High afterload and increased fibroblasts amplify hypercontractility and disrupt structural alignment in MYBPC3fs micro-heart tissues.
Why the study?
Clinical severity and adverse outcomes in HCM correlate poorly with sarcomeric genotype alone and are strongly influenced by fibrosis.
Population
Engineered human micro-heart tissue combining iPSC-derived cardiomyocytes with defined primary cardiac fibroblast fractions
Comparison
MYBPC3fs vs isogenic control across varied afterloads and cardiac fibroblast fractions
Design
Preclinical in vitro tissue engineering study
Key result
High afterload and increased cardiac fibroblast content amplified hypercontractility and disrupted structural alignment in MYBPC3fs engineered micro-heart tissues compared to isogenic controls.
Authors
Discussion
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Member takes
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“There's always this question of how sophisticated you need these models to actually be. And here, we're seeing this crosstalk between the cardiomyocytes and the fibroblasts. That crosstalk is an argument that we really do need to think not just about how the cardiomyocytes with the mutation might secrete things that affect fibroblasts but how having them together — and having that paracrine crosstalk in real time — might be important.”
Overview
May guide in vitro HCM modeling; leaves open whether modulating afterload or fibroblasts alters clinical progression.
Key Points
- To investigate how mechanical afterload and cardiac fibroblast density influence the contractile, structural, and signaling phenotypes of human engineered heart tissues harboring a truncating MYBPC3 mutation.
- Engineered human micro-heart tissues by combining isogenic control or MYBPC3-frameshift variant iPSC-derived cardiomyocytes with defined proportions of primary cardiac fibroblasts (0%, 5%, and 25%).
- Assayed tissue active force, calcium handling, Z-disc alignment, and resting tension under modulated low versus high afterload conditions and in response to TGF-β stimulation.
- High afterload and elevated fibroblast fractions (5% and 25%) amplified active force hypercontractility and altered excitation–contraction calcium coupling in MYBPC3-mutant tissues relative to isogenic controls.
- Increasing fibroblast density progressively ordered myofibrillar Z-discs in control tissues, but this structural alignment was blunted in MYBPC3-mutant tissues despite their heightened contractile force.
- MYBPC3-mutant tissues showed an exaggerated response to TGF-β exposure, exhibiting elevated tissue-level resting tension and increased alpha-smooth muscle actin expression.
Structured PICO
P
Population
Engineered human micro-heart tissue (μHT) combining iPSC-derived cardiomyocytes harboring an HCM-linked frameshift variant in MYBPC3 (MYBPC3fs) with defined primary cardiac fibroblast (cFB) fractions.
E
Exposure
Mechanical stress (high afterload), varying cardiac fibroblast fractions (0%, 5%, 25%), and TGF-β exposure.
C
Comparator
Isogenic control μHT and low afterload conditions.
O
Outcome
Total active force, Ca2+ handling, Z-disc alignment, resting tension, and α-smooth muscle actin expression.surrogate
Biomechanical stress and fibroblast interactions synergistically drive hypercontractility and structural disarray in MYBPC3-mutant hypertrophic cardiomyopathy models.
Cite This Study
Jiang et al. (2026) studied Hypertrophic cardiomyopathy (HCM). MYBPC3 frameshift variant (MYBPC3fs) with varying cardiac fibroblast fractions and mechanical afterload vs. Isogenic control micro-heart tissue was evaluated on Total active force, Ca2+ handling, Z-disc alignment, and response to TGF-β. High afterload and increased cardiac fibroblast content amplified hypercontractility and disrupted structural alignment in MYBPC3fs engineered micro-heart tissues compared to isogenic controls.