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Purification and Transplantation of Myogenic Progenitor Cell Derived Exosomes to Improve Cardiac Function in Duchenne Muscular Dystrophic Mice
Published on: April 10, 2019
Donor-specific phenotypic variation in hiPSC cardiomyocyte-derived exosomes impacts endothelial cell function
Amy Turner1, Praful Aggarwal1, Andrea Matter1
1Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Children's Research Institute and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Insights
Cardiomyocyte-derived exosomes differ between individuals with and without left ventricular hypertrophy (LVH). These exosomes impact endothelial cell function, suggesting a role in cardiovascular disease and regenerative medicine.
Area of Science:
- Cardiovascular Biology
- Cell Signaling
- Regenerative Medicine
Background:
- Exosomes mediate cell-cell communication in the cardiovascular system.
- Interindividual variations in exosome content may contribute to cardiovascular disease pathology.
Purpose of the Study:
- To investigate the impact of cardiomyocyte (CM) variation on exosomal content.
- To characterize exosome content from human induced pluripotent stem cell-derived CMs (hiPSC-CMs) from individuals with and without left ventricular hypertrophy (LVH).
Main Methods:
- Generated hiPSC-CM lines from six HyperGEN cohort participants (3 with LVH, 3 with normal left ventricular mass).
- Analyzed intracellular and exosomal RNA populations.
- Performed functional assays on hiPSC-endothelial cells (hiPSC-ECs) treated with exosomes.
Main Results:
- Distinct RNA expression patterns were observed between hiPSC-CMs from LVH and normal LVM individuals.
- Exosomes from LVH-affected donors altered hiPSC-EC proliferation, tube formation, and migration.
- Exosome treatment induced significant expression changes related to angiogenesis and vasculogenesis.
Conclusions:
- Intracellular RNA and exosomal miRNA content differ significantly in hiPSC-CMs from LVH-affected individuals.
- Exosomes from different donors functionally impact endothelial cell phenotypes distinctly.
- Findings offer insights into hypertrophic cell signaling and have implications for cardiovascular regenerative medicine.
Abstract:
Exosomes are an important mechanism of cell-cell interaction in the cardiovascular system, both in maintaining homeostasis and in stress response. Interindividual differences that alter content in exosomes may play a role in cardiovascular disease pathology. To study the effect of interindividual cardiomyocyte (CM) variation, we characterized exosomal content in phenotypically diverse human induced pluripotent stem cell-derived CMs (hiPSC-CMs). Cell lines were generated from six participants in the HyperGEN cohort: three with left ventricular hypertrophy (LVH) and three with normal left ventricular mass (LVM). Sequence analysis of the intracellular and exosomal RNA populations showed distinct expression pattern differences between hiPSC-CM lines derived from individuals with LVH and those with normal LVM. Functional analysis of hiPSC-endothelial cells (hiPSC-ECs) treated with exosomes from both hiPSC-CM groups showed significant variation in response, including differences in tube formation, migration, and proliferation. Overall, treatment of hiPSC-ECs with exosomes resulted in significant expression changes associated with angiogenesis and endothelial cell vasculogenesis. However, the hiPSC-ECs treated with exosomes from the LVH-affected donors exhibited significantly increased proliferation but decreased tube formation and migration, suggesting angiogenic dysregulation.NEW & NOTEWORTHY The intracellular RNA and the miRNA content in exosomes are significantly different in hiPSC-CMs derived from LVH-affected individuals compared with those from unaffected individuals. Treatment of endothelial cells with these exosomes functionally affects cellular phenotypes in a donor-specific manner. These findings provide novel insight into underlying mechanisms of hypertrophic cell signaling between different cell types. With a growing interest in stem cells and exosomes for cardiovascular therapeutic use, this also provides information important for regenerative medicine.
