CKD) progression involves tubulointerstitial fibrosis, a process characterized by excessive extracellular matrix accumulation. To identify potential biomarkers for kidney fibrosis, we performed mass spectrometry-based proteomic profiling of human kidney tubular epithelial cells and kidney tissue from a 5/6 nephrectomy rat model. Multidisciplinary analysis across kidney fibrosis models revealed 351 differentially expressed proteins associated with kidney fibrosis, and they were enriched in processes related to the extracellular matrix, kidney aging, and mitochondrial functions. Network analysis of the selected proteins revealed five crucial proteins, of which transgelin emerged as a candidate protein that interacts with known fibrosis-related proteins. Concordantly, the gene expression of transgelin in the kidney tissue from the 5/6 nephrectomy model was elevated. Transgelin expression in kidney tissue gradually increased from intermediate to advanced fibrosis stages in 5/6 Nx rats and mice with unilateral ureteral obstruction. Subsequent validation in kidney tissue and urine samples from patients with CKD confirmed the upregulation of transgelin, particularly under advanced disease stages. Moreover, we investigated whether blocking TAGLN ameliorated kidney fibrosis and reduced reactive oxygen species levels in cellular models. In conclusion, our proteomic approach identified TAGLN as a potential noninvasive biomarker and therapeutic target for CKD-associated kidney fibrosis, suggesting its role in modulating mitochondrial dysfunction and oxidative stress responses. Chronic kidney disease is caused by kidney fibrosis, where healthy kidney tissue becomes scar, affecting kidney function. This research aimed to find noninvasive signs of kidney fibrosis by studying proteins in human kidney cells and animal CKD models. They used mass spectrometry, a method to identify and quantify proteins, to find potential signs in the body fluids that could show kidney fibrosis without needing kidney biopsy. The study found that the protein TAGLN increases in kidney tissue and urine in CKD conditions, suggesting it could be a useful sign of kidney fibrosis. Further tests showed that blocking TAGLN could reduce kidney fibrosis, indicating its potential as a target for new treatments. The researchers conclude that TAGLN is a promising sign of kidney fibrosis and could lead to better diagnostic and treatment options for CKD patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Unveiling the role of transgelin as a prognostic and therapeutic target in kidney fibrosis via a proteomic approach","authors":"Soie Kwon, Seongmin Cheon, Kyu-Hong Kim, Areum Seo, Eunjin Bae, Jae Wook Lee, Ran-Hui Cha, Jin Ho Hwang, Yong Chul Kim, Dong Ki Kim, Yon Su Kim, Dohyun Han, Seung-Hee Yang","doi":"10.1038/s12276-024-01319-7","DOIUrl":"10.1038/s12276-024-01319-7","url":null,"abstract":"Chronic kidney disease (CKD) progression involves tubulointerstitial fibrosis, a process characterized by excessive extracellular matrix accumulation. To identify potential biomarkers for kidney fibrosis, we performed mass spectrometry-based proteomic profiling of human kidney tubular epithelial cells and kidney tissue from a 5/6 nephrectomy rat model. Multidisciplinary analysis across kidney fibrosis models revealed 351 differentially expressed proteins associated with kidney fibrosis, and they were enriched in processes related to the extracellular matrix, kidney aging, and mitochondrial functions. Network analysis of the selected proteins revealed five crucial proteins, of which transgelin emerged as a candidate protein that interacts with known fibrosis-related proteins. Concordantly, the gene expression of transgelin in the kidney tissue from the 5/6 nephrectomy model was elevated. Transgelin expression in kidney tissue gradually increased from intermediate to advanced fibrosis stages in 5/6 Nx rats and mice with unilateral ureteral obstruction. Subsequent validation in kidney tissue and urine samples from patients with CKD confirmed the upregulation of transgelin, particularly under advanced disease stages. Moreover, we investigated whether blocking TAGLN ameliorated kidney fibrosis and reduced reactive oxygen species levels in cellular models. In conclusion, our proteomic approach identified TAGLN as a potential noninvasive biomarker and therapeutic target for CKD-associated kidney fibrosis, suggesting its role in modulating mitochondrial dysfunction and oxidative stress responses. Chronic kidney disease is caused by kidney fibrosis, where healthy kidney tissue becomes scar, affecting kidney function. This research aimed to find noninvasive signs of kidney fibrosis by studying proteins in human kidney cells and animal CKD models. They used mass spectrometry, a method to identify and quantify proteins, to find potential signs in the body fluids that could show kidney fibrosis without needing kidney biopsy. The study found that the protein TAGLN increases in kidney tissue and urine in CKD conditions, suggesting it could be a useful sign of kidney fibrosis. Further tests showed that blocking TAGLN could reduce kidney fibrosis, indicating its potential as a target for new treatments. The researchers conclude that TAGLN is a promising sign of kidney fibrosis and could lead to better diagnostic and treatment options for CKD patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2296-2308"},"PeriodicalIF":9.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01319-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1038/s12276-024-01328-6
Seoyeon Kim, Jihae Lee, In Gyeong Koh, Jungeun Ji, Hyun Jung Kim, Eunha Kim, Jihwan Park, Jong-Eun Park, Joon-Yong An
Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. Lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage’s influence on disease determination. Our findings facilitate unbiased comparisons of cell type‒disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders. The growth of the human brain is a complicated process that begins before birth and continues into young adulthood. Researchers focused on how genes related to brain disorders are expressed in different cells over time. They gathered data from 114 human brain samples, creating a single-cell atlas that traces brain growth from early fetal stages to adulthood. The results showed distinct patterns of gene expression linked to disorders like autism and developmental delay, especially in neurons during early growth. The study also emphasized the role of glial cells in brain conditions, such as Alzheimer’s and Parkinson’s disease, by showing specific gene expression patterns in these cells related to the disorders. Researchers conclude that their single-cell atlas greatly improves our understanding of brain growth and the molecular mechanisms behind brain disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development","authors":"Seoyeon Kim, Jihae Lee, In Gyeong Koh, Jungeun Ji, Hyun Jung Kim, Eunha Kim, Jihwan Park, Jong-Eun Park, Joon-Yong An","doi":"10.1038/s12276-024-01328-6","DOIUrl":"10.1038/s12276-024-01328-6","url":null,"abstract":"Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. Lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage’s influence on disease determination. Our findings facilitate unbiased comparisons of cell type‒disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders. The growth of the human brain is a complicated process that begins before birth and continues into young adulthood. Researchers focused on how genes related to brain disorders are expressed in different cells over time. They gathered data from 114 human brain samples, creating a single-cell atlas that traces brain growth from early fetal stages to adulthood. The results showed distinct patterns of gene expression linked to disorders like autism and developmental delay, especially in neurons during early growth. The study also emphasized the role of glial cells in brain conditions, such as Alzheimer’s and Parkinson’s disease, by showing specific gene expression patterns in these cells related to the disorders. Researchers conclude that their single-cell atlas greatly improves our understanding of brain growth and the molecular mechanisms behind brain disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2271-2282"},"PeriodicalIF":9.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01328-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N6-methyladenosine (m6A) modification is one of the most prevalent forms of epigenetic modification and plays an important role in the development of degenerative diseases such as osteoarthritis (OA). However, the evidence concerning the role of m6A modification in OA is insufficient. Here, m6A modification was increased in human OA cartilage and degenerated chondrocytes. Among all of the m6A enzymes, the expression of the demethylase fat mass and obesity-associated protein (FTO) decreased dramatically. Conditional knockout of FTO in chondrocytes accelerates OA progression. FTO transcription is regulated by runt-related transcription factor-1 (RUNX1). Reduced FTO elevates m6A modification at the adenosine N6 position in SMAD family member 2 (SMAD2) mRNA, whose stability is subsequently modulated by the recruited m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2). Collectively, these findings reveal the function and mechanism of the m6A family member FTO in OA progression. Therefore, reducing m6A modification to increase SMAD2 stability by activating FTO might be a potential therapeutic strategy for OA treatment. Osteoarthritis is a widespread joint disease-causing pain and disability. It involves the deterioration of joint cartilage and bone, but the exact reasons are unclear. This study aimed to investigate the role of a specific change in RNA molecules, called N6-methyladenosine, in OA development. The researchers focused on the enzyme FTO, which can remove this change, and its effect on cartilage cells in mice. They used different methods, including genetic modification to create mice lacking FTO in their cartilage cells, to see how changes in m6A levels affect OA progression. The main findings show that reducing FTO expression worsens OA progression by affecting the stability and function of specific RNA molecules in cartilage cells. The researchers conclude that targeting the m6A change pathway, especially by modulating FTO activity, could provide new treatment strategies for OA. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
N6-甲基腺苷（m6A）修饰是最常见的表观遗传修饰形式之一，在骨关节炎（OA）等退行性疾病的发展过程中发挥着重要作用。然而，有关m6A修饰在OA中作用的证据尚不充分。在这里，m6A修饰在人类OA软骨和退化软骨细胞中有所增加。在所有的m6A酶中，去甲基化酶脂肪量和肥胖相关蛋白（FTO）的表达急剧下降。在软骨细胞中条件性敲除 FTO 会加速 OA 的发展。FTO 的转录受 RUNT 相关转录因子-1（RUNX1）的调控。FTO的减少会使SMAD家族成员2（SMAD2）mRNA中腺苷N6位的m6A修饰升高，其稳定性随后会受到m6A阅读蛋白YTH N6-甲基腺苷RNA结合蛋白F2（YTHDF2）的调控。这些发现共同揭示了 m6A 家族成员 FTO 在 OA 进展中的功能和机制。因此，通过激活 FTO 减少 m6A 修饰以增加 SMAD2 的稳定性可能是治疗 OA 的一种潜在治疗策略。
{"title":"FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis","authors":"Hongyi Zhou, Ziang Xie, Yu Qian, Weiyu Ni, Lei Cui, Xiangqian Fang, Shuanglin Wan, Xiangde Zhao, An Qin, Shunwu Fan, Yizheng Wu","doi":"10.1038/s12276-024-01330-y","DOIUrl":"10.1038/s12276-024-01330-y","url":null,"abstract":"N6-methyladenosine (m6A) modification is one of the most prevalent forms of epigenetic modification and plays an important role in the development of degenerative diseases such as osteoarthritis (OA). However, the evidence concerning the role of m6A modification in OA is insufficient. Here, m6A modification was increased in human OA cartilage and degenerated chondrocytes. Among all of the m6A enzymes, the expression of the demethylase fat mass and obesity-associated protein (FTO) decreased dramatically. Conditional knockout of FTO in chondrocytes accelerates OA progression. FTO transcription is regulated by runt-related transcription factor-1 (RUNX1). Reduced FTO elevates m6A modification at the adenosine N6 position in SMAD family member 2 (SMAD2) mRNA, whose stability is subsequently modulated by the recruited m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2). Collectively, these findings reveal the function and mechanism of the m6A family member FTO in OA progression. Therefore, reducing m6A modification to increase SMAD2 stability by activating FTO might be a potential therapeutic strategy for OA treatment. Osteoarthritis is a widespread joint disease-causing pain and disability. It involves the deterioration of joint cartilage and bone, but the exact reasons are unclear. This study aimed to investigate the role of a specific change in RNA molecules, called N6-methyladenosine, in OA development. The researchers focused on the enzyme FTO, which can remove this change, and its effect on cartilage cells in mice. They used different methods, including genetic modification to create mice lacking FTO in their cartilage cells, to see how changes in m6A levels affect OA progression. The main findings show that reducing FTO expression worsens OA progression by affecting the stability and function of specific RNA molecules in cartilage cells. The researchers conclude that targeting the m6A change pathway, especially by modulating FTO activity, could provide new treatment strategies for OA. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2283-2295"},"PeriodicalIF":9.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01330-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01318-8
Sarita Saraswati, Paula Martínez, Rosa Serrano, Diego Mejías, Osvaldo Graña-Castro, Ruth Álvarez Díaz, Maria A. Blasco
Tubulointerstitial fibrosis associated with chronic kidney disease (CKD) represents a global health care problem. We previously reported that short and dysfunctional telomeres lead to interstitial renal fibrosis; however, the cell-of-origin of kidney fibrosis associated with telomere dysfunction is currently unknown. We induced telomere dysfunction by deleting the Trf1 gene encoding a telomere-binding factor specifically in renal fibroblasts in both short-term and long-term life-long experiments in mice to identify the role of fibroblasts in renal fibrosis. Short-term Trf1 deletion in renal fibroblasts was not sufficient to trigger kidney fibrosis but was sufficient to induce inflammatory responses, ECM deposition, cell cycle arrest, fibrogenesis, and vascular rarefaction. However, long-term persistent deletion of Trf1 in fibroblasts resulted in kidney fibrosis accompanied by an elevated urinary albumin-to-creatinine ratio (uACR) and a decrease in mouse survival. These cellular responses lead to the macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndMT), and partial epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at the humane endpoint (HEP) when the deletion of Trf1 in fibroblasts is maintained throughout the lifespan of mice. Our findings contribute to a better understanding of the role of dysfunctional telomeres in the onset of the profibrotic alterations that lead to kidney fibrosis. Chronic kidney disease, a condition that can lead to kidney failure and death, affects millions worldwide. It’s characterized by kidney fibrosis, a process where healthy kidney tissue becomes scar tissue. The exact cells that start this process were unknown. Researchers studied the role of a protein called TRF1, which protects the ends of chromosomes, in kidney fibroblasts, cells that make connective tissue. They removed TRF1 from these cells in mice and observed the effects. Results showed that removing TRF1 from fibroblasts increased fibrosis, inflammation, and kidney damage. Specifically, fibroblasts without TRF1 were more likely to change into myofibroblasts, leading to more scar tissue. Study concluded that TRF1 is vital in preventing kidney fibrosis by keeping fibroblasts healthy. This finding improves our understanding of CKD and suggests potential treatments targeting fibroblasts and TRF1 to fight kidney fibrosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres","authors":"Sarita Saraswati, Paula Martínez, Rosa Serrano, Diego Mejías, Osvaldo Graña-Castro, Ruth Álvarez Díaz, Maria A. Blasco","doi":"10.1038/s12276-024-01318-8","DOIUrl":"10.1038/s12276-024-01318-8","url":null,"abstract":"Tubulointerstitial fibrosis associated with chronic kidney disease (CKD) represents a global health care problem. We previously reported that short and dysfunctional telomeres lead to interstitial renal fibrosis; however, the cell-of-origin of kidney fibrosis associated with telomere dysfunction is currently unknown. We induced telomere dysfunction by deleting the Trf1 gene encoding a telomere-binding factor specifically in renal fibroblasts in both short-term and long-term life-long experiments in mice to identify the role of fibroblasts in renal fibrosis. Short-term Trf1 deletion in renal fibroblasts was not sufficient to trigger kidney fibrosis but was sufficient to induce inflammatory responses, ECM deposition, cell cycle arrest, fibrogenesis, and vascular rarefaction. However, long-term persistent deletion of Trf1 in fibroblasts resulted in kidney fibrosis accompanied by an elevated urinary albumin-to-creatinine ratio (uACR) and a decrease in mouse survival. These cellular responses lead to the macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndMT), and partial epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at the humane endpoint (HEP) when the deletion of Trf1 in fibroblasts is maintained throughout the lifespan of mice. Our findings contribute to a better understanding of the role of dysfunctional telomeres in the onset of the profibrotic alterations that lead to kidney fibrosis. Chronic kidney disease, a condition that can lead to kidney failure and death, affects millions worldwide. It’s characterized by kidney fibrosis, a process where healthy kidney tissue becomes scar tissue. The exact cells that start this process were unknown. Researchers studied the role of a protein called TRF1, which protects the ends of chromosomes, in kidney fibroblasts, cells that make connective tissue. They removed TRF1 from these cells in mice and observed the effects. Results showed that removing TRF1 from fibroblasts increased fibrosis, inflammation, and kidney damage. Specifically, fibroblasts without TRF1 were more likely to change into myofibroblasts, leading to more scar tissue. Study concluded that TRF1 is vital in preventing kidney fibrosis by keeping fibroblasts healthy. This finding improves our understanding of CKD and suggests potential treatments targeting fibroblasts and TRF1 to fight kidney fibrosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2216-2230"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01318-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01317-9
Yunju Jo, Hye-In Sim, Bohwan Yun, Yoon Park, Hyung-seung Jin
Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy. Immunotherapy, including immune checkpoint inhibitors and adoptive T-cell therapy, has transformed cancer treatment, yet durable responses are limited to a minority of patients. Anticancer immunity, shaped by co-inhibitory and co-stimulatory signals in tumor-infiltrating immune cells, underscores co-stimulatory receptors as promising targets for immunotherapy. This review explores the roles of CD226 and CD2 in regulating T cell responses, particularly in tumor immunity. CD2 and CD226, primarily on T and NK cells, are crucial for cell adhesion and recognition, known for their role in overcoming T cell exhaustion and boosting anti-tumor responses. The review examines their potential as targets in novel cancer immunotherapeutic strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
癌症免疫疗法旨在启动或扩大免疫反应，从而消灭癌细胞并形成免疫记忆以防止复发。免疫检查点抑制剂（ICIs）靶向免疫效应细胞上的共抑制受体，如 CTLA-4 和 PD-(L)1，在癌症治疗方面取得了重大进展。然而，它们在实现广泛而持久的反应方面仍面临挑战。抗癌免疫的有效性是由肿瘤浸润免疫细胞中的共抑制信号和成本刺激信号的相互作用决定的，这凸显了成本刺激受体作为免疫疗法关键靶点的潜力。这篇综述探讨了我们目前对 CD2 和 CD226 功能的理解，特别强调了它们作为癌症免疫疗法新型激动剂靶点的潜力。CD2 和 CD226 主要存在于 T 细胞和 NK 细胞中，在细胞粘附和识别中发挥着重要功能。这些分子目前已被公认具有成本刺激作用，特别是在克服 T 细胞衰竭和增强抗肿瘤反应方面。CD226 和 CD2-CD58 轴在克服 ICI 或嵌合抗原受体 (CAR) T 细胞疗法的抗药性方面的重要性，尤其是在抗 TIGIT 疗法中的重要性，为超越目前癌症免疫疗法的障碍提供了宝贵的见解，突显了它们作为新型激动剂疗法靶点的前景。
{"title":"Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2","authors":"Yunju Jo, Hye-In Sim, Bohwan Yun, Yoon Park, Hyung-seung Jin","doi":"10.1038/s12276-024-01317-9","DOIUrl":"10.1038/s12276-024-01317-9","url":null,"abstract":"Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy. Immunotherapy, including immune checkpoint inhibitors and adoptive T-cell therapy, has transformed cancer treatment, yet durable responses are limited to a minority of patients. Anticancer immunity, shaped by co-inhibitory and co-stimulatory signals in tumor-infiltrating immune cells, underscores co-stimulatory receptors as promising targets for immunotherapy. This review explores the roles of CD226 and CD2 in regulating T cell responses, particularly in tumor immunity. CD2 and CD226, primarily on T and NK cells, are crucial for cell adhesion and recognition, known for their role in overcoming T cell exhaustion and boosting anti-tumor responses. The review examines their potential as targets in novel cancer immunotherapeutic strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2113-2126"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01317-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01315-x
Ding Zhou, Jia-Ming Tian, Zi Li, Jun Huang
Brominated domain protein 4 (BRD4) is a chromatin reader known to exacerbate the inflammatory response in post-traumatic osteoarthritis (PTOA) by controlling the expression of inflammatory cytokines. However, the extent to which this regulatory effect is altered after BRD4 translation remains largely unknown. In this study, we showed that the E3 SUMO protein ligase CBX4 (Cbx4) is involved in the SUMO modification of BRD4 to affect its ability to control the expression of the proinflammatory genes IL-1β, TNF-α, and IL-6 in synovial fibroblasts. Specifically, Cbx4-mediated SUMOylation of K1111 lysine residues prevents the degradation of BRD4, thereby activating the transcriptional activities of the IL-1β, TNF-α and IL-6 genes, which depend on BRD4. SUMOylated BRD4 also recruits the multifunctional methyltransferase subunit TRM112-like protein (TRMT112) to further promote the processing of proinflammatory gene transcripts to eventually increase their expression. In vivo, treatment of PTOA with a Cbx4 inhibitor in rats was comparable to treatment with BRD4 inhibitors, indicating the importance of SUMOylation in controlling BRD4 to alleviate PTOA. Overall, this study is the first to identify Cbx4 as the enzyme responsible for the SUMO modification of BRD4 and highlights the central role of the Cbx4-BRD4 axis in exacerbating PTOA from the perspective of inflammation. In research on post-traumatic osteoarthritis, scientists found a lack of knowledge on how inflammation worsens the disease. Researchers found that the protein BRD4, when altered by a process called SUMOylation, is crucial in causing inflammation in PTOA. The study used human tissue and rats to see how blocking BRD4 and a related protein, Cbx4, affects inflammation and disease development. The study involved 45 rats and examined how these proteins contribute to PTOA, using various techniques to understand their roles in inflammation. The findings showed that blocking BRD4 and Cbx4 lessened inflammation and joint damage in rats with PTOA. Specifically, treatments targeting these proteins lowered inflammation markers and improved joint health. The team concluded that the BRD4-Cbx4 interaction is a major factor in PTOA inflammation and progression, marking a significant step in understanding the disease’s molecular workings. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Cbx4 SUMOylates BRD4 to regulate the expression of inflammatory cytokines in post-traumatic osteoarthritis","authors":"Ding Zhou, Jia-Ming Tian, Zi Li, Jun Huang","doi":"10.1038/s12276-024-01315-x","DOIUrl":"10.1038/s12276-024-01315-x","url":null,"abstract":"Brominated domain protein 4 (BRD4) is a chromatin reader known to exacerbate the inflammatory response in post-traumatic osteoarthritis (PTOA) by controlling the expression of inflammatory cytokines. However, the extent to which this regulatory effect is altered after BRD4 translation remains largely unknown. In this study, we showed that the E3 SUMO protein ligase CBX4 (Cbx4) is involved in the SUMO modification of BRD4 to affect its ability to control the expression of the proinflammatory genes IL-1β, TNF-α, and IL-6 in synovial fibroblasts. Specifically, Cbx4-mediated SUMOylation of K1111 lysine residues prevents the degradation of BRD4, thereby activating the transcriptional activities of the IL-1β, TNF-α and IL-6 genes, which depend on BRD4. SUMOylated BRD4 also recruits the multifunctional methyltransferase subunit TRM112-like protein (TRMT112) to further promote the processing of proinflammatory gene transcripts to eventually increase their expression. In vivo, treatment of PTOA with a Cbx4 inhibitor in rats was comparable to treatment with BRD4 inhibitors, indicating the importance of SUMOylation in controlling BRD4 to alleviate PTOA. Overall, this study is the first to identify Cbx4 as the enzyme responsible for the SUMO modification of BRD4 and highlights the central role of the Cbx4-BRD4 axis in exacerbating PTOA from the perspective of inflammation. In research on post-traumatic osteoarthritis, scientists found a lack of knowledge on how inflammation worsens the disease. Researchers found that the protein BRD4, when altered by a process called SUMOylation, is crucial in causing inflammation in PTOA. The study used human tissue and rats to see how blocking BRD4 and a related protein, Cbx4, affects inflammation and disease development. The study involved 45 rats and examined how these proteins contribute to PTOA, using various techniques to understand their roles in inflammation. The findings showed that blocking BRD4 and Cbx4 lessened inflammation and joint damage in rats with PTOA. Specifically, treatments targeting these proteins lowered inflammation markers and improved joint health. The team concluded that the BRD4-Cbx4 interaction is a major factor in PTOA inflammation and progression, marking a significant step in understanding the disease’s molecular workings. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2184-2201"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01315-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01316-w
Daehee Hwang, Seonguk Baek, Jeeyoon Chang, Taejun Seol, Bomin Ku, Hongseok Ha, Hyeonji Lee, Suhyeon Cho, Tae-Young Roh, Yoon Ki Kim, Dae-Sik Lim
Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies. This research investigates how cells manage their size and proliferation by coordinating two signaling pathways, Hippo and mTOR. As these pathways are fundamental for normal development, their dysregulation results in numerous diseases, including many cancers. In particular, the study aims to understand how YAP and TAZ—effectors of the Hippo pathway—influence mTOR-mediated protein synthesis in cells, a previously unclear process. Surprisingly, our findings show that YAP and TAZ can maintain active protein synthesis even when cells are deprived of nutrients in both cultured cells and mice. Since self-sufficiency in growth signals is a key hallmark of cancer, targeting this axis could serve as a novel and effective therapeutic strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"YAP promotes global mRNA translation to fuel oncogenic growth despite starvation","authors":"Daehee Hwang, Seonguk Baek, Jeeyoon Chang, Taejun Seol, Bomin Ku, Hongseok Ha, Hyeonji Lee, Suhyeon Cho, Tae-Young Roh, Yoon Ki Kim, Dae-Sik Lim","doi":"10.1038/s12276-024-01316-w","DOIUrl":"10.1038/s12276-024-01316-w","url":null,"abstract":"Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies. This research investigates how cells manage their size and proliferation by coordinating two signaling pathways, Hippo and mTOR. As these pathways are fundamental for normal development, their dysregulation results in numerous diseases, including many cancers. In particular, the study aims to understand how YAP and TAZ—effectors of the Hippo pathway—influence mTOR-mediated protein synthesis in cells, a previously unclear process. Surprisingly, our findings show that YAP and TAZ can maintain active protein synthesis even when cells are deprived of nutrients in both cultured cells and mice. Since self-sufficiency in growth signals is a key hallmark of cancer, targeting this axis could serve as a novel and effective therapeutic strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2202-2215"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01316-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01321-z
Seongmin Jun, Myeong-Hwa Song, Seung-Cheol Choi, Ji-Min Noh, Kyung Seob Kim, Jae Hyoung Park, Da Eun Yoon, Kyoungmi Kim, Minseok Kim, Sun Wook Hwang, Do-Sun Lim
Direct cardiac reprogramming represents a novel therapeutic strategy to convert non-cardiac cells such as fibroblasts into cardiomyocytes (CMs). This process involves essential transcription factors, such as Mef2c, Gata4, Tbx5 (MGT), MESP1, and MYOCD (MGTMM). However, the small molecules responsible for inducing immature induced CMs (iCMs) and the signaling mechanisms driving their maturation remain elusive. Our study explored the effects of various small molecules on iCM induction and discovered that the combination of FGF4 and ascorbic acid (FA) enhances CM markers, exhibits organized sarcomere and T-tubule structures, and improves cardiac function. Transcriptome analysis emphasized the importance of ECM-integrin-focal adhesions and the upregulation of the JAK2–STAT3 and TGFB signaling pathways in FA-treated iCMs. Notably, JAK2–STAT3 knockdown affected TGFB signaling and the ECM and downregulated mature CM markers in FA-treated iCMs. Our findings underscore the critical role of the JAK2–STAT3 signaling pathway in activating TGFB signaling and ECM synthesis in directly reprogrammed CMs. Cardiovascular diseases are a major global cause of death, often due to the loss of cardiomyocytes and increased heart scarring. Existing treatments, like medication and heart transplants, have limitations, emphasizing the need for new cell regeneration therapies. This study investigates direct cardiac reprogramming—a new method to regenerate heart muscle cells by transforming fibroblasts into induced cardiomyocytes using specific factors and small molecules. The team tested various small molecules and found that a mix of FGF4 and ascorbic acid significantly improves the maturation of iCMs. They used techniques like immunofluorescence staining, flow cytometry, and electrophysiological analysis to evaluate the conversion and maturation of iCMs. This study shows that direct cardiac reprogramming can be enhanced with the right combination of small molecules, providing a promising strategy for heart regeneration. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
直接心脏重编程是将成纤维细胞等非心脏细胞转化为心肌细胞（CM）的一种新型治疗策略。这一过程涉及重要的转录因子，如 Mef2c、Gata4、Tbx5 (MGT)、MESP1 和 MYOCD (MGTMM)。然而，负责诱导未成熟诱导型 CMs（iCMs）的小分子和驱动其成熟的信号机制仍未确定。我们的研究探索了各种小分子对 iCM 诱导的影响，发现 FGF4 和抗坏血酸（FA）的组合能增强 CM 标记，显示有组织的肌节和 T 管结构，并改善心脏功能。转录组分析强调了ECM-整合素-局灶粘附的重要性，以及JAK2-STAT3和TGFB信号通路在FA处理的iCM中的上调。值得注意的是，敲除 JAK2-STAT3 会影响 TGFB 信号传导和 ECM，并下调 FA 处理的 iCM 中的成熟 CM 标记。我们的发现强调了 JAK2-STAT3 信号通路在激活直接重编程 CM 的 TGFB 信号和 ECM 合成中的关键作用。示意图显示 FA 可增强心脏直接重编程和心肌细胞成熟所依赖的 JAK-STAT3 信号通路。
{"title":"FGF4 and ascorbic acid enhance the maturation of induced cardiomyocytes by activating JAK2–STAT3 signaling","authors":"Seongmin Jun, Myeong-Hwa Song, Seung-Cheol Choi, Ji-Min Noh, Kyung Seob Kim, Jae Hyoung Park, Da Eun Yoon, Kyoungmi Kim, Minseok Kim, Sun Wook Hwang, Do-Sun Lim","doi":"10.1038/s12276-024-01321-z","DOIUrl":"10.1038/s12276-024-01321-z","url":null,"abstract":"Direct cardiac reprogramming represents a novel therapeutic strategy to convert non-cardiac cells such as fibroblasts into cardiomyocytes (CMs). This process involves essential transcription factors, such as Mef2c, Gata4, Tbx5 (MGT), MESP1, and MYOCD (MGTMM). However, the small molecules responsible for inducing immature induced CMs (iCMs) and the signaling mechanisms driving their maturation remain elusive. Our study explored the effects of various small molecules on iCM induction and discovered that the combination of FGF4 and ascorbic acid (FA) enhances CM markers, exhibits organized sarcomere and T-tubule structures, and improves cardiac function. Transcriptome analysis emphasized the importance of ECM-integrin-focal adhesions and the upregulation of the JAK2–STAT3 and TGFB signaling pathways in FA-treated iCMs. Notably, JAK2–STAT3 knockdown affected TGFB signaling and the ECM and downregulated mature CM markers in FA-treated iCMs. Our findings underscore the critical role of the JAK2–STAT3 signaling pathway in activating TGFB signaling and ECM synthesis in directly reprogrammed CMs. Cardiovascular diseases are a major global cause of death, often due to the loss of cardiomyocytes and increased heart scarring. Existing treatments, like medication and heart transplants, have limitations, emphasizing the need for new cell regeneration therapies. This study investigates direct cardiac reprogramming—a new method to regenerate heart muscle cells by transforming fibroblasts into induced cardiomyocytes using specific factors and small molecules. The team tested various small molecules and found that a mix of FGF4 and ascorbic acid significantly improves the maturation of iCMs. They used techniques like immunofluorescence staining, flow cytometry, and electrophysiological analysis to evaluate the conversion and maturation of iCMs. This study shows that direct cardiac reprogramming can be enhanced with the right combination of small molecules, providing a promising strategy for heart regeneration. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2231-2245"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01321-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s12276-024-01313-z
Sang Hun Lee, David L. Sacks
The skin serves as a complex barrier organ populated by tissue-resident macrophages (TRMs), which play critical roles in defense, homeostasis, and tissue repair. This review examines the functions of dermis resident TRMs in different inflammatory settings, their embryonic origins, and their long-term self-renewal capabilities. We highlight the M2-like phenotype of dermal TRMs and their specialized functions in perivascular and perineuronal niches. Their interactions with type 2 immune cells, autocrine cytokines such as IL-10, and their phagocytic clearance of apoptotic cells have been explored as mechanisms for M2-like dermal TRM self-maintenance and function. In conclusion, we address the need to bridge murine models with human studies, with the possibility of targeting TRMs to promote skin immunity or restrain cutaneous pathology. Our skin is more than just a physical shield; it’s a complex immune organ, filled with specialized cells like macrophages. In a detailed review, researchers explore these macrophages, focusing on their adaptability and function maintenance in the skin. This study synthesizes findings how macrophages interact with other immune cells, respond to inflammatory triggers, and contribute to tissue repair and homeostasis. The findings show that these macrophages can remain anti-inflammatory, even when faced with infections that usually trigger a strong immune response. They achieve this through various mechanisms, including interactions with specific immune cells that support their anti-inflammatory state, and engaging in processes that promote tissue repair without increasing inflammation. The researchers conclude that understanding these mechanisms opens new possibilities for treating skin diseases by targeting or mimicking the ways these macrophages control inflammation and support healing. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Resilience of dermis resident macrophages to inflammatory challenges","authors":"Sang Hun Lee, David L. Sacks","doi":"10.1038/s12276-024-01313-z","DOIUrl":"10.1038/s12276-024-01313-z","url":null,"abstract":"The skin serves as a complex barrier organ populated by tissue-resident macrophages (TRMs), which play critical roles in defense, homeostasis, and tissue repair. This review examines the functions of dermis resident TRMs in different inflammatory settings, their embryonic origins, and their long-term self-renewal capabilities. We highlight the M2-like phenotype of dermal TRMs and their specialized functions in perivascular and perineuronal niches. Their interactions with type 2 immune cells, autocrine cytokines such as IL-10, and their phagocytic clearance of apoptotic cells have been explored as mechanisms for M2-like dermal TRM self-maintenance and function. In conclusion, we address the need to bridge murine models with human studies, with the possibility of targeting TRMs to promote skin immunity or restrain cutaneous pathology. Our skin is more than just a physical shield; it’s a complex immune organ, filled with specialized cells like macrophages. In a detailed review, researchers explore these macrophages, focusing on their adaptability and function maintenance in the skin. This study synthesizes findings how macrophages interact with other immune cells, respond to inflammatory triggers, and contribute to tissue repair and homeostasis. The findings show that these macrophages can remain anti-inflammatory, even when faced with infections that usually trigger a strong immune response. They achieve this through various mechanisms, including interactions with specific immune cells that support their anti-inflammatory state, and engaging in processes that promote tissue repair without increasing inflammation. The researchers conclude that understanding these mechanisms opens new possibilities for treating skin diseases by targeting or mimicking the ways these macrophages control inflammation and support healing. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2105-2112"},"PeriodicalIF":9.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01313-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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