Disease-driven Changes in the Extracellular Matrix


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It is widely accepted that cell-based assays traditionally performed in 2D on plastic surfaces are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to make these systems relatively poor models to predict drug responses, and therefore a contributing factor to the high failure rate in drug discovery. It is believed that 3D cell culture can better reproduce the physiochemical environment of in vivo tissue, providing cells mechanical and biochemical cues like those of native ECM. Therefore, it can provide more physiologically-relevant results, which can ultimately lead to better precision in drug discovery. Despite increased focus, major challenges remain in creating 3D cell-based assays which are reproducible and can recapitulate microenvironmental factors that resemble in vivo tissue as well as disease pathology.

From the smoothness of brain tissue to the toughness of bone, the mechanical properties of organs vary dramatically. The differences in these environments arise through cells secreting various ECM proteins and macromolecules in different proportionsin addition to intrinsic phenotypic intracellular cell type differences. Whilst such environments are regulated by depositions and degradation of these molecules during homeostasis, some diseases and injuries can disrupt this balancing process. Macromolecules in diseased ECM can be over-represented (upregulated) or reduced (downregulated) compared to levels in healthy tissue, meaning the microenvironment experienced by the cells drastically different in terms of the biochemical composition and in turn, mechanical properties. For example, major components of the microenvironment of the liver are collagen I, II, and IV, laminin, and elastin. During hepatic fibrosis downregulation of elastin is observed alongside an increase in liver stiffness as the disease progresses.

Similarly, with regards to cancer it is known that most solid tumours are stiffer  than normal tissue, indeed breast cancer is usually screened by detecting hard lumps in the breast. This stiffening is generally accompanied by an increase in deposition of collagen I, II, III, V, and IX during tumour formation. These examples demonstrate that the different properties of the ECM are not independent; rather, they are intertwined. When the ECM stiffens under pathological conditions, its biomechanical properties change, and cells respond by exerting markedly different kinds of force. In addition, matrix stiffening also changes other ECM physical properties and, consequently, directly impacts how migrating cells interact with the ECM.

Therefore, when developing cell-based models the ability to not only replicate the mechanical properties of the tissue of interest, but also being able to recapitulate the unbalanced ECM composition in diseased/injured tissue is important for providing a more physiologically relevant environment. This will enable amongst other things deeper investigation of the underlying mechanism of disease development, and more predictive pre-clinical assessment on the effects of drugs on both diseased and healthy tissue.

Employing 3D cell culture matrices which incorporate cell adhesion peptides (CAPs) offers an excellent way to reproduce both healthy tissue- and diseases-specific ECM compositions in a synthetic system. Biogelx offers a range of peptide-based hydrogels which not only allow the stiffness of the final gels to be controlled to match the mechanical properties of specific tissues, but also incorporate biomimetic peptide sequences to mimic key ECM proteins, including fibronectin (RGD), Collagen (GFOGER) and Laminin (IKVAV and YIGSR). Whilst these products are available off the shelf, the simple modular nature of Biogelx technology means that it can be easily customised to your requirements e.g. we can work with you to develop gel formulations incorporating alternative CAPs to remodel a specific tissue microenvironment, or we can optimise the concentration and ratio of CAPs incorporated with your specific application in mind. So, if you are looking to develop more disease-relevant cell culture models, get in touch to discuss our hydrogel customisation service .

 

References

  1. Forget et. al., Trends Biotechnol., 2018, 36, 4, 372-383
  2. Bataller & D. Brenner, J. Clin. Invest., 2005, 115, 209-218
  3. Lu et. al., J. Cell Biol., 2012, 196, 4, 395–406
  4. Yu et. al.,Trends Cell Biol.,2011, 21, 47–56

 

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