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1,978 results on '"Mooney, David J"'

153. VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits

Author

Anderson, Erin M, Silva, Eduardo A, Hao, Yibai, Martinick, Kathleen D, Vermillion, Sarah A, Stafford, Alexander G, Doherty, Elisabeth G, Wang, Lin, Doherty, Edward J, Grossman, Paul M, and Mooney, David J

Subjects
Biotechnology, Regenerative Medicine, Bioengineering, Cardiovascular, Age Factors, Alginates, Angiogenesis Inducing Agents, Angiography, Digital Subtraction, Animals, Disease Models, Animal, Drug Carriers, Drug Compounding, Female, Glucuronic Acid, Hexuronic Acids, Hindlimb, Hydrogels, Insulin-Like Growth Factor I, Ischemia, Mice, Inbred C57BL, Muscle, Skeletal, Neovascularization, Physiologic, Rabbits, Recovery of Function, Regional Blood Flow, Time Factors, Vascular Endothelial Growth Factor A, Angiogenesis, Peripheral vascular disease, Medical and Health Sciences, Cardiovascular System & Hematology
Abstract

Biomaterial-based delivery of angiogenic growth factors restores perfusion more effectively than bolus delivery methods in rodent models of peripheral vascular disease, but the same success has not yet been demonstrated in clinically relevant studies of aged or large animals. These studies explore, in clinically relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease that overcomes the challenges encountered in previous clinical trials. Alginate hydrogels providing sustained release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) were injected into ischemic hind limbs in middle-aged and old mice, and also in young rabbits, as a test of the scalability of this local growth factor treatment. Spontaneous perfusion recovery diminished with increasing age, and only the combination of VEGF and IGF delivery from gels significantly rescued perfusion in middle-aged (13 months) and old (20 months) mice. In rabbits, the delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose 2 orders of magnitude lower than the typical doses used in past rabbit studies, enhanced perfusion recovery when given immediately after surgery, or as a treatment for chronic ischemia. Capillary density measurements and angiographic analysis demonstrated the benefit of gel delivery. These data together suggest that alginate hydrogels providing local delivery of low doses of VEGF and IGF constitute a safe and effective treatment for hind-limb ischemia in clinically relevant animal models, thereby supporting the potential clinical translation of this concept.

Published
2017

156. Development of a physiological insulin resistance model in human stem cell–derived adipocytes

Author

Massachusetts Institute of Technology. Department of Biology, Friesen, Max, Khalil, Andrew S, Barrasa, M Inmaculada, Jeppesen, Jacob F, Mooney, David J, Jaenisch, Rudolf, Massachusetts Institute of Technology. Department of Biology, Friesen, Max, Khalil, Andrew S, Barrasa, M Inmaculada, Jeppesen, Jacob F, Mooney, David J, and Jaenisch, Rudolf

Abstract

Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell–derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell–derived adipocytes.

Published
2022

157. STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models

Author

Berger, Gilles, Knelson, Erik H., Jimenez-Macias, Jorge L, Nowicki, Michal O., Han, Saemi, Panagioti, Eleni, Lizotte, Patrick, Adu-Berchie, Kwasi, Stafford, Alexander, Dimitrakakis, Nikolaos, Zhou, Lanlan, Chiocca, Antonio EA, Mooney, David J, Barbie, David A., Lawler, Sean E, Berger, Gilles, Knelson, Erik H., Jimenez-Macias, Jorge L, Nowicki, Michal O., Han, Saemi, Panagioti, Eleni, Lizotte, Patrick, Adu-Berchie, Kwasi, Stafford, Alexander, Dimitrakakis, Nikolaos, Zhou, Lanlan, Chiocca, Antonio EA, Mooney, David J, Barbie, David A., and Lawler, Sean E

Abstract

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100–loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2022

158. Hydrogel viscoelasticity modulates migration and fusion of mesenchymal stem cell spheroids.

Author

Wu, David T., Diba, Mani, Yang, Stephanie, Freedman, Benjamin R., Elosegui‐Artola, Alberto, and Mooney, David J.

Subjects
MESENCHYMAL stem cells, PLATELET-derived growth factor, CELL migration, HYDROGELS, STEM cells, VISCOELASTICITY, STRESS relaxation (Mechanics)
Abstract

Multicellular spheroids made of stem cells can act as building blocks that fuse to capture complex aspects of native in vivo environments, but the effect of hydrogel viscoelasticity on cell migration from spheroids and their fusion remains largely unknown. Here, we investigated the effect of viscoelasticity on migration and fusion behavior of mesenchymal stem cell (MSC) spheroids using hydrogels with a similar elasticity but different stress relaxation profiles. Fast relaxing (FR) matrices were found to be significantly more permissive to cell migration and consequent fusion of MSC spheroids. Mechanistically, inhibition of ROCK and Rac1 pathways prevented cell migration. Moreover, the combination of biophysical and biochemical cues provided by fast relaxing hydrogels and platelet‐derived growth factor (PDGF) supplementation, respectively, resulted in a synergistic enhancement of migration and fusion. Overall, these findings emphasize the important role of matrix viscoelasticity in tissue engineering and regenerative medicine strategies based on spheroids. [ABSTRACT FROM AUTHOR]

Published
2023
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170. Immune-responsive biodegradable scaffolds for enhancing neutrophil regeneration

Author

Kerr, Matthew D, McBride, David A, Johnson, Wade T, Chumber, Arun K, Najibi, Alexander J, Seo, Bo Ri, Stafford, Alexander G, Scadden, David T, Mooney, David J, and Shah, Nisarg J

Subjects
Transplantation, neutrophils, 5.2 Cellular and gene therapies, Inflammatory and immune system, Stem Cell Research - Nonembryonic - Non-Human, Hematology, Development of treatments and therapeutic interventions, hematopoietic stem cell transplant, Regenerative Medicine, Stem Cell Research, immunodeficiency, biomaterials
Abstract

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Published
2022

186. Matrix viscoelasticity controls spatio-temporal tissue organization

Author

Elosegui-Artola, Alberto, primary, Gupta, Anupam, additional, Najibi, Alexander J., additional, Seo, Bo Ri, additional, Garry, Ryan, additional, Darnell, Max, additional, Gu, Wei, additional, Zhou, Qiao, additional, Weitz, David A., additional, Mahadevan, L., additional, and Mooney, David J., additional

Published
2022
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188. Scaffold Vaccines for Generating Robust and Tunable Antibody Responses

Author

Najibi, Alexander J., primary, Dellacherie, Maxence O., additional, Shih, Ting‐Yu, additional, Doherty, Edward J., additional, White, Des A., additional, Bauleth‐Ramos, Tomás, additional, Stafford, Alexander G., additional, Weaver, James C., additional, Yeager, Chyenne D., additional, Seiler, Benjamin T., additional, Pezone, Matthew, additional, Li, Aileen W., additional, Sarmento, Bruno, additional, Santos, Hélder A., additional, Mooney, David J., additional, and Gu, Luo, additional

Published
2022
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190. Actuated 3D microgels for single cell mechanobiology

Author

Özkale, Berna, primary, Lou, Junzhe, additional, Özelçi, Ece, additional, Elosegui-Artola, Alberto, additional, Tringides, Christina M., additional, Mao, Angelo S., additional, Sakar, Mahmut Selman, additional, and Mooney, David J., additional

Published
2022
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192. Quantifying face mask comfort

Author

Koh, Esther, primary, Ambatipudi, Mythri, additional, Boone, DaLoria L., additional, Luehr, Julia B. W., additional, Blaise, Alena, additional, Gonzalez, Jose, additional, Sule, Nishant, additional, Mooney, David J., additional, and He, Emily M., additional

Published
2021
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198. Cytokine conjugation to enhance T cell therapy.

Author

Yutong Liu, Adu-Berchie, Kwasi, Brockman, Joshua M., Pezone, Matthew, Zhang, David K. Y., Jingyi Zhou, Pyrdol, Jason W., Hua Wang, Wucherpfennig, Kai W., and Mooney, David J.

Subjects
T cells, CELLULAR therapy, CYTOKINES, MANUFACTURING processes, POISONS, ELECTROCONVULSIVE therapy
Abstract

Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings. [ABSTRACT FROM AUTHOR]

Published
2023
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