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When it comes to the development of multicellular organisms (MCO), most discussions look only at the intracellular processes while ignoring the extracellular space. The first part of this series looked at what is actually needed to maintain homeostasis for just some of the chemical parameters of the extracellular space of a MCO, else death (e.g. oxygen, water and glucose). However, your cells mostly consist of water and so do all the tissues and organs in your body. So, how do they maintain their shape and what gives them structural and mechanical support? As the last article noted it is the cell’s cytoskeleton (microtubules, microfilaments and intermediate filaments) that give it shape and structural and mechanical support. And it is the connective tissue, consisting of cells (mostly fibroblasts) that secrete a gel-like ground substance and protein fibers, that crisscross through it, which provide your body’s tissues and organs with structural and mechanical support. The ground substance and protein fibers are called the extracellular matrix (ECM) which is the non-cellular component of connective tissue. In fact, different types of connective tissue provide different types of support. In the human body this runs from solid bones, to softer and more elastic cartilage, to high tensile strength ligaments and tendons, to the delicate web-like laced spider-like networks (bubble wrap) that supports most of its organs and passageways. It all depends upon the different types of cells which secrete different types of ground substance and the density and material qualities of the different protein fibers running through it. But the ECM does much more than just provide the body’s tissues and organs with structural and mechanical support. It also affects cell signaling, migration, growth, proliferation, differentiation and survival, all of which regulates tissue morphology, development, homeostasis and function. This is the first of six articles that will look at how the ECM manages all of these functions through its main components, collagen and elastin fibers, the gel-like ground substance made of water, glycoaminoglycans (GAGs), proteoglycans (PGs) and glycoproteins (GPs), along with growth factors (GFs), enzymes and more (Figure 1).
Collagens (and Elastins)Collagens are the most abundant protein in the ECM, and the body, making up about 30% of its total protein mass. They are secreted mainly by fibroblasts and also several specialized ECM cells like osteoblasts (bone-forming cells) and chondroblasts (cartilage-forming cells). Collagen fibers are large proteins made up of thousands of collagen fibrils which in turn consist of many thousands to millions of triple helical tropocollagen molecules (Figure 2). They act as scaffolding and depending on the amount and types of collagens within a given tissue, provide different degrees of structural and mechanical support due to their different tensile strength to resist pulling and stretching.
Collagen starts out in the cell as single α-chains made in ribosomes. They get sent to the endoplasmic reticulum where, with the help of Vitamin C and two iron-dependent enzymes, they combine with each other to form triple helical molecules called procollagen. Procollagen remains dissolved in the cytoplasm due to having globular hydrophilic extensions (peptides) at each end of its three α-chains (coming out of solution while still in the cell would be disastrous). After procollagen is released from the cell into the ECM, two zinc-dependent enzymes cleave off the peptides from the ends of its α-chains and it becomes tropocollagen. These actions allow the tropocollagen molecules to spontaneously interact with each other to form collagen fibrils, and in so doing, come out of solution. After this a copper-dependent enzyme helps to strengthen the collagen fibrils by forming crosslinking bonds all of which eventually results in the formation of collagen fibers (Figure 3). This is why zinc, iron, Vitamin C and copper are vital for proper connective tissue function and deficiency of any of them results in fragile skin and poor wound healing among other problems.
Collagen I, which is like a “braided steel cable”, strong, stiff and resistant to stretch, represents about 90% of the total, and is in tissues requiring high tensile strength and rigidity, like tendons, ligaments, bone, skin and the cornea. Collagen II, which is like a “shock absorbing gel”, resistant to compression, while flexibly cushioning, is in the cartilage within the joints and intervertebral discs and the vitreous humor. Collagen III, which is like a “nylon fishing net”, resilient, flexible and elastic, is in skin, blood vessels, lungs, muscles, intestines and hollow organs like the uterus and bladder. Collagen IV, unlike the fibers of types I, II & III, forms “sheet-like networks” and is part of the basement membrane that separates tissues like the epithelium and endothelium from the ECM. Besides these four types of collagen, which are the most abundant and studied, the rest of them works to provide additional structural and mechanical support while helping cell attachment, and the processes of differentiation and proliferation, gene expression, wound healing, blood clotting, the delivery of bioactive molecules, and modulating immune function. The ECM also has elastic fibers, composed of proteins called elastins that are sheathed with a glycoprotein called fibrillin, and stabilized by another called fibulin, that act like “rubber bands” to provide stretch and recoil in tissues like the major arteries, lungs, tendons, ligaments and skin. Evolutionary “Explanations”“One of the specific components of metazoan extracellular matrices is collagen, which is present in organisms ranging from sponges to humans. By comparing data obtained in diploblastic, protostomic, and deuterostomic animals, we have attempted to trace the evolution of collagens and collagen-like proteins. Moreover, the collagen story is closely involved with the emergence and evolution of metazoa. The collagen triple helix is one of numerous modules that arose during the metazoan radiation which permit the formation of large multi-modular proteins.” AnatRec 268:302–316, 2002. ©2002 Wiley-Liss, Inc. “The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily –comprising 28 types in vertebrates – that exist in diverse supramolecular assemblies ranging from networks to fibrils. Each assembly is characterized by a hallmark feature, a protein structure called a triple helix. A current gap in knowledge is understanding the mechanisms of how the triple helix encodes and utilizes information in building scaffolds on the outside of cells. Type IV collagen, recently revealed as the evolutionarily most ancient member of the collagen superfamily, serves as an archetype for a fresh view of fundamental structural features of a triple helix that underlie the diversity of biological activities of collagens. In this Opinion, we argue that the triple helix is a protein structure of fundamental importance in building the extracellular matrix, which enabled animal multicellularity and tissue evolution.” Questions:
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| Table of Contents - The Extracellular Space |
Howard Glicksman MD is a G.P. who graduated from the University of Toronto in 1978. He had an office/hospital practice for 25 years and recently retired from providing medical care for hospice patients in their homes for over 20 years. His online articles on “how the body works” culminated in a book he co-authored with Steve Laufmann called Your Designed Body (2022). Read his other online articles here.