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Human cardiomyopathy islands as a novel iPSC based strategy for modeling adult onset cardiomyopathies in-vivo

Session Basic Science

Speaker Oren Caspi

Event : Heart Failure 2018

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Diseases: Gene Therapy, Cell Therapy
  • Session type : Rapid Fire Abstracts

Authors : O Caspi (Haifa,IL), SC Chrona (Haifa,IL), IH Huber (Haifa,IL), AG Gepstein (Haifa,IL), GA Arbel (Haifa,IL), GA Gruber (Haifa,IL), BI Budniatzky (Haifa,IL), LG Gepstein (Haifa,IL)

O Caspi1 , SC Chrona2 , IH Huber2 , AG Gepstein2 , GA Arbel2 , GA Gruber2 , BI Budniatzky2 , LG Gepstein1 , 1Rambam Health Care Campus, Cardiology - Haifa - Israel , 2Technion - Israel Institute of Technology - Haifa - Israel ,


Introduction: The study of cardiomyopathies is hampered both by the inability to assess the myocardial tissue early during disease development and the lack of suitable models. The advent of human induced pluripotent stem cells (hiPSCs) technology may provide essential means for overcoming this hurdle, since it allows deriving and studying human cardiomyocytes that carry the disease-causing phenotype. However, hiPSCs based in-vitro, "disease in a dish models", are limited by the relative structural, functional and metabolic immaturity of the cardiomyocytes, the inability to assess for the effects of systemically delivered therapeutic interventions and the lack of supporting microenvironment.

Purpose: In the current study, we aimed to establish hiPSCs based in-vivo models for cardiomyopathies and assess whether such a strategy can: (1) unmask the phenotype of adult onset cardiomyopathies (e.g. arrhythmogenic right ventricular cardiomyopathy, Pompe disease);  (2) obtain functional information from the engrafted hiPSCs derived cardiomyocytes (hiPSC-CMs), and; (3) assess the effect of systemically delivered therapies on hiPSC-CMs.

Methods: Heterotopic and orthotopic strategies were used to transplant hiPSCs derived cardiomyocytes (following 15-30 days of differentiation) to NOD-SCID mice. Orthotopic experiments were conducted by direct intra-myocardial delivery of the hiPSC-CMs.

Results: Orthotopic transplantation of hiPSC-CMs to the mice myocardium resulted in stable, large and discrete grafted tissue islands. The hiPSC-CMs within the islands presented both structural and molecular hallmarks of cardiomyocyte maturation following 30 days, when compared with same stage in-vitro cultured cardiomyocytes. Importantly, when hiPSC-CMs from adult onset cardiomyopathies (i.e. Arrhythmogenic right ventricular cardiomyopathy (ARVC) and Pompe disease) were transplanted, the in-vivo environment resulted in the generation of human cardiomyopathy islands (hCI) recapitulating the adult onset cardiomyopathy phenotype without the need for stressors usually required for uncovering the phenotype of these cardiomyopathies in-vitro. Additionally, The hCI strategy was used for evaluating the effect of systemic therapies on the cardiomyopathy phenotype. Heterotopic transplantation demonstrated that transplanted cells survived within the dermal thin layer of the outer ear (for up to 3 months) but was not associated with structural maturation of the hCIs nor did it promote cardiomyopathy phenotype unmasking.

Conclusions: Orthotropic hCI may serve as an attractive strategy for modeling the structural and functional alterations associated with adult onset cardiomyopathies. Apart from phenotype uncovering, this strategy may more accurately model systemic therapy effects, interaction with the immune system and adult metabolic energetics which have significant clinical importance.

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