A team at the Mechanobiology Institute, National University of Singapore, engineers hybrid polyacrylamide–ECM scaffolds that decellularize heart tissue in situ and tune stiffness independently to probe age-related biochemical and mechanical effects on cardiac fibroblasts.
Key points
DECIPHER embeds thin murine heart slices in acrylamide pretreated with formaldehyde to form stable polyacrylamide–ECM hybrids while preserving native ligand distribution.
Hydrogel formulations are tuned to Young’s moduli of ~10 kPa or ~40 kPa, replicating young and aged cardiac tissue stiffness independently of ECM composition.
Young ECM ligand presentation overrides profibrotic stiffness in maintaining cardiac fibroblast quiescence; aged ECM drives activation and senescence through specific receptor and mechanotransduction pathways.
Why it matters:
This platform decouples biochemical ligands and mechanics in aged cardiac ECM, offering precise targets for anti-fibrotic and rejuvenation therapies.
Q&A
What is a hybrid hydrogel–ECM scaffold?
How does DECIPHER preserve native ECM properties?
Why study mechanical stiffness and ligand cues separately?
What role do cardiac fibroblasts play in heart aging?
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Academy
The Extracellular Matrix and Cardiac Aging
The extracellular matrix (ECM) is the network of proteins, glycoproteins, and polysaccharides that surround cells within tissues. In the heart, the ECM provides mechanical support, transmits contractile forces, and regulates biochemical signals that direct cell behavior. Major ECM components include:
- Collagens (primarily types I, III, and V): provide tensile strength and structural framework.
- Fibronectin: mediates cell adhesion and migration.
- Glycosaminoglycans (GAGs) and proteoglycans: retain growth factors and maintain hydration.
- Elastin: contributes elasticity and recoil.
Why ECM Matters in Cardiac Aging
With age, the composition and mechanics of the cardiac ECM change: collagen fibers become thicker and more crosslinked, elastin content decreases, and overall stiffness increases from ~10 kPa in young hearts to ~40 kPa in aged hearts. These changes:
- Stiffen the tissue, disrupting normal contraction and relaxation.
- Alter cell signaling by modifying receptor binding and mechanical cues.
- Promote fibroblast activation, leading to fibrosis and reduced pump function.
Modeling ECM Aging with DECIPHER
Traditional ECM hydrogels lose native fiber architecture and have limited stiffness range. DECIPHER (DECellularized In situ Polyacrylamide Hydrogel–ECM hybRid) overcomes these limits:
- In Situ Hydrogel Stabilization: Acrylamide monomers are pretreated with formaldehyde, then polymerized under UV to crosslink directly with tissue proteins, embedding heart slices in a polyacrylamide network.
- Decellularization: Detergents and DNase remove cells while preserving the ECM-hydrogel hybrid structure.
- Independent Stiffness Tuning: By varying acrylamide and bis-acrylamide ratios, researchers match Young (~10 kPa) or aged (~40 kPa) cardiac stiffness without altering ECM composition or architecture.
Insights into Cardiac Fibroblast Responses
Cardiac fibroblasts sense both biochemical ligands and mechanical stiffness. Using DECIPHER, studies show:
- Young ECM ligands can override fibrotic stiffness cues, keeping fibroblasts quiescent.
- Aged ECM composition drives activation markers (α-SMA, LOX) even at low stiffness.
- Mechanotransduction pathways (integrins, YAP, DDR2) differ with cell age and ECM state.
Applications in Longevity and Heart Health
Understanding how pure biochemical vs. mechanical cues direct fibroblast behavior helps:
- Identify therapeutic targets to prevent or reverse fibrosis.
- Design biomaterials that maintain healthy ECM properties in aging hearts.
- Screen anti-fibrotic compounds under physiologically relevant conditions.
By recapitulating the complex microenvironment of young and aged hearts, DECIPHER advances our ability to probe and eventually modulate aging processes at the tissue level.