There are more than twenty different types of collagens expressed in human skin, each with its own unique role in the skin, which together maintain skin health. Among them, the most abundant in the skin are fibrillar collagen types I and III. In fact, as the main component of the basement membrane, type IV collagen is closely associated with a variety of components to build a stable basement membrane network, playing a vital role. One of the main differences between type IV collagen and other types of collagen is that it retains the globular amino and carboxyl termini, and can self-assemble into hexamers through the carboxyl termini and dodecamers through the amino termini to form a mesh structure that is laid flat between the true epidermis. Type IV collagen is an important structural component of the basement membrane and the most abundant collagen. The basement membrane is a special sheet-like extracellular matrix that lies beneath epithelial and endothelial cells and acts as a barrier between tissue compartments. Type IV collagen is a network-forming collagen that provides a molecular scaffold and interacts with cells, growth factors, integrins, and other basement membrane components (such as laminin and entactin). Specific interactions give rise to a specialized basement membrane that is unique to each tissue and is involved in several important biological processes, including cell adhesion and migration, development, tissue regeneration, and wound healing.
Figure 1. Collagen for drug delivery. (An B, et al. 2016)
Type IV collagen has a rod-like structure of about 400 nm in length, of which the central triple helical collagen domain of about 330 nm consists of two globular domains that remain attached in the mature protein, in contrast to fibrillar collagen. Type IV collagen α chains have similar domain structures and have 50-70% homology at the amino acid level. Each α chain is a rope-like structure consisting of a short N-terminal 7S domain of about 120 amino acids, a central collagen triple helical domain (about 1400 residues), and a C-terminal globular non-collagen (NC) 1. There are six types of α-peptide chains that make up IV-C, namely α1, α2, α3, α4, α5, and α6 peptide chains. According to the similarity of the amino acid sequences, these peptide chains can be divided into two categories: α1, α3, and α5-peptide chains are α1-like peptide chains (α1-like chain), while α2, α4, and α6-peptide chains are α2-like peptide chains. (α2-like chain). Although the genes encoding each type of peptide chain are different, the structures of the six types of α-peptide chains are similar to each other. So far, the amino acid sequence determination of human type six α-peptide chain has been completed. The α1-6 peptide chain consists of 1642, 1676, 1652, 1652, 1659 and 1670 amino acid residues respectively. Each α-peptide chain contains an N-terminal 7S structure, a middle collagen domain, and more than twenty non-collagen domains and NC1. The 7S structure at the N-terminal end of the α-peptide chain consists of approximately 23 amino acid residues, rich in cysteine and lysine, and contains 5 conserved cysteine residues. The middle of the peptide chain is composed of collagen and non-collagen domains. The collagen domain in the middle of the peptide chain consists of approximately 1,400 amino acid residues, which are mainly composed of repeated Gly-Xaa-Yaa collagen motifs, where Xaa is usually proline or lysine and Yaa is usually hydroxyproline or hydroxylysine. The homology of the central collagen helical domain is 47%~49%, derived mainly from glycine and proline in the repeating motif. These repeating motifs are interspersed with approximately 21 to 26 non-collagenous sequences. There are also two conserved cysteines in the 9th non-collagenous domain interspersed in the collagenous domain. Type IV collagen is mainly found in tissues such as the glomerular basement membrane, cornea, cochlea, and synovium. It plays an important supporting and protective role in these tissues. For example, in the glomerular basement membrane, type IV collagen forms a sieve-like structure that prevents large molecules from entering the urine and protects the normal function of the glomerulus. In the cornea, type IV collagen forms a transparent structure, maintaining the transparency and strength of the cornea. In addition, type IV collagen is also involved in the assembly of the extracellular matrix and cell adhesion, and has a regulatory effect on cell migration and proliferation.
Type IV collagen has wide application value in the medical field. First, it can be used as a biomaterial in tissue engineering and regenerative medicine. Due to its good biocompatibility and bioactivity, type IV collagen can be used to repair damaged tissues and regenerate organs. For example, combining type IV collagen with stem cells can produce bioactive artificial skin and bone tissue. In addition, type IV collagen can also be used to prepare drug sustained-release systems to improve the stability and bioavailability of drugs. Type IV collagen is also widely used in clinical diagnosis and treatment. Due to its specific expression in different tissues, type IV collagen can serve as an important biomarker for disease diagnosis and monitoring. For example, abnormal expression of type IV collagen in the glomerular basement membrane is associated with kidney disease. By testing levels of type IV collagen, the severity of kidney disease can be detected and assessed at an early stage. In addition, type IV collagen can be used as a carrier for targeted therapy by modifying drugs or cells on its surface to target specific diseases.
Alternate Names:
Type IV collagen
Alpha-4(IV) collagen
Alpha-IV collagen
COL4A4
References:
1. Wu Y, Ge G. Complexity of type IV collagens: from network assembly to function. Biol Chem. 2019, 400(5):565-574.
2. Shahrajabian MH, Sun W. Mechanism of Action of Collagen and Epidermal Growth Factor: A Review on Theory and Research Methods. Mini Rev Med Chem. 2024, 24(4):453-477.
3. An B, et al. Collagen interactions: Drug design and delivery. Adv Drug Deliv Rev. 2016, 97:69-84.
Collagen-based formulations for wound healing: A literature review
Life Sci.
Authors: Sharma S, Rai VK, Narang RK, Markandeywar TS.
Abstract
Wounds have always been the point of concern owing to the involvement of infections and the level of severity. Therefore, the management of wounds always requires additional effort for comprehensive healing and subsequent removal of the scar from the wound site. The role of biomaterials in the management of chronic wounds has been well established. One of such biomaterials is collagen (Col) that is considered to be the crucial component of most of the formulations being developed for wound healing. The role of Col extracted from marine invertebrates remains an unmarked origin of the proteinaceous constituent in the evolution of innovative pharmaceuticals. Col is a promising, immiscible, fibrous amino acid of indigenous origin that is ubiquitously present in extracellular matrices and connective tissues. There are different types of Col present in the body such as type I, II, III, IV, and V however the natural sources of Col are vegetables and marine animals. Its physical properties like high tensile strength, adherence nature, elasticity, and remodeling contribute significantly in the wound healing process. Col containing formulations such as hydrogels, sponges, creams, peptides, and composite nanofibers have been utilized widely in wound healing and tissue engineering purposes truly as the first line of defense. Here we present the recent advancements in Col based dosage forms for wound healing. The Col based market of topical preparations and the published reports identify Colas a useful biomaterial for the delivery of pharmaceuticals and a platform for tissue engineering.
Engineering a collagen matrix for cell-instructive regenerative angiogenesis
J Biomed Mater Res B Appl Biomater
Authors: Minor AJ, Coulombe KLK.
Abstract
Engineering an angiogenic material for regenerative medicine requires knowledge of native extracellular matrix remodeling by cellular processes in angiogenesis. Vascularization remains a key challenge in the field of tissue engineering, one that can be mitigated by developing platforms conducive to guiding dynamic cell-matrix interactions required for new vessel formation. In this review, we highlight nuanced processes of angiogenesis and demonstrate how materials engineering is being used to interface with dynamic type I collagen remodeling, Notch and VEGF signaling, cell migration, and tissue morphogenesis. Because α1(I)-collagen is secreted by endothelial tip cells during sprouting angiogenesis and required for migration, collagen is a very useful natural biomaterial and its angiogenic modifications are described. The balance between collagen types I and IV via secretion and degradation is tightly controlled by proteinases and other cell types that are capable of internalizing collagen to maintain tissue integrity. Thus, we provide examples in skin and cardiac tissue engineering of collagen tailoring in diverse cellular microenvironments for tissue regeneration. As our understanding of how to drive collagen remodeling and cellular phenotype through angiogenic pathways grows, our capabilities to model and manipulate material systems must continue to expand to develop novel applications for wound healing, angiogenic therapy, and regenerative medicine.
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