Hyaluronic acid-serum hydrogels rapidly restore metabolism of encapsulated stem cells and promote engraftment |
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| Affiliation: | 1. Department of Medicine, Johns Hopkins University, Baltimore, MD, USA;2. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA;3. Department of Radiology, Johns Hopkins University, Baltimore, MD, USA;4. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA;1. Department of Veterinary Medicine and Epidemiology, University of California, Davis, One Shields Ave., Davis, CA 95616, USA;2. Department of Biomedical Engineering, University of California, Davis, One Shields Ave., Davis, CA 95616, USA;1. Molecular Immunology Unit, Institute of Child Health, University College London, London, United Kingdom;2. Great Ormond Street Hospital National Health Service Trust, London, United Kingdom;3. London Centre for Nanotechnology and Department of Physics and Astronomy, University College London, London, United Kingdom;4. Neural Development Unit, Institute of Child Health, University College London, London, United Kingdom;5. London Centre for Nanotechnology and Department of Cell & Developmental Biology, University College London, London, United Kingdom;6. Peninsula College of Medicine and Dentistry, Peninsula Medical School, University of Exeter, St Luke''s Campus, Exeter, United Kingdom;1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;2. Department of Medicine, University of Washington, Seattle, WA;3. Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA;4. Department of Pharmaceutical Sciences, Washington State University, Pullman, WA;5. Department of Pediatrics and Immunology, University of Washington, Seattle, WA;6. Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA;1. Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research (CPR), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;2. Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science (CEMS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan |
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| Abstract: | BackgroundCell death due to anoikis, necrosis and cell egress from transplantation sites limits functional benefits of cellular cardiomyoplasty. Cell dissociation and suspension, which are a pre-requisite for most cell transplantation studies, lead to depression of cellular metabolism and anoikis, which contribute to low engraftment.ObjectiveWe tissue engineered scaffolds with the goal of rapidly restoring metabolism, promoting viability, proliferation and engraftment of encapsulated stem cells.MethodsThe carboxyl groups of HA were functionalized with N-hydroxysuccinimide (NHS) to yield HA succinimidyl succinate (HA-NHS) groups that react with free amine groups to form amide bonds. HA-NHS was cross-linked by serum to generate HA:Serum (HA:Ser) hydrogels. Physical properties of HA:Ser hydrogels were measured. Effect of encapsulating cardiosphere-derived cells (CDCs) in HA:Ser hydrogels on viability, proliferation, glucose uptake and metabolism was assessed in vitro. In vivo acute intra-myocardial cell retention of 18FDG-labeled CDCs encapsulated in HA:Ser hydrogels was quantified. Effect of CDC encapsulation in HA:Ser hydrogels on in vivo metabolism and engraftment at 7 days was assessed by serial, dual isotope SPECT-CT and bioluminescence imaging of CDCs expressing the Na-iodide symporter and firefly luciferase genes respectively. Effect of HA:Ser hydrogels ± CDCs on cardiac function was assessed at 7 days & 28 days post-infarct.ResultsHA:Ser hydrogels are highly bio-adhesive, biodegradable, promote rapid cell adhesion, glucose uptake and restore bioenergetics of encapsulated cells within 1 h of encapsulation, both in vitro and in vivo. These metabolic scaffolds can be applied epicardially as a patch to beating hearts or injected intramyocardially. HA:Ser hydrogels markedly increase acute intramyocardial retention (∼6 fold), promote in vivo viability, proliferation, engraftment of encapsulated stem cells and angiogenesis.ConclusionHA:Ser hydrogels serve as ‘synthetic stem cell niches’ that rapidly restore metabolism of encapsulated stem cells, promote stem cell engraftment and angiogenesis. These first ever, tissue engineered metabolic scaffolds hold promise for clinical translation in conjunction with CDCs and possibly other stem cell types. |
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| Keywords: | HA:Serum hydrogels Stem cells Metabolism Molecular imaging Angiogenesis Engraftment |
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