Uncovering the importance of the extracellular matrix in tissue growth and medical applications

Viola Vogel, a professor at ETH, and her senior assistant Mario C. Benn, are interested in understanding how body tissue grows, from embryo development to wound healing and cancer progression. However, instead of studying cells and their biochemical processes in isolation, they are focusing on the extracellular matrix (ECM), a fibrous structure that surrounds body cells and is a major component of all tissue.

Their research shows that there are various interactions between body cells and the ECM, some of which are mechanical or physical rather than purely biochemical. For example, cells can sense mechanical stimuli from the ECM. With their team of researchers, Vogel and Benn have replicated tissue growth in vitro to study this process in detail. Benn emphasizes the significance of these interactions between cells and the ECM and hopes to eventually apply these findings in medicine, particularly in preventing wound-healing disorders and treating cancer and connective-tissue diseases.

Cell transformation

Viola Vogel and Mario C. Benn’s recent study, published in Science Advances, focused on fibroblasts and myofibroblasts, two important cell types for human tissue functionality. Fibroblasts are located in the connective tissue of our organs, where they ensure the extracellular matrix remains healthy and continuously renewed. When tissue growth or injury occurs, they transform into myofibroblasts, which play a crucial role in wound healing and tissue growth by producing large amounts of ECM and exerting force to pull tissue together in wounds.

However, it is crucial for myofibroblasts to transform back into less active fibroblasts once their work is complete. Failure to do so can lead to fibrosis, the excessive formation of scar tissue. Myofibroblasts are also present in cancer tissue and are linked to poor prognosis in many cancers. Benn notes the importance of understanding the behavior of these cells to improve wound healing and prevent fibrosis and cancer progression.

Three-dimensional matrix

There is limited understanding of how the extracellular matrix (ECM) influences the transformation of myofibroblasts into fibroblasts, despite knowledge of the biochemical processes involved. According to Vogel, conventional cell-culture methods produce an artificial ECM as the cells grow flat on the culture dish. However, studying cells without the ECM is akin to studying spiders without their webs. To address this, Vogel and Benn developed a silicone scaffold with microscopic triangular clefts coated in specific proteins, which allows for the formation of natural ECM over two weeks.

During tissue growth, myofibroblasts are consistently located at the tissue’s growth front and generate new ECM, initially in a provisional and then in a more stable form, before reverting to fibroblasts. This process is similar to the late-phase wound healing process in human subcutaneous tissue. Rapidly changing ECM is one trigger for myofibroblast-to-fibroblast reversion, with fibronectin changing from a stretched to a relaxed state.

The researchers intentionally disrupted the cell transition using agents that alter the ECM’s composition or structure. This enabled them to mimic the stabilization of myofibroblasts by the ECM in pathologies such as fibrosis or cancer, where they do not revert to fibroblasts as they would in healthy tissue.

Future mechano-medicine

The utilization of miniature tissue cultures is anticipated by the researchers to provide a better understanding of the interaction between human cells and their extracellular matrix. This approach not only avoids animal testing which is often employed in biomedical research but can also be used to evaluate candidate substances during drug development. Benn emphasizes that comprehending how myofibroblasts and fibroblasts transition into one another and being able to control that process can significantly improve conditions such as wound-healing disorders, fibrosis, and cancer.

Benn and Vogel also foresee the emergence of mechano-medicine, a future field that applies mechanobiology research findings to medical practice. Mechano-medicine aims to utilize the insights gained from mechanobiology to develop new diagnostic methods for the early detection of fibrotic tissue. Benn explains that early detection is essential in successfully treating many conditions, including pulmonary fibrosis.

Currently, screening methods are unable to accurately detect myofibroblasts in lung tissue. The researchers hope that the study of the extracellular matrix will reveal biomarkers that enable earlier and simpler detection of fibrosis and related connective-tissue diseases.

Source: ETH Zurich

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