Pub Date : 2024-11-01DOI: 10.1038/s12276-024-01338-4
Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh, Kyung Ah Kim, Ji-Hyun Ma, John Hoon Rim, Jung Ah Kim, Se Jin Kim, Seung Hyun Jang, Young Ik Koh, Hye-Youn Kim, Ho Lee, Byoung Choul Kim, Heon Yung Gee, Jinwoong Bok, Jae Young Choi, Je Kyung Seong
Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans. Hearing loss is a major health problem affecting many people globally, with a large part due to genes. Researchers studied the MYH1 gene, which was previously associated with hearing in mice but not in humans. The team studied the hearing in mice without the MYH1 gene and looked at genetic data from people with hearing loss. They found mice without the MYH1 gene had hearing problems and impaired hair cell function. They also found several people with changes in the MYH1 gene, providing the first proof of its role in human hearing loss. Research shows how changes in MYH1 affect the function of cells in the inner ear, causing hearing problems in both mice and humans. They hope their work will lead to improved diagnostic tools and treatments for hearing loss. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss","authors":"Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh, Kyung Ah Kim, Ji-Hyun Ma, John Hoon Rim, Jung Ah Kim, Se Jin Kim, Seung Hyun Jang, Young Ik Koh, Hye-Youn Kim, Ho Lee, Byoung Choul Kim, Heon Yung Gee, Jinwoong Bok, Jae Young Choi, Je Kyung Seong","doi":"10.1038/s12276-024-01338-4","DOIUrl":"10.1038/s12276-024-01338-4","url":null,"abstract":"Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans. Hearing loss is a major health problem affecting many people globally, with a large part due to genes. Researchers studied the MYH1 gene, which was previously associated with hearing in mice but not in humans. The team studied the hearing in mice without the MYH1 gene and looked at genetic data from people with hearing loss. They found mice without the MYH1 gene had hearing problems and impaired hair cell function. They also found several people with changes in the MYH1 gene, providing the first proof of its role in human hearing loss. Research shows how changes in MYH1 affect the function of cells in the inner ear, causing hearing problems in both mice and humans. They hope their work will lead to improved diagnostic tools and treatments for hearing loss. 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 11","pages":"2423-2435"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01338-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559286","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 : 2024-11-01DOI: 10.1038/s12276-024-01342-8
Eun Jin Go, Sung-Min Hwang, Hyunjung Jo, Md. Mahbubur Rahman, Jaeik Park, Ji Yeon Lee, Youn Yi Jo, Byung-Gil Lee, YunJae Jung, Temugin Berta, Yong Ho Kim, Chul-Kyu Park
Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9–39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9–39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9–39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund’s adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9–39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9–39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9–39 fragments, exendin 20–29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20–29 as a promising therapeutic candidate. People often consume more sweet and fatty foods when they’re hurting, a pattern observed in both humans and animals. This research investigates how eating can lessen pain, focusing on a hormone named glucagon-like peptide-1 (GLP-1), which is created in the stomach after eating. Researchers carried out tests on mice, using different techniques to see how GLP-1 and its byproducts influence pain perception through their impact on a specific pain receptor located in sensory nerves. The main discovery is that GLP-1 and its byproducts provide a potential new technique for pain relief by directly inhibiting the TRPV1 receptor, which could result in new pain management strategies without the negative effects linked with current treatments. The scientists conclude that targeting the GLP-1 pathway could be a promising approach to developing safer pain medications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation","authors":"Eun Jin Go, Sung-Min Hwang, Hyunjung Jo, Md. Mahbubur Rahman, Jaeik Park, Ji Yeon Lee, Youn Yi Jo, Byung-Gil Lee, YunJae Jung, Temugin Berta, Yong Ho Kim, Chul-Kyu Park","doi":"10.1038/s12276-024-01342-8","DOIUrl":"10.1038/s12276-024-01342-8","url":null,"abstract":"Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9–39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9–39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9–39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund’s adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9–39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9–39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9–39 fragments, exendin 20–29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20–29 as a promising therapeutic candidate. People often consume more sweet and fatty foods when they’re hurting, a pattern observed in both humans and animals. This research investigates how eating can lessen pain, focusing on a hormone named glucagon-like peptide-1 (GLP-1), which is created in the stomach after eating. Researchers carried out tests on mice, using different techniques to see how GLP-1 and its byproducts influence pain perception through their impact on a specific pain receptor located in sensory nerves. The main discovery is that GLP-1 and its byproducts provide a potential new technique for pain relief by directly inhibiting the TRPV1 receptor, which could result in new pain management strategies without the negative effects linked with current treatments. The scientists conclude that targeting the GLP-1 pathway could be a promising approach to developing safer pain medications. 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 11","pages":"2449-2464"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01342-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559283","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 : 2024-11-01DOI: 10.1038/s12276-024-01334-8
Yun-Jeong Kim, Byunghee Kang, Solbi Kweon, Sejin Oh, Dayeon Kim, Dayeon Gil, Hyeonji Lee, Jung-Hyun Kim, Ji Hyeon Ju, Tae-Young Roh, Chang Pyo Hong, Hyuk-Jin Cha
Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus. Human pluripotent stem cells (hPSCs) hold significant potential in regenerative medicine due to their ability to produce all types of cells. This study examines how genetic changes in hPSCs impact their stability and safety. Researchers used a set of identical human embryonic stem cells, grown for up to six years, and analyzed them using whole genome sequencing and single-cell sequencing techniques. The study found that certain genetic aberrations, especially mutations in the TP53 gene and a recurrent gain at 20q11.21, become more frequent as hPSCs are grown longer. These findings emphasize that TP53 mutations and 20q11.21 gains can alter the biological characteristics of hPSCs, affecting their safety more than the number of times the cells have been replicated. Understanding these changes is important for establishing guidelines to ensure the safety of stem cell therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Longitudinal analysis of genetic and epigenetic changes in human pluripotent stem cells in the landscape of culture-induced abnormality","authors":"Yun-Jeong Kim, Byunghee Kang, Solbi Kweon, Sejin Oh, Dayeon Kim, Dayeon Gil, Hyeonji Lee, Jung-Hyun Kim, Ji Hyeon Ju, Tae-Young Roh, Chang Pyo Hong, Hyuk-Jin Cha","doi":"10.1038/s12276-024-01334-8","DOIUrl":"10.1038/s12276-024-01334-8","url":null,"abstract":"Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus. Human pluripotent stem cells (hPSCs) hold significant potential in regenerative medicine due to their ability to produce all types of cells. This study examines how genetic changes in hPSCs impact their stability and safety. Researchers used a set of identical human embryonic stem cells, grown for up to six years, and analyzed them using whole genome sequencing and single-cell sequencing techniques. The study found that certain genetic aberrations, especially mutations in the TP53 gene and a recurrent gain at 20q11.21, become more frequent as hPSCs are grown longer. These findings emphasize that TP53 mutations and 20q11.21 gains can alter the biological characteristics of hPSCs, affecting their safety more than the number of times the cells have been replicated. Understanding these changes is important for establishing guidelines to ensure the safety of stem cell therapy. 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 11","pages":"2409-2422"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01334-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559285","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 : 2024-11-01DOI: 10.1038/s12276-024-01326-8
Tae-Su Han, Dae-Soo Kim, Mi-Young Son, Hyun-Soo Cho
Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy. Understanding cancer growth and spread is vital for creating new treatments. Histone methyltransferases play a key role in cancer by controlling genes that can either encourage or inhibit tumor growth. This review focuses on the SMYD family of HMTs, which are associated with cancer progression, spread, and resistance to chemotherapy. The researchers studied the structure, function, and effects of different SMYD family members on cancer, using clinical data and biological experiments. The review also explores how these enzymes can be targeted by specific inhibitors, potentially offering new cancer treatments. The findings suggest that targeting SMYD family members, especially SMYD2 and SMYD3, could be an effective cancer treatment strategy. By developing drugs that specifically inhibit SMYD2 and SMYD3, researchers hope to provide new, more effective treatments for cancer patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
表观遗传修饰因子（miRNA、组蛋白甲基转移酶（HMT）/脱甲基酶和 DNA 甲基转移酶/脱甲基酶）与癌症的增殖、转移、血管生成和耐药性有关。在这些修饰因子中，HMTs 经常在各种癌症中过表达，最近的研究越来越多地发现这些蛋白是潜在的治疗靶点。在这篇综述中，我们将讨论 SET 和含 MYND 结构域蛋白（SMYD）家族的成员，它们是癌症相关基因组蛋白甲基化和非组蛋白甲基化广泛研究的主题。SMYD 家族的各种成员通过调节癌症特异性组蛋白甲基化和非组蛋白甲基化，在癌症增殖、转移和耐药性方面发挥着重要作用。因此，开发针对 SMYD 家族成员的特异性抑制剂可能会促进癌症治疗方法的开发，而与各种抗癌治疗药物的联合治疗可能会提高疗效。
{"title":"SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance","authors":"Tae-Su Han, Dae-Soo Kim, Mi-Young Son, Hyun-Soo Cho","doi":"10.1038/s12276-024-01326-8","DOIUrl":"10.1038/s12276-024-01326-8","url":null,"abstract":"Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy. Understanding cancer growth and spread is vital for creating new treatments. Histone methyltransferases play a key role in cancer by controlling genes that can either encourage or inhibit tumor growth. This review focuses on the SMYD family of HMTs, which are associated with cancer progression, spread, and resistance to chemotherapy. The researchers studied the structure, function, and effects of different SMYD family members on cancer, using clinical data and biological experiments. The review also explores how these enzymes can be targeted by specific inhibitors, potentially offering new cancer treatments. The findings suggest that targeting SMYD family members, especially SMYD2 and SMYD3, could be an effective cancer treatment strategy. By developing drugs that specifically inhibit SMYD2 and SMYD3, researchers hope to provide new, more effective treatments for cancer 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 11","pages":"2325-2336"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01326-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559288","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 : 2024-11-01DOI: 10.1038/s12276-024-01344-6
Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Xiangguo Che, Je-Yong Choi, Jeong-Tae Koh, Nacksung Kim
Several CC subfamily chemokines have been reported to regulate bone metabolism by affecting osteoblast or osteoclast differentiation. However, the role of monocyte chemotactic protein 3 (MCP-3), a CC chemokine, in bone remodeling is not well understood. Here, we show that MCP-3 regulates bone remodeling by promoting osteoblast differentiation and inhibiting osteoclast differentiation. In a Ccr3-dependent manner, MCP-3 promoted osteoblast differentiation by stimulating p38 phosphorylation and suppressed osteoclast differentiation by upregulating interferon beta. MCP-3 increased bone morphogenetic protein 2-induced ectopic bone formation, and mice with MCP-3-overexpressing osteoblast precursor cells presented increased bone mass. Moreover, MCP-3 exhibited therapeutic effects by abrogating receptor activator of nuclear factor kappa-B ligand-induced bone loss. Therefore, MCP-3 has therapeutic potential for diseases involving bone loss due to its positive role in osteoblast differentiation and negative role in osteoclast differentiation. Our bones are always changing, needing a balance between bone creation and bone breakdown. Researchers investigates how a specific protein, MCP-3, affects this balance. They found that MCP-3 promotes the creation of osteoblasts and stops the creation of osteoclasts. The study involved both in vitro and in vivo methods, looking at how changing MCP-3 levels impacts bone change processes. Researchers found that increasing MCP-3 levels in bone-making cells resulted in stronger bones in mice, suggesting MCP-3 is key in promoting bone creation and stopping excessive bone loss. This was partly due to MCP-3’s interaction with specific cell receptors and signaling pathways that affect bone cell activity. This research paves the way for future studies on MCP-3 as a target for bone-strengthening therapies, potentially leading to new treatments for diseases that weaken bones. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The MCP-3/Ccr3 axis contributes to increased bone mass by affecting osteoblast and osteoclast differentiation","authors":"Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Xiangguo Che, Je-Yong Choi, Jeong-Tae Koh, Nacksung Kim","doi":"10.1038/s12276-024-01344-6","DOIUrl":"10.1038/s12276-024-01344-6","url":null,"abstract":"Several CC subfamily chemokines have been reported to regulate bone metabolism by affecting osteoblast or osteoclast differentiation. However, the role of monocyte chemotactic protein 3 (MCP-3), a CC chemokine, in bone remodeling is not well understood. Here, we show that MCP-3 regulates bone remodeling by promoting osteoblast differentiation and inhibiting osteoclast differentiation. In a Ccr3-dependent manner, MCP-3 promoted osteoblast differentiation by stimulating p38 phosphorylation and suppressed osteoclast differentiation by upregulating interferon beta. MCP-3 increased bone morphogenetic protein 2-induced ectopic bone formation, and mice with MCP-3-overexpressing osteoblast precursor cells presented increased bone mass. Moreover, MCP-3 exhibited therapeutic effects by abrogating receptor activator of nuclear factor kappa-B ligand-induced bone loss. Therefore, MCP-3 has therapeutic potential for diseases involving bone loss due to its positive role in osteoblast differentiation and negative role in osteoclast differentiation. Our bones are always changing, needing a balance between bone creation and bone breakdown. Researchers investigates how a specific protein, MCP-3, affects this balance. They found that MCP-3 promotes the creation of osteoblasts and stops the creation of osteoclasts. The study involved both in vitro and in vivo methods, looking at how changing MCP-3 levels impacts bone change processes. Researchers found that increasing MCP-3 levels in bone-making cells resulted in stronger bones in mice, suggesting MCP-3 is key in promoting bone creation and stopping excessive bone loss. This was partly due to MCP-3’s interaction with specific cell receptors and signaling pathways that affect bone cell activity. This research paves the way for future studies on MCP-3 as a target for bone-strengthening therapies, potentially leading to new treatments for diseases that weaken bones. 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 11","pages":"2465-2474"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01344-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559289","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 : 2024-11-01DOI: 10.1038/s12276-024-01341-9
Su Jeong Lee, Ju Ang Kim, Hye Jung Ihn, Je-Yong Choi, Tae-Yub Kwon, Hong-In Shin, Eui-Sic Cho, Yong Chul Bae, Rulang Jiang, Jung-Eun Kim, Eui Kyun Park
Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx−/−) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx−/− mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)2D3 induced an interaction of the 1,25(OH)2D3 receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)2D3 regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)2D3. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice. Phosphate, a vital component for various bodily functions, is regulated by a complex system involving hormones like FGF23. Researchers investigated how the absence of a gene called Bobby sox homolog (BBX) impacts phosphate balance and bone health. Researchers created BBX-deficient mice, and measured various factors, including bone mineral density and strength, as well as the impact of BBX on phosphate-regulating hormones. They found that lack of BBX in mice leads to lower phosphate levels, weaker bones, and increased FGF23 levels, disrupting phosphate balance. Additionally, they discovered that an active form of vitamin D3 lowers BBX levels through a process called ubiquitin-dependent proteasomal degradation, which is important for controlling FGF23. The study concluded that BBX deficiency causes significant bone weakness and disrupts phosphate levels by increasing FGF23. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23","authors":"Su Jeong Lee, Ju Ang Kim, Hye Jung Ihn, Je-Yong Choi, Tae-Yub Kwon, Hong-In Shin, Eui-Sic Cho, Yong Chul Bae, Rulang Jiang, Jung-Eun Kim, Eui Kyun Park","doi":"10.1038/s12276-024-01341-9","DOIUrl":"10.1038/s12276-024-01341-9","url":null,"abstract":"Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx−/−) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx−/− mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)2D3 induced an interaction of the 1,25(OH)2D3 receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)2D3 regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)2D3. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice. Phosphate, a vital component for various bodily functions, is regulated by a complex system involving hormones like FGF23. Researchers investigated how the absence of a gene called Bobby sox homolog (BBX) impacts phosphate balance and bone health. Researchers created BBX-deficient mice, and measured various factors, including bone mineral density and strength, as well as the impact of BBX on phosphate-regulating hormones. They found that lack of BBX in mice leads to lower phosphate levels, weaker bones, and increased FGF23 levels, disrupting phosphate balance. Additionally, they discovered that an active form of vitamin D3 lowers BBX levels through a process called ubiquitin-dependent proteasomal degradation, which is important for controlling FGF23. The study concluded that BBX deficiency causes significant bone weakness and disrupts phosphate levels by increasing FGF23. 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 11","pages":"2436-2448"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01341-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559290","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 : 2024-11-01DOI: 10.1038/s12276-024-01336-6
Raymond J. Zhang, Tae Kon Kim
Over the past decade, V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been established as a negative immune checkpoint molecule. Since the role of VISTA in inhibiting T-cell activation was described, studies have demonstrated other diverse regulatory functions in multiple immune cell populations. Furthermore, its relevance has been identified in human cancers. The role of VISTA in cancer immune evasion has been determined, but its mechanisms in the tumor microenvironment remain to be further elucidated. Understanding its contributions to cancer initiation, progression, and resistance to current treatments will be critical to its utility as a target for novel immunotherapies. Here, we summarize the current understanding of VISTA biology in cancer. Cancer immune surveillance, the body’s method of using the immune system to find and kill cancer cells, is sometimes thwarted, leading to tumor growth. This review focuses on a protein named V-domain immunoglobulin suppressor of T-cell activation (VISTA) and examines how it may help cancer cells avoid immune detection. Studies with both human and mouse cells have identified how VISTA works and its effect on immune cells. Mouse model experiments and analyses of human cancer samples have also investigated how VISTA affects the immune system’s cancer-fighting ability. Together, these studies suggest that high VISTA levels in immune cells can hinder the immune response against tumors, aiding cancer cell growth and spread. Therefore, future strategies targeting VISTA could improve the immune system’s ability to find and kill cancer cells and require further investigation. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
在过去十年中，V 域免疫球蛋白 T 细胞活化抑制因子（VISTA）已被确定为一种负性免疫检查点分子。自 VISTA 在抑制 T 细胞活化方面的作用被描述以来，研究已经证明了它在多种免疫细胞群中的其他不同调节功能。此外，还发现了它与人类癌症的相关性。VISTA 在癌症免疫逃避中的作用已经确定，但其在肿瘤微环境中的作用机制仍有待进一步阐明。了解 VISTA 对癌症的发生、发展以及对目前治疗方法的耐受性所起的作用，对于将其作为新型免疫疗法的靶点至关重要。在此，我们总结了目前对癌症中 VISTA 生物学特性的理解。
{"title":"VISTA-mediated immune evasion in cancer","authors":"Raymond J. Zhang, Tae Kon Kim","doi":"10.1038/s12276-024-01336-6","DOIUrl":"10.1038/s12276-024-01336-6","url":null,"abstract":"Over the past decade, V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been established as a negative immune checkpoint molecule. Since the role of VISTA in inhibiting T-cell activation was described, studies have demonstrated other diverse regulatory functions in multiple immune cell populations. Furthermore, its relevance has been identified in human cancers. The role of VISTA in cancer immune evasion has been determined, but its mechanisms in the tumor microenvironment remain to be further elucidated. Understanding its contributions to cancer initiation, progression, and resistance to current treatments will be critical to its utility as a target for novel immunotherapies. Here, we summarize the current understanding of VISTA biology in cancer. Cancer immune surveillance, the body’s method of using the immune system to find and kill cancer cells, is sometimes thwarted, leading to tumor growth. This review focuses on a protein named V-domain immunoglobulin suppressor of T-cell activation (VISTA) and examines how it may help cancer cells avoid immune detection. Studies with both human and mouse cells have identified how VISTA works and its effect on immune cells. Mouse model experiments and analyses of human cancer samples have also investigated how VISTA affects the immune system’s cancer-fighting ability. Together, these studies suggest that high VISTA levels in immune cells can hinder the immune response against tumors, aiding cancer cell growth and spread. Therefore, future strategies targeting VISTA could improve the immune system’s ability to find and kill cancer cells and require further investigation. 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 11","pages":"2348-2356"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01336-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559291","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 : 2024-11-01DOI: 10.1038/s12276-024-01339-3
Taylor Roh, Wonhyoung Seo, Minho Won, Woo Seok Yang, Asmita Sapkota, Eun-Jin Park, Sung-Ho Yun, Sang Min Jeon, Kyung Tae Kim, Bomi Lee, Gyoungah Ryu, Sang-Hee Lee, Jung-Min Shin, Hyo Jung Shin, Young Jae Kim, Young Lee, Chaeuk Chung, Ik-Chan Song, Hyun Kyu Song, Eun-Kyeong Jo
Poxviruses are implicated in a variety of infectious diseases; however, little is known about the molecular mechanisms that underlie the immune response during poxvirus infection. We investigated the function and mechanisms of the monkeypox virus envelope protein (A30L) and its core peptide (IAMP29) during the activation of innate immune responses. The A30L protein and its core peptide, IAMP29 (a 29-amino-acid inflammasome-activating peptide encompassing His40 to Asp69 of A30L), strongly activated the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome by inducing the production of mitochondrial reactive oxygen species in human monocytes. Specifically, IAMP29 triggered metabolic reprogramming toward glycolysis and interacted with pyruvate kinase M isoforms (PKM1 and PKM2), thus activating the NLRP3 inflammasome and interleukin (IL)-1β production in human monocytes and murine macrophages. In human primary monocyte-derived macrophages, IAMP29-induced inflammasome activation promoted an antimicrobial response to rapidly growing non-tuberculous mycobacteria. Furthermore, IAMP29 exhibited cytotoxic activity against leukemia cells, which was mediated by pyroptosis and apoptosis. These findings provide insights into the immunological function of the poxvirus envelope peptide and suggest its therapeutic potential. Poxviruses, a group of viruses causing diseases like smallpox and mpox, can manipulate our immune system, but the exact process is not fully understood. This study reveals that a specific poxvirus protein, IAMP29, can stimulate our immune response. It does this by causing NLRP3 inflammasome activation and boosting our body’s defenses against infections and cancer. The research, which involved experiments with human immune cells and mice, found that IAMP29 increases the production of inflammation-causing molecules and strengthens the immune system’s ability to combat fast-growing non-tuberculous mycobacteria (bacteria that do not cause tuberculosis and leprosy) and leukemia cells. The study suggests that IAMP29 could be used as a treatment for these bacterial infections and certain cancers, providing a significant insight into how poxviruses interact with our immune system. This could pave the way for new treatments for infectious diseases and cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
痘病毒与多种传染性疾病有关；然而，人们对痘病毒感染过程中免疫反应的分子机制知之甚少。我们研究了猴痘病毒包膜蛋白（A30L）及其核心肽（IAMP29）在激活先天性免疫反应过程中的功能和机制。A30L蛋白及其核心肽IAMP29（包含A30L的His40至Asp69的29个氨基酸的炎性体激活肽）通过诱导人单核细胞产生线粒体活性氧，强烈激活了核苷酸结合寡聚域、富亮氨酸重复和含吡喃结构域3（NLRP3）炎性体。具体来说，IAMP29 会引发新陈代谢向糖酵解方向重编程，并与丙酮酸激酶 M 同工酶（PKM1 和 PKM2）相互作用，从而激活 NLRP3 炎症小体，并在人类单核细胞和鼠巨噬细胞中产生白细胞介素（IL）-1β。在人类原代单核细胞衍生巨噬细胞中，IAMP29 诱导的炎性体活化促进了对快速生长的非结核分枝杆菌的抗菌反应。此外，IAMP29 还对白血病细胞具有细胞毒性活性，这种活性是由细胞的热解和凋亡介导的。这些发现深入揭示了痘病毒包膜肽的免疫学功能，并提示了其治疗潜力。
{"title":"The inflammasome-activating poxvirus peptide IAMP29 promotes antimicrobial and anticancer responses","authors":"Taylor Roh, Wonhyoung Seo, Minho Won, Woo Seok Yang, Asmita Sapkota, Eun-Jin Park, Sung-Ho Yun, Sang Min Jeon, Kyung Tae Kim, Bomi Lee, Gyoungah Ryu, Sang-Hee Lee, Jung-Min Shin, Hyo Jung Shin, Young Jae Kim, Young Lee, Chaeuk Chung, Ik-Chan Song, Hyun Kyu Song, Eun-Kyeong Jo","doi":"10.1038/s12276-024-01339-3","DOIUrl":"10.1038/s12276-024-01339-3","url":null,"abstract":"Poxviruses are implicated in a variety of infectious diseases; however, little is known about the molecular mechanisms that underlie the immune response during poxvirus infection. We investigated the function and mechanisms of the monkeypox virus envelope protein (A30L) and its core peptide (IAMP29) during the activation of innate immune responses. The A30L protein and its core peptide, IAMP29 (a 29-amino-acid inflammasome-activating peptide encompassing His40 to Asp69 of A30L), strongly activated the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome by inducing the production of mitochondrial reactive oxygen species in human monocytes. Specifically, IAMP29 triggered metabolic reprogramming toward glycolysis and interacted with pyruvate kinase M isoforms (PKM1 and PKM2), thus activating the NLRP3 inflammasome and interleukin (IL)-1β production in human monocytes and murine macrophages. In human primary monocyte-derived macrophages, IAMP29-induced inflammasome activation promoted an antimicrobial response to rapidly growing non-tuberculous mycobacteria. Furthermore, IAMP29 exhibited cytotoxic activity against leukemia cells, which was mediated by pyroptosis and apoptosis. These findings provide insights into the immunological function of the poxvirus envelope peptide and suggest its therapeutic potential. Poxviruses, a group of viruses causing diseases like smallpox and mpox, can manipulate our immune system, but the exact process is not fully understood. This study reveals that a specific poxvirus protein, IAMP29, can stimulate our immune response. It does this by causing NLRP3 inflammasome activation and boosting our body’s defenses against infections and cancer. The research, which involved experiments with human immune cells and mice, found that IAMP29 increases the production of inflammation-causing molecules and strengthens the immune system’s ability to combat fast-growing non-tuberculous mycobacteria (bacteria that do not cause tuberculosis and leprosy) and leukemia cells. The study suggests that IAMP29 could be used as a treatment for these bacterial infections and certain cancers, providing a significant insight into how poxviruses interact with our immune system. This could pave the way for new treatments for infectious diseases and cancer. 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 11","pages":"2475-2490"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01339-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607419","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 : 2024-10-28DOI: 10.1038/s12276-024-01252-9
Dong Soo Kyung, Eunmin Lee, Sehyun Chae, Yeonho Son, Ye-Jin Moon, Daehee Hwang, Jong Kyoung Kim, Yun-Hee Lee, Je Kyung Seong
PDGFRA+ cells have been identified as adipocyte stem cells (ASCs) that differentiate into beige adipocytes in white adipose tissue (WAT) following thermogenic stimuli. To elucidate the molecular heterogeneity of ASCs, we conducted single-cell transcriptomic profiling of PDGFRA+ cells isolated from the inguinal WAT (iWAT) of mice treated with the beta3 adrenergic receptor agonist CL316243. Single-cell RNA-seq revealed nine major clusters, which were categorized into four groups: resting, proliferating, differentiating, and adipogenic factor-expressing cells (AFECs). Trajectory analysis revealed sequential activation of molecular pathways, including the Hedgehog and Notch signaling pathways, during beige adipogenesis. AFECs expressed Dpp4 and did not differentiate into adipocytes in culture or after transplantation. Furthermore, genetic lineage tracing studies indicated that DPP4+ cells did not differentiate into adipocytes in iWAT during CL316243-induced beige adipogenesis. However, high-fat diet feeding led to the recruitment of adipocytes from DPP4+ cells in iWAT. Overall, this study improved our understanding of the dynamic molecular basis of beige adipogenesis and the potential contribution of DPP4+ adipocyte lineages to the pathological expansion of WAT during diet-induced obesity. This research examines beige adipogenesis, or the creation of ‘beige’ fat cells that burn energy and could help fight obesity. The scientists discovered a group of cells, identifed by specific markers PDGFRA and DPP4, which serve as a source for beige adipogenesis but don’t turn into beige fat cells themselves. They also found that these cells can change to become fat cells under certain situations, like a high-fat diet. The study also showed that the Hedgehog and Notch signaling pathways are vital in the transformation of PDGFRA+ cells into beige fat cells. These discoveries could be important for developing anti-obesity therapeutics. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Single-cell transcriptomic analysis reveals dynamic activation of cellular signaling pathways regulating beige adipogenesis","authors":"Dong Soo Kyung, Eunmin Lee, Sehyun Chae, Yeonho Son, Ye-Jin Moon, Daehee Hwang, Jong Kyoung Kim, Yun-Hee Lee, Je Kyung Seong","doi":"10.1038/s12276-024-01252-9","DOIUrl":"10.1038/s12276-024-01252-9","url":null,"abstract":"PDGFRA+ cells have been identified as adipocyte stem cells (ASCs) that differentiate into beige adipocytes in white adipose tissue (WAT) following thermogenic stimuli. To elucidate the molecular heterogeneity of ASCs, we conducted single-cell transcriptomic profiling of PDGFRA+ cells isolated from the inguinal WAT (iWAT) of mice treated with the beta3 adrenergic receptor agonist CL316243. Single-cell RNA-seq revealed nine major clusters, which were categorized into four groups: resting, proliferating, differentiating, and adipogenic factor-expressing cells (AFECs). Trajectory analysis revealed sequential activation of molecular pathways, including the Hedgehog and Notch signaling pathways, during beige adipogenesis. AFECs expressed Dpp4 and did not differentiate into adipocytes in culture or after transplantation. Furthermore, genetic lineage tracing studies indicated that DPP4+ cells did not differentiate into adipocytes in iWAT during CL316243-induced beige adipogenesis. However, high-fat diet feeding led to the recruitment of adipocytes from DPP4+ cells in iWAT. Overall, this study improved our understanding of the dynamic molecular basis of beige adipogenesis and the potential contribution of DPP4+ adipocyte lineages to the pathological expansion of WAT during diet-induced obesity. This research examines beige adipogenesis, or the creation of ‘beige’ fat cells that burn energy and could help fight obesity. The scientists discovered a group of cells, identifed by specific markers PDGFRA and DPP4, which serve as a source for beige adipogenesis but don’t turn into beige fat cells themselves. They also found that these cells can change to become fat cells under certain situations, like a high-fat diet. The study also showed that the Hedgehog and Notch signaling pathways are vital in the transformation of PDGFRA+ cells into beige fat cells. These discoveries could be important for developing anti-obesity therapeutics. 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":"2309-2322"},"PeriodicalIF":9.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01252-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512268","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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