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  • 1.
    Granéli, Cecilia
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Global Medicines Development, CVRM, AstraZeneca Gothenburg, Mölndal, Sweden.
    Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models2019In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 15, no 1, p. 13-22Article in journal (Refereed)
    Abstract [en]

    The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. 

  • 2.
    Nguyen, Duong T.
    et al.
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    O'Hara, Matthew
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Granéli, Cecilia
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Miliotis, Tasso
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Nyström, Ann-Christin
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hansson, Sara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Davidsson, Pia
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Gan, Li-Ming
    Early Clinical and Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Magnone, Maria Chiara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Althage, Magnus
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Humanizing Miniature Hearts through 4-Flow Cannulation Perfusion Decellularization and Recellularization2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 7458Article in journal (Refereed)
    Abstract [en]

    Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.

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