Tissue-mimicking hydrogels drive cell reprogramming via matrix remodeling

The mechanical properties of tissue matrix are crucial for maintaining cell health and 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 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, and multiple reprogramming-related pathways including Wnt signaling, Hippo signaling, and PPAR signaling were activated. More importantly, genes related to both adipogenesis and osteogenesis were simultaneously upregulated, breaking the traditional notion that these two differentiation pathways mutually inhibit each other. Functional validation experiments confirmed that cells cultured on tissue-mimicking hydrogels showed a 2.5-fold increase in lipid droplet accumulation after adipogenic induction and significantly elevated ALP expression after osteogenic induction.

Breakthrough application in cancer transdifferentiation therapy

The research team successfully applied this technology to cancer therapy. Non-small cell lung cancer H1975 cells on tissue-mimicking hydrogels transformed from a spread mesenchymal morphology to an aggregated state and successfully differentiated into adipocyte-like cells, expressing adipocyte markers such as Perilipin and PPARγ. Meanwhile, mesenchymal stress fibers reorganized into cortical actin, indicating cell immobilization.

Transcriptomic analysis showed that cancer cells underwent critical molecular changes on tissue-mimicking hydrogels: epithelial-mesenchymal transition-related genes were suppressed while mesenchymal-epithelial transition (MET)-related genes were activated; oncogenes such as EGFR, BRCA1, and CDC20 were downregulated, while tumor suppressor genes such as ACSL1, GADD45G, and CRB3 were upregulated. These molecular changes indicate that tissue-mimicking hydrogels can not only induce cancer cell transdifferentiation but also reverse their malignant characteristics.

Clinical significance and application prospects

This technology has broad application prospects in regenerative medicine, serving as a platform for ex vivo expansion and reprogramming of patient autologous cells to enhance their therapeutic potential, and can be developed as injectable scaffold materials to promote cell aggregation and differentiation in tissue repair. In cancer treatment, this technology opens new transdifferentiation therapy strategies, converting cancer cells into non-proliferative adipocytes to fundamentally change tumor properties, and can be combined with traditional chemotherapy and radiotherapy to improve treatment efficacy.

Compared to traditional reprogramming methods, this technology has significant advantages: it avoids potential off-target effects and tumorigenic risks of gene editing, requires no complex biochemical factor combinations or gene vectors, provides sustained reprogramming environment through matrix-mediated mechanical signals, and shows effectiveness across multiple cell types. This technology can also serve as an innovative platform for drug screening, used to study key molecular targets in cell reprogramming processes, evaluate the effects of candidate drugs on cell transdifferentiation, and assess drug safety in environments closer to native tissues.

Conclusion

The tissue-mimicking hydrogel technology developed by Professor Yiwei Li’s team at HUST represents a major breakthrough in the field of cell reprogramming. By achieving purely mechanical signal-induced cell reprogramming for the first time, this technology not only provides new perspectives for understanding the role of tissue mechanical microenvironment in maintaining cell health but also opens new therapeutic avenues for regenerative medicine and cancer treatment. The core innovation of this research lies in discovering the mechanism of matrix-mediated long-range cell-cell mechanical interactions and revealing the critical role of enhanced cellular contractility in the reprogramming process. This work has not only made important theoretical advances but also demonstrated tremendous practical potential. With further technological refinement and clinical translation research, it promises to make important contributions to human health, particularly in addressing global aging and cancer treatment challenges.