TY - JOUR
T1 - Activating hidden signals by mimicking cryptic sites in a synthetic extracellular matrix
AU - Zhu, Yumeng
AU - Shmidov, Yulia
AU - Harris, Elizabeth A.
AU - Theus, Michelle H.
AU - Bitton, Ronit
AU - Matson, John B.
N1 - Funding Information:
This work was supported by the Binational Science Foundation (2016096 to J.B.M. and R.B.) and the National Institutes of Health (R01GM123508 to J.B.M.). We thank Dr. Matthew Webber, Dr. Yin Wang, Zhao Li, and Dr. Mingjun Zhou for helpful discussions; Katlyn F. Morales for experimental assistance; Dr. Padma Rajagopalan and Rosalyn Hatlen for HUVEC cells and providing suggestions on cell culture; Dr. Andrew Lowell and Dr. Jennifer McCord for instrument access; Gal Yosefi for SEM; Dr. Olga Iliashevsky for assistance with hydrogel characterization; Dina Aranovich for helpful suggestions on cell studies; and Dr. Keith Ray for assistance with MALDI-TOF experiments.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85162191762&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39349-w
DO - 10.1038/s41467-023-39349-w
M3 - Article
C2 - 37336876
AN - SCOPUS:85162191762
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3635
ER -