Extracellular Matrix Production at the cell-biomaterial interface

The extracellular matrix (ECM) is the physiologic material that surrounds cells in tissues. The ECM has several biological functions, which include providing physical support to cells, serving as a reservoir for growth factors and activating signaling pathways within cells. Indeed, when life science researchers need to study cell functions and diseases, they often use hydrogels that have been developed from natural biopolymers to engineer 3D tissues in vitro (in a dish). These natural ECM hydrogels are commonly isolated from animal cell cultures or tissues. However, their application due to the presence of multiple biopolymer-inherent properties has been limited. Therefore, Dr. Martin Ehrbar, professor at the University of Zurich, bioengineers synthetic hydrogels with properties that are similar to natural ECM and enable the reproducible and adjustable formation of 3D culture environments.

“Cells within synthetic hydrogels have been found to secrete ECM and during my PhD I had asked myself how this secreted ECM affects the behavior and fate of cells”, explained Dr. Ulrich Blache, scientist at the University and ETH Zurich. To ensure continued success of regenerative medicine, there is an urgent need to better understand the reciprocal interaction of cells with synthetic biomaterials and in particular the role of secreted ECM at the cell-material interface. Now, Dr. Edward Horton at University of Copenhagen in Denmark, together with the Swiss research team led by Dr. Ehrbar and Dr. Blache, carefully looked at how cell-derived ECM and culture conditions influence the gene expression of mesenchymal stromal cells (MSCs) in synthetic hydrogels. The authors showed that ECM gene expression is influenced by the 3D culture and strongly modulated by fibroblast growth factor 2 (FGF-2), a cytokine widely used in MSC and stem cell cultures around the world. The study is published in the Journal  Advanced Healthcare Materials.

The authors selected bone marrow-derived MSCs, a commonly used cell population in tissue engineering and regenerative studies. The research team observed that hydrogel-encapsulated MSCs secreted Fibronectin (FN) and that their spreading in  hydrogels was strongly decreased by FN depletion, independent of the presence of cell adhesion motifs. However, in FN-depleted cells that were grown on tissue culture glass or plastic in 2D, cell spreading was unaffected.

The researchers also observed that the expression of ECM genes was influenced by the 3D culture conditions itself. Furthermore, when MSCs are in hydrogels, the team found that FGF-2 modulated genes associated with cell cycle, contractile cytoskeleton and ECM. This could influence how MSCs in hydrogels remodel their microenvironment, which in turn can affect cell behavior and fate.

With the elegant comprehensive studies conducted, the authors were able to demonstrate that cell-secreted ECM is a key component at the cell-material interface in synthetic hydrogels. To advance even further the use of synthetic biomaterials in medicine, the Swiss scientists recommend better understanding the reciprocal interaction of cells and secreted ECM in the synthetic hydrogels and to examine the effects of other culture properties on ECM regulation.