Activating hidden signals by mimicking cryptic sites in a synthetic extracellular matrix

In this work, the authors synthetized hydrogels that mimic cryptic sites in the native extracellular matrix (ECM) using switch peptides. They report how in response to enzymes on the surface of endothelial cells the inert matrix is transformed into a bioadhesive synthetic ECM. Cryptic sites are short signaling peptides buried within the native extracellular matrix (ECM). Enzymatic cleavage of an ECM protein reveals these hidden peptide sequences, which interact with surface receptors to control cell behavior. Materials that mimic this dynamic interplay between cells and their surroundings via cryptic sites could enable application of this endogenous signaling phenomenon in synthetic ECM hydrogels. We demonstrate that depsipeptides (switch peptides) can undergo enzyme-triggered changes in their primary sequence, with proof-of-principle studies showing how trypsin-triggered primary sequence rearrangement forms the bioadhesive pentapeptide YIGSR. We then engineered cryptic site-mimetic synthetic ECM hydrogels that experienced a cell-initiated gain of bioactivity. Responding to the endothelial cell surface enzyme aminopeptidase N, the inert matrix transformed into an adhesive synthetic ECM capable of supporting endothelial cell growth. This modular system enables dynamic reciprocity in synthetic ECMs, reproducing the natural symbiosis between cells and their matrix through inclusion of tunable hidden signals.

Automated summary

In this research, hydrogels that imitate cryptic sites in the native extracellular matrix (ECM) were synthesized using switch peptides. The inert matrix undergoes a transformation into a bioadhesive synthetic ECM in response to enzymes on endothelial cells' surface. Cryptic sites are short signaling peptides that are hidden within the native ECM. Enzymatic cleavage of an ECM protein reveals these hidden peptide sequences, which interact with surface receptors to control cell behavior. Materials that mimic this dynamic interplay between cells and their surroundings via cryptic sites could enable application of this endogenous signaling phenomenon in synthetic ECM hydrogels.