Abstract
Extracellular-matrix remodeling is an emerging hallmark of complex tissue pathologies, generating biomechanical and molecular signals to the cells at various stages of disease progression. As a fundamental component of virtually all tissues, the extracellular matrix has been widely studied. But as a complete, defined and dynamic entity in its own right, it remains poorly understood. Here, we took a systematic, holistic approach, to investigate the multidimensional extracellular-matrix landscape, spanning structure, stiffness, and protein and metabolite compositions, both in healthy animals, and as a dynamic test case, during intestinal inflammation. By integrating computational and advanced imaging analyses, we correlate proteomic composition to structural damage while revealing the potential of the extracellular matrix as a metabolite reservoir. Unexpectedly, this comprehensive analysis uncovered a previously undescribed, silent pathological tissue state occurring before the onset of inflammatory symptoms in the colon, characterized by discrete morphological and molecular changes in the extracellular matrix, along with protein and biomarker variation. This early pathology is exhibited as a multidimensional extracellular-matrix footprint by two different types of colitis models and represents a tissue state that readily leads to full-blown disease. We offer this powerful diagnostic modality as a novel method, which we term “Multi-ECM”, and suggest that application of Multi-ECM to other tissue-damaging diseases will reveal additional clinically silent states that foretell their onset.