Deciphering the extracellular matrix (ECM) code
The extracellular matrix (ECM) is an essential mediator of tissue function that provides both chemical and mechanical stimuli to influence cellular behavior in both health and disease. Remodelling of cellular microenvironments, including its biomineralization, and ECM by enzymes such as matrix metalloproteases (MMPs/ADAMs) and lysyl oxidases (LOX/LOXL) is a fundamental process, which is why its importance is becoming increasingly acknowledged. However, formidable challenges remain towards identifying the diverse and novel roles of such enzymatic ECM reactions, especially with regard to their distinct biophysical, biochemical, and cellular impact.
Considering the heterogeneous, dynamic and hierarchical nature of both the ECM and cellular microenvironments, we set to decipher remodelling molecular mechanisms dictating cell behavior in various physiological and pathological scenarios. Accordingly, we utilize a multidisciplinary integrated research scheme which provides a three-dimensional functional molecular view of ECM remodelling, driven by proteolysis and covalent collagen cross linking. This scheme integrates methods including optical imaging, electron and atomic force microscopies, diffraction and X-ray based spectroscopic methods, in order to span wide ranges of spatial and temporal resolutions. Subsequently, we employ systems biology tools to reveal changes in ECM molecular compositions, focusing on native and reconstituted ECM environments.
By implementing our discoveries of these highly selective functions, into the design of novel molecular agents targeting pathological ECM remodeling, we can impact invasive diseases causing inflammation and cancer.
Second-harmonic imaging of native human colon biopsies revealing extracellular matrix (ECM) remodelling in IBD. Left: Healthy colon biopsy from a patient without IBD. Right: Inflamed colon biopsy from a patient with IBD. Note the thickening of ECM barrier between crypts (indicated by curvy arrows), the formation of holes within this barrier (indicated by arrowheads) and changes in collagen microstructure. For full paper go to: Shimshoni, Gut, 2015.