Decellularized heart extracellular matrix alleviates activation of hiPSC-derived cardiac fibroblasts

Area of Science:

• Biomaterials Science
• Stem Cell Biology
• Cardiovascular Research

Background:

• Human induced pluripotent stem cell derived cardiac fibroblasts (hiPSC-CFs) are crucial for in vitro cardiovascular disease modeling.
• Current substrates like Matrigel and tissue culture plastic (TCPs) are tissue-mismatched and can induce pathogenic fibroblast activation.
• hiPSC-CFs cultured on Matrigel and TCPs (M-TCP-iCFs) show transcriptomic signs of activation, limiting their utility.

Purpose of the Study:

• To develop a biomimetic substrate that improves hiPSC-CF phenotype and reduces pathogenic activation.
• To evaluate the efficacy of decellularized porcine heart extracellular matrix (HEM) as a substrate for hiPSC-CFs.
• To assess the impact of HEM-cultured hiPSC-CFs on cardiac organoid models.

Main Methods:

• hiPSC-CFs were differentiated and expanded on both conventional substrates (Matrigel/TCP) and decellularized heart extracellular matrix (HEM).
• Transcriptomic analysis was performed to compare fibroblast activation markers between conditions.
• HEM-cultured hiPSC-CFs (HEM-iCFs) were integrated into hiPSC-derived cardiac organoid models.

Main Results:

• HEM-iCFs exhibited reduced expression of activated fibroblast markers compared to M-TCP-iCFs, while maintaining cardiac fibroblast identity.
• HEM-iCFs retained reduced pathogenic fibroblast gene expression even when subsequently cultured on TCPs.
• HEM-iCFs integrated more uniformly into cardiac organoids, promoting improved cardiomyocyte sarcomere development.

Conclusions:

• Decellularized heart extracellular matrix (HEM) serves as a superior biomimetic substrate for hiPSC-CF differentiation and expansion.
• HEM substrate mitigates pathogenic activation of hiPSC-CFs, preserving their desired phenotype.
• HEM-iCFs enhance the development of hiPSC-derived cardiac organoid models for cardiovascular disease research.