Molecular Therapy最新文献_第9页

Retraction Notice to: Hypoxia-induced lncHILAR promotes renal cancer metastasis via ceRNA for the miR-613/206/ 1-1-3p/Jagged-1/Notch/CXCR4 signaling pathway.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-31 DOI: 10.1016/j.ymthe.2025.01.044

Guanghui Hu, Junjie Ma, Jin Zhang, Yonghui Chen, Huan Liu, Yiran Huang, Junhua Zheng, Yunfei Xu, Wei Xue, Wei Zhai

引用次数: 0

Centrosome protein TAX1BP mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in Hepatocellular Carcinoma.

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-28 DOI: 10.1016/j.ymthe.2025.01.043

Qingmei Zhang,Wing-Lim Chan,Sin-Yee Fung,Li Pang,Tao Ding,Jia Ming Nickolas Teo,Yuan Zhou,Chung Ming Alex Wu,Kam-Leung Siu,Jiacheng Bi,Guang Sheng Ling,Dong-Yan Jin,Kwan Man,Yick Pang Ching

{"title":"Centrosome protein TAX1BP mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in Hepatocellular Carcinoma.","authors":"Qingmei Zhang,Wing-Lim Chan,Sin-Yee Fung,Li Pang,Tao Ding,Jia Ming Nickolas Teo,Yuan Zhou,Chung Ming Alex Wu,Kam-Leung Siu,Jiacheng Bi,Guang Sheng Ling,Dong-Yan Jin,Kwan Man,Yick Pang Ching","doi":"10.1016/j.ymthe.2025.01.043","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.043","url":null,"abstract":"Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T-cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type 1 interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"54 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systematic empirical evaluation of individual base editing targets: validating therapeutic targets in USH2A and comparison of methods.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-28 DOI: 10.1016/j.ymthe.2025.01.042

Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander

{"title":"Systematic empirical evaluation of individual base editing targets: validating therapeutic targets in USH2A and comparison of methods.","authors":"Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander","doi":"10.1016/j.ymthe.2025.01.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.042","url":null,"abstract":"Base editing shows promise for the correction of human mutations at a higher efficiency than other repair methods and is especially attractive for mutations in large genes that are not amenable to gene augmentation therapy. Here, we demonstrate a comprehensive workflow for in vitro screening of potential therapeutic base editing targets for the USH2A gene and empirically validate the efficiency of adenine and cytosine base editor/guide combinations for correcting 35 USH2A mutations. Editing efficiency and bystander edits are compared between different target templates (plasmids versus transgenes) and assays (Next generation sequencing versus Sanger), as well as comparisons between unbiased empirical results and computational predictions. Based on these observations, practical assay recommendations are discussed. Finally, a humanized knock-in mouse model was created with the best-performing target, the nonsense mutation c.11864G>A p.(Trp3955*). Split-intein AAV9 delivery of editing reagents resulted in the restoration of USH2A protein and a correction rate of 65 ± 3% at the mutant base pair and of 52 ± 3% excluding bystander amino acid changes. This efficiency is higher than that seen in a retinal gene editing program testing in a clinical trial. These results demonstrate the effectiveness of this overall strategy to identify and test base editing reagents with the potential for human therapeutic applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering resilient CAR T cells for immunosuppressive environment.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.035

Malak Khalifeh, Huda Salman

{"title":"Engineering resilient CAR T cells for immunosuppressive environment.","authors":"Malak Khalifeh, Huda Salman","doi":"10.1016/j.ymthe.2025.01.035","DOIUrl":"10.1016/j.ymthe.2025.01.035","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site, and on/off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and reengineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.037

Bingxin Liu, Yamato Sajiki, Nicole Littlefield, Yongan Hu, William D Stuart, Anusha Sridharan, Xuemei Cui, Matthew E Siefert, Koichi Araki, Assem G Ziady, Donglu Shi, Jeffery A Whitsett, Yutaka Maeda

{"title":"PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery.","authors":"Bingxin Liu, Yamato Sajiki, Nicole Littlefield, Yongan Hu, William D Stuart, Anusha Sridharan, Xuemei Cui, Matthew E Siefert, Koichi Araki, Assem G Ziady, Donglu Shi, Jeffery A Whitsett, Yutaka Maeda","doi":"10.1016/j.ymthe.2025.01.037","DOIUrl":"10.1016/j.ymthe.2025.01.037","url":null,"abstract":"Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles (LNPs) provides a framework for treating various genetic and acquired disorders. However, LNPs that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought to determine whether poly(β-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination with 4A3-SC8/DOPE/cholesterol/DOTAP LNPs could deliver mRNA into different types of lung cells in vivo. PBAE-PEG/LNP was similar to Lipofectamine MessengerMAX followed by PBAE/LNP for mRNA transfection efficiency in HEK293T cells in vitro. PBAE-PEG/LNP administered by intravenous (IV) injection achieved 73% mRNA transfection efficiency into lung endothelial cells, while PBAE-PEG/LNP administered by intratracheal (IT) injection achieved 55% efficiency in lung alveolar type II (ATII) epithelial cells in mice in vivo. PBAE/LNP administered by IT injection were superior for specific delivery into lung airway club epithelial cells compared to PBAE-PEG/LNP. Lipofectamine MessengerMAX was inactive in vivo. 5-Methoxyuridine-modified mRNA was more efficient than unmodified mRNA in vivo but not in vitro. Our findings indicate that PBAE-PEG/LNP and PBAE/LNP can transfect multiple lung cell types in vivo, which can be applied in gene therapy targeting genetic lung diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comprehensive atlas of AAV tropism in the mouse.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.041

Christopher J Walkey, Kathy J Snow, Jote Bulcha, Aaron R Cox, Alexa E Martinez, M Cecilia Ljungberg, Denise G Lanza, Marco De Giorgi, Marcel A Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M Hartig, Susan G Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea, Seth Hannigan, Mary E Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M Lutz, Jason D Heaney, Guangping Gao, Stephen A Murray, William R Lagor

{"title":"A comprehensive atlas of AAV tropism in the mouse.","authors":"Christopher J Walkey, Kathy J Snow, Jote Bulcha, Aaron R Cox, Alexa E Martinez, M Cecilia Ljungberg, Denise G Lanza, Marco De Giorgi, Marcel A Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M Hartig, Susan G Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea, Seth Hannigan, Mary E Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M Lutz, Jason D Heaney, Guangping Gao, Stephen A Murray, William R Lagor","doi":"10.1016/j.ymthe.2025.01.041","DOIUrl":"10.1016/j.ymthe.2025.01.041","url":null,"abstract":"Gene therapy with adeno-associated virus (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of 10 naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery into male and female mice. A transgene-expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent manner based on fluorescence. Cre-driven activation of tdTomato fluorescence offered superior sensitivity for transduced cells. All serotypes except AAV3B and AAV4 had high liver tropism. Fluorescence activation revealed transduction of unexpected tissues, including adrenals, testes, and ovaries. Rare transduced cells within tissues were also readily visualized. Biodistribution of AAV genomes correlated with fluorescence, except in immune tissues. AAV4 was found to have a pan-endothelial tropism while also targeting pancreatic beta cells. This public resource enables selection of the best AAV serotypes for basic science and preclinical applications in mice.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner. TRAF1 以 AKT 依赖性方式增强氧化磷酸化的代谢适应性，从而促进破骨细胞生成。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.040

Honglei Kang, Renpeng Peng, Yimin Dong, Fuben Liao, Meipeng Zhu, Pengju Wang, Shi-An Hu, Peixuan Hu, Jia Wang, Zheming Liu, Kehan Song, Feng Li

{"title":"TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner.","authors":"Honglei Kang, Renpeng Peng, Yimin Dong, Fuben Liao, Meipeng Zhu, Pengju Wang, Shi-An Hu, Peixuan Hu, Jia Wang, Zheming Liu, Kehan Song, Feng Li","doi":"10.1016/j.ymthe.2025.01.040","DOIUrl":"10.1016/j.ymthe.2025.01.040","url":null,"abstract":"Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a crucial signaling adaptor involved in multiple cellular events. However, its role in regulating osteoclastogenesis and energy metabolism remains unclear. Here, we report that TRAF1 promotes osteoclastogenesis and oxidative phosphorylation (OXPHOS). Employing RNA sequencing, we found that TRAF1 is markedly upregulated during osteoclastogenesis and is positively associated with osteoporosis. TRAF1 knockout inhibits osteoclastogenesis and increases bone mass in both normal and ovariectomized adult mice without affecting bone mass in childhood. Furthermore, TRAF1 promotes osteoclast OXPHOS by increasing the phosphorylation level of AKT. Mechanistically, TRAF1 functions to inhibit TRAF2-induced ubiquitination of Gβl, a known activator of AKT, and further upregulates AKT phosphorylation. Rescue experiments revealed that the inhibitory effects of TRAF1 knockout on osteoclastogenesis, OXPHOS, and bone mass are dependent on AKT. Collectively, our findings uncover a previously unrecognized function of TRAF1 in regulating osteoclastogenesis and energy metabolism, and establish a novel TRAF1-AKT-OXPHOS axis in osteoclasts.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.038

Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen

{"title":"Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.","authors":"Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen","doi":"10.1016/j.ymthe.2025.01.038","DOIUrl":"10.1016/j.ymthe.2025.01.038","url":null,"abstract":"Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial cells, including choroidal vascular mural cells, retinal astrocytes, and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction, and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy, and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326 treatment significantly enriched Gene Ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy. GITRL 可增强 CAR-T 细胞在癌症治疗中的细胞毒性和持久性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.036

Binghe Tan, Chuntian Tu, Hao Xiong, Yongqian Xu, Xiujuan Shi, Xiaolin Zhang, Ruijie Yang, Na Zhang, Boxu Lin, Mingyao Liu, Juliang Qin, Bing Du

{"title":"GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy.","authors":"Binghe Tan, Chuntian Tu, Hao Xiong, Yongqian Xu, Xiujuan Shi, Xiaolin Zhang, Ruijie Yang, Na Zhang, Boxu Lin, Mingyao Liu, Juliang Qin, Bing Du","doi":"10.1016/j.ymthe.2025.01.036","DOIUrl":"10.1016/j.ymthe.2025.01.036","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of GITR ligand enhances the anti-tumor activity of CAR-T cells. Compared to prostate-specific membrane antigen-BB-Z (PSMA-BB-Z) CAR-T, PSMA-BB-Z-GITRL CAR-T cells have much more interferon (IFN)-γ, TNF-α, and interleukin (IL)-9 secretion, a higher proportion of central memory T (TCM) cells and T helper 9 (Th9) cells, less expression of exhaustion markers, and robust proliferation capacity. Consequently, PSMA-BB-Z-GITRL CAR-T cells exhibited more potent anti-tumor activity against established solid tumors in vivo than PSMA-BB-Z CAR-T cells. The results of the in vivo persistence experiment also indicated that PSMA-BB-Z-GITRL CAR-T cells exhibited much more retention in mouse blood, spleen, and tumor tissue than PSMA-BB-Z CAR-T cells 15 days after CAR-T cell therapy. In addition, PSMA-BB-Z-GITRL CAR-T cells produce higher levels of IFN-γ, TNF-α, and IL-9 in mouse blood, exhibiting a higher proportion of TCM cells and a lower proportion of Treg cells compared to PSMA-BB-Z CAR-T cells. Our results demonstrate that the overexpression of GITRL has important implications for improving CAR-T cell-based human solid tumor immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.039

Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri

{"title":"CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice.","authors":"Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri","doi":"10.1016/j.ymthe.2025.01.039","DOIUrl":"10.1016/j.ymthe.2025.01.039","url":null,"abstract":"Small extracellular vesicles (sEVs) mediate intercellular signaling to coordinate the proliferation of cell types that promote re-epithelialization of skin following injury. Cyclin-dependent kinase 1 (CDK1) drives cell division and is a key regulator of entry to the cell cycle. To understand the potential of sEV-mediated delivery of CDK1 to reverse impaired wound healing, we generated CDK1-loaded sEVs (CDK1-sEVs) and evaluated their ability to mediate cell proliferation, re-epithelialization, and downstream signaling responses in the wound bed. We found that treatment of human keratinocytes with CDK1-sEVs increased phosphorylation of the CDK1 target, eukaryotic translation inhibition factor 4E-binding protein 1 (4E-BP1), and histone H3 within 24 h via AKT and ERK phosphorylation, driving increased proliferation and cell migration. Treatment of the wound bed of diabetic obese mice, a model of delayed wound healing, with a single dose of CDK1-sEVs accelerated wound closure, increased re-epithelialization, and promoted the proliferation of keratinocytes. These studies show that delivery of CDK1 by sEVs can stimulate selective and transient proliferation of cell types that increase re-epithelialization and promote proliferation of keratinocytes to accelerate wound healing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0