Written by Ian Jay B. Francisco

Connective tissues occur throughout the body. They provide support, bind stuff together, and protect the body’s organs. Looking at a microscopic photo of connective tissues, you will see fibroblasts.

Connective tissues consist of cells, protein fibers, and a ground substance. Fibroblasts are the most common cell type that you can find in a connective tissue specimen. They produce and maintain the extracellular matrix of your connective tissues.

Fibroblasts secrete collagen proteins that support many tissues. They also help heal wounds. These cells are spindle-shaped, elongated, and have several processes that extend their bodies.

You can find them in the skin, tendons, and other tough tissues of the body. These are collagen-secreting cells. They can be grown in a lab for genotypic and phenotypic testing of the associated disease.

Like any other cell, organelles make up fibroblasts. They have an oval nucleus that is euchromatic. You would find an abundant endoplasmic reticulum and a well-developed Golgi apparatus. It is because they produce large amounts of protein.

The more minor, inactive form of this cell is the fibrocyte. The cells differ because the nuclei of fibrocytes are heterochromatic. Their cytoplasm and organelles are also lesser in comparison to fibroblasts.

Fibroblasts produce extracellular matrix (ECM) proteins, such as collagen and elastin. Aside from these proteins, the ECM also contains glycosaminoglycans, reticular fibers, and glycoproteins.

Contractile myofibroblasts, which are essential in wound healing, are unique fibroblasts. When tissue undergoes damage, fibrocytes become stimulated. They then undergo mitosis or multiplication by replication and division.

What is produced by fibroblasts?

Aside from tissue repair, fibroblasts have other functions. They are responsible for regulating and maintaining the body’s connective tissues. They achieve this by producing fibrous proteins and ground substances.

The ECM’s compositions are fibrous proteins and ground substances produced by fibroblasts. It provides an adjustable structural base for tissue growth and stores growth factors. The ECM also transmits signals within the tissue and acts as an adhesive substrate.

Fibrin, fibronectin, and collagen are the fibrous proteins produced by fibroblasts. Collagen provides the mechanical strength required for tissue formation. Meanwhile, fibrin and fibronectin give the basic framework for cell adhesion.

The ground substance is the collection of the ECM’s non-fibrous proteins. It is a clear gel that fills in cell gaps and helps tissues resist compression.

Glycosaminoglycans are long unbranched polysaccharide chains that you can find in-ground substances. An example would be proteoglycan. It plays a role in growth factor propagation and enzyme regulation.

Fibers and connector proteins produced by fibroblasts give tissues their structure. Reciprocal positive feedback regulation of these proteins can promote profibrotic myofibroblast differentiation. ECM structures can serve as lamina delineating borders separating distinct cell types

Fibroblasts secrete a diverse array of structural proteins with unique properties. Its rope-shaped triple-stranded helical tertiary protein structure reinforces its tensile strength. This structure also prevents overstretching.

Elastin proteins form cross-linked but unstructured elastic networks that stretch without breaking. Skin and lung tissues differ in their expression of collagen and elastin proteins. Moreover, fibrosis pathology includes an increase in the relative balance of collagen.

How do fibroblasts make collagen?

Like all other proteins, collagen’s components are amino acids. It supports extracellular connective tissue structure. Collagen synthesis occurs both inside and outside your fibroblasts.

Its rigidity and stretch resistance allow it to be a part of your skin, tendons, bones, and ligaments. Amino acids, which are the building blocks of proteins, also make up collagen. Collagen’s primary amino acid sequence is glycine-proline-X.

Collagen has three chains. The chains form a triple helix. Glycine allows the chain to create a closed configuration and withstand stress. Its synthesis usually occurs in fibroblasts.

Outlined below are the mechanisms involved in the synthesis of collagen.

Intracellular synthesis

mRNA transcription in the nucleus

• Transcription of genes for pro-a1 and pro-a2 chains.

Translation

• Translation requires mRNA to interact with ribosomes in the cytoplasm.
• In the endoplasmic reticulum (ER), it undergoes modification after translation.

Modifications after translation

• From there, the chain undergoes three alterations to create procollagen.
  1. Removal of N-terminal signal peptide
  2. Addition of hydroxyl groups by hydroxylase enzymes to lysine and proline residues
  3. Selective hydroxyl-lysine glycosylation with galactose and glucose b
• Three hydroxylated and glycosylated pro-a-chains form a triple helix through zipper folding. Three left-handed helices wrapped into a right-handed coil.
• The procollagen molecule now enters the Golgi apparatus for final alterations and assembly.

Extracellular synthesis

Cleavage of the propeptide

• Collagen peptidases are enzymes that cleave procollagen and turn it into tropocollagen.

Assembly of collagen fibril

• Tropocollagen molecules form covalent bonds between each other. The catalyst for this is a copper-dependent enzyme known as lysyl oxidase.

Collagen is the body’s most prevalent protein. So, it has various types. Collagen types I through V are the most frequent, each with distinct roles.

There are concerns about collagen’s biochemical production. Clinical symptoms of collagen synthesis errors exist. Scurvy, osteogenesis imperfecta, and Ehlers–Danlos syndrome are some notable disorders.

What do fibroblasts do in the heart?

Fibroblasts are important in heart development and remodeling. But, you might not know that they are crucial in cardiac anatomy and function. The cardiac fibroblast supports and maintains normal heart function.

With their regulatory function, cardiac fibroblasts coordinate communication between components of the heart. A cardiac fibroblast is a cell that makes connective tissue. Its ECM consists of collagens, proteoglycans, and glycoproteins, unlike bones and tendons.

These cells produce periostin, vimentin, fibronectin, and collagen types I, III, V, and VI. Although they are the prominent synthesizers, other cardiac cell types also produce these.

Studies show that cardiac fibroblasts respond to injury by generating ECM components. But their activities in uninjured hearts remain unknown. Endothelial cells are the most frequent non-cardiomyocyte cell type in the heart.

Although not the majority, fibroblasts still play a role in normal heart physiology. Their mechanisms include matrix degradation, conduction system insulation, and cardiomyocyte electrical coupling. Also involved are vascular maintenance and stress sensing.

Cardiac fibroblasts regulate the heart’s basal structure and take part in wound healing. After your heart receives damage, tissue-resident fibroblasts develop into disease-activated fibroblasts and myofibroblasts.

In the past, most fibroblast studies concerned markers and in vitro models. Despite having two developmental sources, cardiac fibroblasts are the most common fibroblast source.

A novel cell type that developed during the fibrotic response is the myofibroblast. Research findings imply that an active fibroblast can revert to a resting fibroblast. But concerns remain on the role of the fibroblast in physiology and illness.

Where are fibroblasts found in the skin?

The barrier system of the body includes the skin and its appendages, which account for 16% of body weight. The skin has an epidermis and dermis, with the dermis being the inner layer. Dermal fibroblasts are cells in the dermis that help the skin heal.

The skin protects the tissues beneath it from injury, infection, and water loss. Regulation of body temperature and reception of sensations are tasks of your skin. It also regulates sweat gland output and absorbs UV light to make vitamin D.

The dermis consists of a top papillary layer and a reticular layer that is denser and deeper in the skin. Collagenous connective tissues support the epidermis and connect the skin to the hypothalamus. In the eyelid, dermal thickness ranges from 0.6 to 3 mm.

The dermis-fascia interface is not well-defined. It is also thicker in the dorsal areas of the body. If you didn’t know, women have a thicker dermis than men.

In connective tissues, fibroblasts predominate. They help secrete extrarenal-matrix prophylactic material to keep connective tissues intact. All extracellular matrix molecules, including the primary material and strands, need precursors.

Fibroblasts, like other connective tissue cells, come from mesenchyme. The intermediate filament secretes vimentin, a protein used to identify mesodermal origins. Changing cells from one type to another happens in the epithelial-mesenchymal transition.

During certain circumstances, fibroblasts can turn into epithelial cells. Some fibroblasts make collagen, glycosaminoglycan, lattice, and elastic fibers. Glycoproteins in the EC and thymic stromal lymphopoietin cytokines are also included.

Unlike epithelium, fibroblasts are not restricted to the basal layer. They also help to build the basal layer. Because myofibroblasts make laminin chains, they don’t have follicular areas. Unlike epithelium, fibroblasts can move to the substrate layer on their own.

Fibroblasts can rebuild the structure of the skin. Injuries cause fibroblasts and mitosis to happen. These cells move to the wound, make ECM, and heal tissues during injuries. Proteins in the extracellular matrix help inflammatory cells move and form granular tissues.

Granular tissue growth allows keratinocytes to strengthen the epithelial tissues. The fibroblasts make contractile elements that help close the ulcer. Type I collagen also speeds up the healing process.

Collagen is the most common ECM component, and it makes fibers that make tissues look the way they do. Precursor collagen gets released by fibroblastic cells. When injected into the skin, you can use fibroblasts to synthesize new skin tissue.

How do fibroblasts heal wounds?

Fibroblasts are one of the most common cell types in connective tissues, and they make up a lot of them. They oversee keeping the body’s tissues in balance under normal conditions. They are also involved with wound healing.

In injury, fibroblasts become activated and become myofibroblasts. This event causes contractions and makes ECM proteins to help close the wound. Both fibroblasts and myofibroblasts generate contractile forces, which allow the injury to close.

Inflammation, proliferation, and remodeling are three typical stages of wound healing. It happens during the growth phase, which signals granulation tissue formation. Contraction is an integral part of healing a wound because it helps close it.

Wound contraction in humans can be both good and bad. It helps wound healing by reducing the size of the wound margins, leading to the wound’s closure. Yet, excessive contraction leads to contracture and scarring, which can cause problems.

Fibroblasts are a type of cell that can be non-contractile or very contractile. You can find them in most tissues, from mesenchymal cells. Fibroblasts help keep tissues healthy by controlling the turnover of ECM.

Studies show that both fibroblasts and myofibroblasts help in the healing process. The traction of fibroblasts and the coordinated contraction of myofibroblasts are vital factors. When too many myofibroblasts are active, scar tissue can form, resulting in immobilization.

What happens to fibroblasts as we age?

Aging is a part of human nature. As all living creatures do, humans deteriorate and die when cells stop regenerating. The same is true with fibroblasts, which undergo impaired metabolism and collagen production.

As you age, your body loses fibrous tissue and slows cell turnover. There is also damage to the water barrier function. Normal physiological skin functions may decline by 50% until middle age.

Progressive tissue decay and hormonal changes are causes of intrinsic aging. Metabolic reactions such as oxidative stress can also be its cause. The elastic fibers in the dermis deteriorate, causing skin atrophy and tiny wrinkles.

Meanwhile, the causes of extrinsic aging are too much sun exposure or smoking. A decrease in antioxidant capacity makes the skin more susceptible to sun damage. Aging also results in increased reactive oxygen species produced by skin cell metabolism.

These stressors affect a lot of different biochemical pathways. Effects include growth factor receptor-II deficiency and damage to the skin’s structural proteins. Furthermore, some studies show that both mechanisms of aging have areas that overlap.

For the skin, telomeres keep getting shorter, making it hard for cells to reproduce. The matrix and fibroblast pattern expression remains fixed in the dermis for a long time. When stimulation, the cells grow, but the telomeres stay the same length.

References:

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Ivey, M. J., & Tallquist, M. D. (2016). Defining the Cardiac Fibroblast. Circulation Journal, 80(11), 2269–2276.

Kendall, R. T., & Feghali-Bostwick, C. A. (2014). Fibroblasts in fibrosis: novel roles and mediators. Frontiers in Pharmacology, 5.

Mandal, A. (2019, February 26). What are Fibroblasts? News-Medical

Nilforoushzadeh, M. A., Ahmadi Ashtiani, H. R., Jaffary, F., Jahangiri, F., Nikkhah, N., Mahmoudbeyk, M., Fard, M., Ansari, Z., & Zare, S. (2017). Dermal Fibroblast Cells: Biology and Function in Skin Regeneration. Journal of Skin and Stem Cell, In Press(In Press).

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Souders, C. A., Bowers, S. L. K., & Baudino, T. A. (2009). Cardiac Fibroblast. Circulation Research, 105(12), 1164–1176.

Wu, M., Cronin, K., & Crane, J. S. (2021, September 13). Biochemistry, Collagen Synthesis. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507709/#:~:text=The%20process%20of%20collagen% 20synthesis,occurs%20both%20intracellularly%20and%20extracellularly.