Engineered Cardiac Tissue With Integrated Vascular Cell Differentiation
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Solution Overview
Problem
Current methods for generating engineered cardiac tissue from pluripotent stem cells fail to accurately recapitulate native heart tissue composition and function, lacking endothelial cells and other vascular cells, and oxidative metabolism inhibits cardiomyocyte proliferation and survival in vivo.
Innovation Solution
A protocol using a single differentiation process to produce engineered human cardiac tissue comprising cardiomyocytes, stromal cells, and endothelial cells, with the aid of FGFR1 and PDGFR agonists, within a hydrogel composition, which is cultured in serum-free medium to create a tissue that better mimics native heart tissue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oxidative metabolism is enhanced to promote advanced maturation and contractility of engineered cardiac tissue, then tissue maturity and contractility are improved, but cardiomyocyte proliferation is inhibited and survival in hypoxic in vivo environment is reduced
Solution Approach 1:
The patent applies dynamic metabolic regulation by transitioning cardiomyocytes from oxidative metabolism to glycolytic metabolism at different stages of tissue development. Initially, oxidative metabolism promotes maturation and contractility. Later, switching to glycolytic metabolism enables proliferation and survival in hypoxic in vivo conditions. This temporal dynamic adjustment resolves the contradiction between tissue maturity and cardiomyocyte proliferation.
2Manufacturing precision
If separate differentiation protocols are used to obtain cardiomyocytes, stromal cells, and endothelial cells, then cell type purity is improved, but process complexity and variability increase
Solution Approach 1:
The patent merges multiple separate differentiation protocols into a single integrated protocol that simultaneously generates cardiomyocytes, stromal cells, and endothelial cells from human pluripotent stem cells. This unified approach maintains cell type purity while reducing process complexity and variability associated with combining cells from separate protocols.
3Manufacturing precision
If endothelial cells and other vascular cells are added to engineered cardiac tissue, then tissue composition accuracy is improved, but manufacturing complexity increases
Solution Approach 1:
The patent combines the generation of multiple cell types including endothelial cells and other vascular cells within a single differentiation protocol, eliminating the need for separate protocols and subsequent cell mixing. This approach achieves accurate native heart tissue composition while simplifying the manufacturing process.
Data Source
AI summary
The present application relates to methods for the generation of engineered human pluripotent stem cell-derived cardiac tissue, engineered cardiac tissue produced by such methods and methods for their use.