Extracellular matrix

Extracellular matrices (ECMs) are the secreted molecules that create the micro-environment for cells and provide tissue with shape and strength^{1, 2}.Biologic scaffolds created from ECMs are becoming increasingly common for the treatment of a variety of medical conditions³. Commercially available scaffolds are created from a wide array of sources; multiple species and tissue types have all been successfully processed into biologic scaffolds⁴. ECM scaffolds have similar constitution regardless of tissue source because all ECM scaffolds will contain the structural and functional molecules native to the source tissue.

The structural component of the ECM is primarily collagen. More specifically, the majority in most tissue is type I collagen⁵. Additional fibril collagen species, types III, V, and XI, and non-fibril collagen forms, types IV and VIII, will be present dependent on tissue type⁶. In addition to the collagen content, ECMs can contain several adhesion molecules⁵ such as elastin, fibronectin, and laminins, which give each tissue type a unique ECM matched to the tissue’s function. The third major structural component of ECMs⁵ are proteoglycans (PGs), a base protein bonded with one or more glycosaminoglycans (GAGs). Some common extracellular PGs are aggrecan, versican, and decorin but similar to other structural molecules, PG content varies based on source tissue type⁶.

The functional component in an ECM is a range of molecules that contribute to the ECM’s function via autocrine, juxtacrine and paracrine signaling ⁷. The functional molecules can be divided into categories based on action, including growth factors, interleukins, and tissue inhibitors of metalloproteinases (TIMPs)^3,6,8,9. Growth factors and signaling proteins that direct cellular activity, are present throughout the body and contribute to the proper function of tissue. Common growth factors include Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factors (IGFs), Platelet Derived Growth Factors (PDGFs), and Transforming Growth Factor-Beta (TGFβ)^9,10. Interleukins, a group of proteins primarily responsible for cell communication of the immune system, are critical for the control of both immune and inflammatory responses. There are more than 50 interleukins that have been identified¹¹. Finally, TIMPs help regulate the function of tissue by inhibiting the activity of matrix metalloproteinases, a collection of enzymes that can degrade the various matrix proteins¹. All of the functional molecules work interactively to maintain normal and reparative activities in the tissue¹².

Quick-freeze, deep-etch electron microscopy image of a cell with its extracellular matrix. Image provided by by Dr. John Heuser and Dr. Robert Mecham, Washington University School of Medicine in St. Louis.

1. Brew, K., D. Dinakarpandian, and H. Nagase, Tissue inhibitors of metalloproteinases; evolution, structure and function. Biochimica et Biophysica Acta (BBA) – Protein Structure and Molecular Enzymology, 2000. 1477(1-2): p. 267-283.

2. Young, J.L., A.W. Holle, and J.P. Spatz, Nanoscale and mechanical properties of the physiological cell-ECM microenvironment . Exp Cell Res, 2016. 343(1): p. 3-6.

3. Hussey, G.S., J.L. Dziki, and S.F. Badylak, Extracellular matrix-based materials for regenerative medicine. Nature Reviews Materials, 2018. 3(7): p. 159-173.

4. Agmon, G. and K.L. Christman, Controlling stem cell behavior with decellularized extracellular matrix scaffolds. Curr Opin Solid State Mater Sci, 2016. 20(4): p. 193-201.

5. Badylak, S.F., D.O. Freytes, and T.W. Gilbert, Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater, 2009. 5(1): p. 1-13.

6. Theocharis, A.D., et al., Extracellular matrix structure. Adv Drug Deliv Rev, 2016. 97: p. 4-27.

7. Wallner, E.I*., et al., Relevance of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis. Am J Physiol, 1998. 275(4): p. F467-77.

8. Engin, A.B., et al., Mechanistic understanding of nanoparticles’ interactions with extracellular matrix: the cell and immune system. Part Fibre Toxicol, 2017. 14(1):p.22.

9. Kim, S.H., J. Turnbull, and S. Guimond, Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol, 2011. 209(2): p. 139-51.

10. Taipale, J. and J. Keski-Oja, Growth factors in the extracellular matrix. FASEB J, 1997. 11(1): p.51-9.

11. Brocker, C., et al., Evolutionary divergence and functions of the human interleukin (IL) gene family. Human Genomics, 2010. 5(1).

12. Schultz, G.S., et al., Dynamic reciprocity in the wound microenvironment. Wound Repair Regen, 2011. 19(2): p. 134-48.