Tissue-Mimicking Hydrogel Restores Cellular Health

The mechanical properties of tissue matrix are crucial for maintaining cell health adn function.With aging, tissue matrix loses its mechanical integrity and exhibits altered biophysical properties, which are closely associated with various diseases including neurodegenerative diseases and cancers. While scientists have recognized the importance of matrix mechanical properties, whether cellular health can be maintained or restored by mimicking the mechanical microenvironment of healthy tissues remains an unsolved mystery.

Traditional cell reprogramming primarily relies on biochemical factors or gene editing technologies, but these methods may have off-target effects or tumorigenic risks. Although recent studies have shown that certain mechanical signals can assist cell reprogramming, there lacks a material platform that can simultaneously mimic both the viscoelastic and nonlinear elastic characteristics of native tissues. Native tissue matrix possesses both viscoelastic and nonlinear elastic properties, but existing synthetic or natural hydrogels mainly mimic only one of these characteristics. This limitation hinders a deeper understanding of the role of tissue mechanical microenvironment in maintaining cellular function.

Innovative technology breakthrough

To overcome these limitations, the HUST team developed a unique alginate-collagen interpenetrating network (IPN) hydrogel system called “tissue-mimicking hydrogel.” This innovative design cleverly combines the nonlinear elastic characteristics provided by collagen networks with the viscoelastic shear-thinning behavior exhibited by alginate networks. By adjusting calcium ion crosslinking concentrations, the research team could precisely control the initial storage modulus of the hydrogel while maintaining consistent collagen and alginate concentrations, thereby mimicking the mechanical properties of tissues of different ages. This design significantly enhances mechanical stability and ensures high reproducibility of experimental results.

The most critically important finding of the research is that cells can achieve long-range mechanical interactions through matrix remodeling. Fibroblasts cultured on tissue-mimicking hydrogels exhibited unprecedented behavioral patterns: cells first spread normally on the hydrogel surface,then began migrating toward each other after 8 hours to form mesenchymal aggregates,with cell aggregation leading to collagen fiber reorganization and bundle structure formation. This phenomenon was not observed on pure collagen or alginate substrates,proving the importance of synergistic effects between viscoelastic and nonlinear elastic components.

Mechanism discovery and validation

Using contractility inhibitors, the research team demonstrated that enhanced cellular contractility is the key factor driving cell aggregation and reprogramming. When cellular contractility was inhibited, mesenchymal aggregates dissociated into individually spreading cells, reprogramming-related gene expression was suppressed, and the enhanced differentiation potential effects disappeared. This indicates that the positive feedback loop between cellular contractility and matrix mechanical properties is the core mechanism for achieving reprogramming.

Transcriptomic analysis revealed the profound impact of tissue-mimicking hydrogels on cell reprogramming. Stemness genes including mesenchymal stem cell markers such as Id1, Id2, Cd36, and Cd9 were significantly upregulated.