Cardiomyocyte Maturation Using Let-7 MicroRNAs
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Solution Overview
Problem
Current methods for deriving cardiomyocytes from stem cells result in cells with a fetal phenotype, which limits their usefulness in modeling and treating adult-related heart diseases, as they do not accurately replicate the adult heart's function and morphology.
Innovation Solution
Contacting cardiomyocytes with let-7 microRNAs from the let-7 family, specifically let-7g or let-7i, to induce maturation, shifting their phenotype to an adult-like state characterized by increased mitochondrial respiration, fatty acid oxidation, and expression of adult cardiac markers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cardiomyocytes are derived from stem cells using current methods, then cardiomyocytes can be obtained for research and therapy, but they exhibit a fetal phenotype that does not accurately replicate adult heart function and morphology
Solution Approach 1:
The patent applies parameter changes by introducing specific microRNAs (let-7 family members) to alter the phenotypic parameters of cardiomyocytes. The microRNA treatment changes key parameters including mitochondrial respiration rates, fatty acid oxidation capacity, and expression levels of adult cardiac markers, thereby transforming fetal phenotype cells into cells with adult-like characteristics suitable for modeling adult cardiac diseases
Solution Approach 2:
The patent uses microRNAs as intermediary molecules to mediate the transformation of cardiomyocyte phenotype. Specifically, let-7 microRNAs serve as intermediaries that regulate gene expression networks controlling cellular metabolism and differentiation, bridging the gap between fetal and adult phenotypic states without requiring direct genetic modification of the cardiomyocytes
2Productivity
If fetal phenotype cardiomyocytes are used for research, then cell availability is high, but their functional characteristics do not match adult cardiomyocytes
Solution Approach 1:
The patent applies preliminary action by treating cardiomyocytes with let-7 microRNAs during culture to pre-establish adult-like phenotypic characteristics before the cells are used for research or therapeutic applications. This preliminary maturation process ensures that when cells are derived from stem cells, they already possess adult cardiac functional characteristics, eliminating the need for subsequent phenotypic correction
3Productivity
If stem cell-derived cardiomyocytes are used for adult cardiac disease modeling, then cell production is efficient, but disease relevance is limited due to fetal phenotype
Solution Approach 1:
The patent changes metabolic and phenotypic parameters of stem cell-derived cardiomyocytes through microRNA treatment, achieving adult-like mitochondrial respiration and fatty acid oxidation while maintaining high cell production efficiency. This enables reliable modeling of adult cardiac diseases without sacrificing productivity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method effectively matures cardiomyocytes to an adult-like phenotype, enhancing their functional and morphological characteristics, making them more suitable for studying and treating adult-onset cardiac diseases and disorders.
Implementation Method 1
Let-7 miRNAs function as gene silencing molecules that regulate the expression of protein-coding genes that comprise a let-7 target sequence. Let-7 miRNAs function to repress the expression of genes at the posttranscriptional level.
Data Source
AI summary
Described herein are methods and compositions useful for inducing maturation of a cardiomyocyte to a mature (e.g., adult) phenotype, such that the function and morphology of the mature cardiomyocyte matches or more closely mimics that of the adult heart. The methods and compositions use Let-7 miRNAs and modified forms thereof. Such methods and compositions permit the study and treatment of adult-onset cardiac diseases, disorders or injuries with mature cardiomyocytes that mimic the heart function of an adult. Methods of using cardiomyocytes matured in this manner for drug identification and drug cardiotoxicity testing are also provided.