Pub Date : 2024-12-04DOI: 10.1126/scitranslmed.adq5796
Tomoyoshi Tamura, Changde Cheng, Ana B. Villaseñor-Altamirano, Kohei Yamada, Kohei Ikeda, Kei Hayashida, Jaivardhan A. Menon, Xi Dawn Chen, Hattie Chung, Jack Varon, Jiani Chen, Jiyoung Choi, Aidan M. Cullen, Jingyu Guo, Xi Lin, Benjamin A. Olenchock, Mayra A. Pinilla-Vera, Reshmi Manandhar, Muhammad Dawood Amir Sheikh, Peter C. Hou, Patrick R. Lawler, William M. Oldham, Raghu R. Seethala, Immunology of Cardiac Arrest Network (I-CAN), Rebecca M. Baron, Erin A. Bohula, David A. Morrow, Richard S. Blumberg, Fei Chen, Louis T. Merriam, Alexandra J. Weissman, Michael B. Brenner, Xiang Chen, Fumito Ichinose, Edy Y. Kim
Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post–cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d−/−), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d−/− mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
{"title":"Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation","authors":"Tomoyoshi Tamura, Changde Cheng, Ana B. Villaseñor-Altamirano, Kohei Yamada, Kohei Ikeda, Kei Hayashida, Jaivardhan A. Menon, Xi Dawn Chen, Hattie Chung, Jack Varon, Jiani Chen, Jiyoung Choi, Aidan M. Cullen, Jingyu Guo, Xi Lin, Benjamin A. Olenchock, Mayra A. Pinilla-Vera, Reshmi Manandhar, Muhammad Dawood Amir Sheikh, Peter C. Hou, Patrick R. Lawler, William M. Oldham, Raghu R. Seethala, Immunology of Cardiac Arrest Network (I-CAN), Rebecca M. Baron, Erin A. Bohula, David A. Morrow, Richard S. Blumberg, Fei Chen, Louis T. Merriam, Alexandra J. Weissman, Michael B. Brenner, Xiang Chen, Fumito Ichinose, Edy Y. Kim","doi":"10.1126/scitranslmed.adq5796","DOIUrl":"10.1126/scitranslmed.adq5796","url":null,"abstract":"<div >Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post–cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (<i>Cd1d</i><sup>−/−</sup>), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. <i>Cd1d</i><sup>−/−</sup> mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780562","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}
Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)–RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.
{"title":"RANKL treatment restores thymic function and improves T cell–mediated immune responses in aged mice","authors":"Jérémy C. Santamaria, Jessica Chevallier, Léa Dutour, Amandine Picart, Camille Kergaravat, Agata Cieslak, Mourad Amrane, Renaud Vincentelli, Denis Puthier, Emmanuel Clave, Arnauld Sergé, Martine Cohen-Solal, Antoine Toubert, Magali Irla","doi":"10.1126/scitranslmed.adp3171","DOIUrl":"10.1126/scitranslmed.adp3171","url":null,"abstract":"<div >Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)–RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776505","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}
Pub Date : 2024-12-04DOI: 10.1126/scitranslmed.adl4616
Lina Dinkel, Selina Hummel, Valerio Zenatti, Mariagiovanna Malara, Yannik Tillmann, Alessio Colombo, Laura Sebastian Monasor, Jung H. Suh, Todd Logan, Stefan Roth, Lars Paeger, Patricia Hoffelner, Oliver Bludau, Andree Schmidt, Stephan A. Müller, Martina Schifferer, Brigitte Nuscher, Jasenka Rudan Njavro, Matthias Prestel, Laura M. Bartos, Karin Wind-Mark, Luna Slemann, Leonie Hoermann, Sebastian T. Kunte, Johannes Gnörich, Simon Lindner, Mikael Simons, Jochen Herms, Dominik Paquet, Stefan F. Lichtenthaler, Peter Bartenstein, Nicolai Franzmeier, Arthur Liesz, Antje Grosche, Tatiana Bremova-Ertl, Claudia Catarino, Skadi Beblo, Caroline Bergner, Susanne A. Schneider, Michael Strupp, Gilbert Di Paolo, Matthias Brendel, Sabina Tahirovic
Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N-acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.
尼曼-皮克C型（Niemann-Pick type C， NPC）病是一种主要由NPC1基因突变驱动的遗传性溶酶体贮积性疾病，引起晚期内体/溶酶体内脂质积累，导致进行性神经退行性变。尽管小胶质细胞的激活先于神经元的丢失，但小胶质细胞中膜蛋白NPC1的丢失是否积极地促进了鼻咽癌的病理仍是一个谜。在骨髓细胞中NPC1缺失的小鼠模型中，我们报告了小胶质脂质组学谱的严重改变，包括磷酸单酰基甘油的富集、胆固醇的增加和胆固醇酯的减少。脂质失衡与小胶质细胞过度活跃有关，其特征是转运蛋白18kda （TSPO）的增加。这些过度活跃的小胶质细胞引发了类似npc样表型的病理级联，包括寿命缩短、运动障碍、星形胶质增生、神经轴突病理和神经损伤生物标志物神经丝轻链（NF-L）增加。在小鼠模型中观察到，通过TSPO-PET成像显示，鼻咽癌患者血液中NF-L升高，小胶质细胞过度活跃。N -乙酰基- 1 -亮氨酸治疗后，鼻咽癌患者血源性巨噬细胞中TSPO表达降低，最近有研究表明，TSPO对鼻咽癌患者有有益作用，这表明TSPO是监测鼻咽癌治疗干预措施的潜在标志物。总之，这些结果表明，由NPC1缺失驱动的髓系功能障碍与NPC疾病有关，应进一步研究其治疗靶向和疾病监测。
{"title":"Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease","authors":"Lina Dinkel, Selina Hummel, Valerio Zenatti, Mariagiovanna Malara, Yannik Tillmann, Alessio Colombo, Laura Sebastian Monasor, Jung H. Suh, Todd Logan, Stefan Roth, Lars Paeger, Patricia Hoffelner, Oliver Bludau, Andree Schmidt, Stephan A. Müller, Martina Schifferer, Brigitte Nuscher, Jasenka Rudan Njavro, Matthias Prestel, Laura M. Bartos, Karin Wind-Mark, Luna Slemann, Leonie Hoermann, Sebastian T. Kunte, Johannes Gnörich, Simon Lindner, Mikael Simons, Jochen Herms, Dominik Paquet, Stefan F. Lichtenthaler, Peter Bartenstein, Nicolai Franzmeier, Arthur Liesz, Antje Grosche, Tatiana Bremova-Ertl, Claudia Catarino, Skadi Beblo, Caroline Bergner, Susanne A. Schneider, Michael Strupp, Gilbert Di Paolo, Matthias Brendel, Sabina Tahirovic","doi":"10.1126/scitranslmed.adl4616","DOIUrl":"10.1126/scitranslmed.adl4616","url":null,"abstract":"<div >Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the <i>NPC1</i> gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after <i>N</i>-acetyl-<span>l</span>-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776503","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}
Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.
{"title":"Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment","authors":"Tomoyuki Minowa, Kenji Murata, Yuka Mizue, Aiko Murai, Munehide Nakatsugawa, Kenta Sasaki, Serina Tokita, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Toshiya Handa, Sayuri Sato, Kohei Horimoto, Junji Kato, Tokimasa Hida, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe","doi":"10.1126/scitranslmed.adk8832","DOIUrl":"10.1126/scitranslmed.adk8832","url":null,"abstract":"<div >Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including <i>KLRC1</i> (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776500","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}
Pub Date : 2024-12-04DOI: 10.1126/scitranslmed.adq5711
Matthew Vogel, Adam Tellier, Rena M. Conti
There is uncertainty regarding which brand-name prescription drugs will have their prices negotiated by Medicare in 2025. This Viewpoint analyzes the process that will be used to select the next 15 drugs for price negotiation.
{"title":"Predicting the next round of drugs for Medicare price negotiation","authors":"Matthew Vogel, Adam Tellier, Rena M. Conti","doi":"10.1126/scitranslmed.adq5711","DOIUrl":"10.1126/scitranslmed.adq5711","url":null,"abstract":"<div >There is uncertainty regarding which brand-name prescription drugs will have their prices negotiated by Medicare in 2025. This Viewpoint analyzes the process that will be used to select the next 15 drugs for price negotiation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776501","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}
Pub Date : 2024-11-27DOI: 10.1126/scitranslmed.adk3118
Abel Torres-Espin, Hannah L. Radabaugh, Scott Treiman, Stephen S. Fitzsimons, Danielle Harvey, Austin Chou, Cutter A. Lindbergh, Kaitlin B. Casaletto, Lauren Goldberger, Adam M. Staffaroni, Pauline Maillard, Bruce L. Miller, Charles DeCarli, Jason D. Hinman, Adam R. Ferguson, Joel H. Kramer, Fanny M. Elahi
Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.
{"title":"Sexually dimorphic differences in angiogenesis markers are associated with brain aging trajectories in humans","authors":"Abel Torres-Espin, Hannah L. Radabaugh, Scott Treiman, Stephen S. Fitzsimons, Danielle Harvey, Austin Chou, Cutter A. Lindbergh, Kaitlin B. Casaletto, Lauren Goldberger, Adam M. Staffaroni, Pauline Maillard, Bruce L. Miller, Charles DeCarli, Jason D. Hinman, Adam R. Ferguson, Joel H. Kramer, Fanny M. Elahi","doi":"10.1126/scitranslmed.adk3118","DOIUrl":"10.1126/scitranslmed.adk3118","url":null,"abstract":"<div >Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (<i>n</i> = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; <i>n</i> = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740594","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}
The maintenance of stable plasma drug concentrations within a therapeutic window can be critical for drug efficacy. Here, we developed a wearable osmotic microneedle (OMN) patch to support sustained drug dosing for at least 24 hours without the use of electronic components. The OMN patch uses an osmotic pressure driving force to deliver drug solution into the skin through three hollow microneedles with diameters of less than 200 micrometers. The rate of drug release was related to the composition and concentration of the osmogen and drug and to the physical properties of the semipermeable membrane separating the low- and high-solute compartments. The OMN patch released the peptide drug exenatide in rats and mice for 24 hours, whereas subcutaneous injection resulted in a burst release and rapid decline in the plasma drug concentration. OMN release of exenatide improved glycemic control in a diabetic mouse model consistent with a sustained effective plasma concentration of the drug. Continuous release of the small-molecule chemotherapeutic drug cytarabine reduced the progression of acute myeloid leukemia in mice more effectively than subcutaneous injection. Further evaluation of the OMN patch in canines demonstrated continuous dosing of cytarabine up to 225 milligrams for 24 hours, satisfying clinical requirements (150 to 300 milligrams daily). OMN patches were well tolerated in human participants with minimal pain or irritation of the skin and a stated preference over other administration routes. This wearable drug delivery system could provide a platform for stable high-dose drug release with convenience and safety.
{"title":"A wearable osmotic microneedle patch provides high-capacity sustained drug delivery in animal models","authors":"Sheng Zhao, Ziyi Lu, Ruisi Cai, Hui Wang, Shukun Gao, Changwei Yang, Ying Zhang, Bowen Luo, Wentao Zhang, Yinxian Yang, Shenqiang Wang, Tao Sheng, Shiqi Wang, Jiahuan You, Ruyi Zhou, Huimin Ji, Haoning Gong, Xiao Ye, Jicheng Yu, Hong-Hu Zhu, Yuqi Zhang, Zhen Gu","doi":"10.1126/scitranslmed.adp3611","DOIUrl":"10.1126/scitranslmed.adp3611","url":null,"abstract":"<div >The maintenance of stable plasma drug concentrations within a therapeutic window can be critical for drug efficacy. Here, we developed a wearable osmotic microneedle (OMN) patch to support sustained drug dosing for at least 24 hours without the use of electronic components. The OMN patch uses an osmotic pressure driving force to deliver drug solution into the skin through three hollow microneedles with diameters of less than 200 micrometers. The rate of drug release was related to the composition and concentration of the osmogen and drug and to the physical properties of the semipermeable membrane separating the low- and high-solute compartments. The OMN patch released the peptide drug exenatide in rats and mice for 24 hours, whereas subcutaneous injection resulted in a burst release and rapid decline in the plasma drug concentration. OMN release of exenatide improved glycemic control in a diabetic mouse model consistent with a sustained effective plasma concentration of the drug. Continuous release of the small-molecule chemotherapeutic drug cytarabine reduced the progression of acute myeloid leukemia in mice more effectively than subcutaneous injection. Further evaluation of the OMN patch in canines demonstrated continuous dosing of cytarabine up to 225 milligrams for 24 hours, satisfying clinical requirements (150 to 300 milligrams daily). OMN patches were well tolerated in human participants with minimal pain or irritation of the skin and a stated preference over other administration routes. This wearable drug delivery system could provide a platform for stable high-dose drug release with convenience and safety.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740588","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}
Pub Date : 2024-11-27DOI: 10.1126/scitranslmed.adl1666
Patrick Danaher, Nicholas Hasle, Elizabeth D. Nguyen, Jordan E. Roberts, Natalie Rosenwasser, Christian Rickert, Elena W. Y. Hsieh, Kristen Hayward, Daryl M. Okamura, Charles E. Alpers, Robyn C. Reed, Sarah K. Baxter, Shaun W. Jackson
Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.
{"title":"Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells","authors":"Patrick Danaher, Nicholas Hasle, Elizabeth D. Nguyen, Jordan E. Roberts, Natalie Rosenwasser, Christian Rickert, Elena W. Y. Hsieh, Kristen Hayward, Daryl M. Okamura, Charles E. Alpers, Robyn C. Reed, Sarah K. Baxter, Shaun W. Jackson","doi":"10.1126/scitranslmed.adl1666","DOIUrl":"10.1126/scitranslmed.adl1666","url":null,"abstract":"<div >Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740590","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}
Pub Date : 2024-11-27DOI: 10.1126/scitranslmed.adh0994
Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez
Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.
{"title":"An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models","authors":"Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez","doi":"10.1126/scitranslmed.adh0994","DOIUrl":"10.1126/scitranslmed.adh0994","url":null,"abstract":"<div >Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740589","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}
Pub Date : 2024-11-27DOI: 10.1126/scitranslmed.adu4658
{"title":"Erratum for the Research Article “Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy” by W. Lu et al.","authors":"","doi":"10.1126/scitranslmed.adu4658","DOIUrl":"10.1126/scitranslmed.adu4658","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740592","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}
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