Fibroblast

Fibroblast
n., plural: fibroblasts
[ˈfaɪbrəʊˌblæst]
Definition: a connective tissue cell that synthesizes collagen for fiber formation

The building block of living things is known as the cell. The cell contributes to many parts and functions of different organisms. Some cells are specialized, meaning they perform specific jobs and functions. They can also be formed from cells that previously had another function which makes them differentiated cells.

These include smooth muscle cells, epithelial cells, and even fibroblast cells. What is fibroblast and what are fibroblast cells? How does one define fibroblast? What do fibroblasts do?

Fibroblasts Definition

A fibroblast is a eukaryotic cell that helps form the body’s connective tissue, a fibrous cellular substance that supports and links other tissues and organs. You might be wondering, what protein do fibroblasts produce? Fibroblasts secrete collagen, which serves as the basic structural component of collagen fiber. The collagen fiber, in turn, is one of the major types of fibers found in connective tissues.

Where are fibroblasts found? One of the most prevalent places fibroblasts are found is in the stroma of the extracellular matrix. It performs a multitude of tasks, especially during tissue repair where it provides the structural foundation for tissues and organs.

What do fibroblasts respond to? When tissue is injured, fibroblasts play a crucial part in responding to the healing process of the wound. Dermal fibroblasts are the main type of cell in the dermis of the skin and together with keratinocytes, aid in the formation of the basement membrane.

Fibroblasts, Fibrocytes, and Fibrocytes

Fibroblasts can be easily confused with the terms “fibrocytes” and “fibroclasts“. Fibrocytes are inactive cells in contrast to fibroblasts, which are active cells. Fibroblast histology is usually described as large, flat, and elongated (spindle-shaped). Apart from spindle shape, fibroblasts also have other shapes, such as stellate and fusiform. In general, though, fibroblasts are characterized by having branched cytoplasm (processes), an elliptical nucleus with two or more nucleoli, and rich in endoplasmic reticula.

Metabolically inactive fibroblasts are referred to as fibrocytes. Fibrocytes are smaller in size, with lesser cytoplasm and fewer rough endoplasmic reticula. They are also less basophilic and so histologically, they appear pale purple as opposed to fibroblasts that are more basophilic and stain purplish-blue in H&E stain.

Nevertheless, both fibroblasts and fibrocytes are derived from mesenchymal cells and involved in tissue repair. However, while fibroblasts are active cells, fibrocytes are inactive as evidenced by their cytological and histological features.

While fibroblasts are capable of differentiating into certain types of cells, such as adipocytes, osteoblasts, and chondroblasts, fibrocytes are deemed as one of the possible precursors of fibroblasts. Fibrocytes are bloodborne cells derived from the bone marrow and are recruited into the site of tissue injury. They leave the bloodstream and enter the tissues of wound sites to become fibroblasts where they aid in wound healing. Fibrocytes are also accounted for fibrosis, which is a thickened or scarred tissue repair.

Watch this video to further learn the differences between fibroblasts and fibrocytes:

Fibrocytes are supposedly fibroblast-like cells that appear to enable collagen resorption. However, most sources prefer to use the term fibroblast to still refer to the cells involved in collagen degradation. Degradation of collagen occurs during the remodeling phase of tissue repair. Baur et al. (1979) could be the first ones to coin the term as they proposed in their paper the use of ‘fibroclast’ for fibroblast with a similar function as osteoclast. They also described the cells as having collagen filament remnants inside residual lysosomes, indicating the cells’ involvement in collagen fiber and filament degradation.

Structure

In general, fibroblasts have an elliptical, speckled nucleus with two or more nucleoli and are surrounded by branching cytoplasm. The rough endoplasmic reticulum is an abundant indicator of active fibroblasts. Fibroblasts that are inactive are smaller, spindle-shaped, and contain less rough endoplasmic reticulum (also known as fibrocytes).

Although they are fragmented and dispersed when they must cover a vast area, fibroblasts frequently locally align in parallel clusters when they are congested. The structural framework within a cell is the cytoskeleton; the fibroblasts use the cytoskeleton dynamics, especially during cell migration and neuronal sprouting.

Tropocollagen, the precursor of collagen, and ground substance, an amorphous gel-like matrix that fills the gaps between cells and fibers in connective tissue, are both produced by human fibroblasts.

Contrary to epithelial cells that line body structures, fibroblasts do not form flat monolayers and are not constrained by a polarizing attachment to a basal lamina on one side, though they may occasionally contribute to the composition of basal laminae (for example, subepithelial myofibroblasts in the intestine may secrete the -2 chain-carrying component of laminin, which is absent only in areas of follicle-associated.)

In addition, unlike epithelial cells, fibroblasts may move slowly over a substrate as individual cells. While epithelial cells provide the lining of bodily structures, the “bulk” of an organism is created by fibroblasts and fibroblasts in connective tissue are also associated with this.

Depending on their location and activity, fibroblasts have different looks due to their heterogeneous morphology. Ectopically transplanted fibroblasts can frequently preserve positional memory of the site and tissue context where they had previously lived, at least over the course of a few generations, while becoming morphologically undetectable. In the extremely unlikely event that they stagnate there excessively, which may cause discomfort.

Relationship with fibrocytes

Both fibrocytes and fibroblasts are involved in tissue metabolism and maintenance. However, some references use the term ‘fibroblasts’ to refer to both cells, especially when fibrocytes have turned into fibroblasts. It could be confusing too, especially, when in cell biology, stem cells or cells with active metabolism are indicated by the suffix ‘-blast’, and the more differentiated form is denoted with‘-cyte’. It’s just that fibroblasts may further differentiate into other cell types as already discussed in the above section.

Development

The primary job of fibroblasts is to continually secrete precursors of the extracellular matrix, preserving the connective tissues’ structural integrity. The extracellular matrix’s antecedents, principally the ground material and a variety of fibers, are all secreted by fibroblasts. The extracellular matrix’s makeup dictates the physical characteristics of fibroblastic connective tissue cell types.

The primitive mesenchyme is where fibroblasts are derived from, along with other cells of connective tissues as well as platelet-derived growth factor (a chemoattractant for fibroblasts).  They do so by expressing the intermediate filament protein vimentin, which is utilized to identify them as being of mesodermal origin. This test is not precise, though, because epithelial cells cultivated in vitro on an adhesive substrate may eventually produce vimentin as well.

Epithelial-mesenchymal transition, a process wherein epithelial cells can give birth to fibroblasts, can occur in specific circumstances (EMT).

Contrarily, in rare circumstances, fibroblasts may undergo a mesenchymal to epithelial transition (MET) and organize into a condensed, polarized, laterally linked genuine epithelial sheet, giving birth to epithelia. This mechanism is evident throughout the formation of various organs (such as the nephron and notochord), as well as during wound healing and carcinogenesis.

Fibroblast Function

Collagen, glycosaminoglycan, reticular, and elastic fibers are all produced by fibroblasts. Fibroblasts in developing people divide and produce ground material. Fibroblast formation is stimulated by tissue injury, which also increases fibrocyte activity.

• Tissue repair, wound healing, and scar formation

Following hemostasis, tissue repair or wound healing occurs via four major overlapping phases. These phases are:

1. Inflammation, inflammatory response, including the secretion of cytokines that will call upon fibroblasts
2. Migratory phase, migration of cells (fibroblasts) to the injured site
3. Proliferative phase, the formation of a provisional wound matrix comprised mainly of fibroblasts, vascular endothelial cells, etc. This phase is in essence to regenerate lost cells or tissues, by collagen fiber deposition, angiogenesis, re-epithelialization, wound contraction, etc.
4. Remodeling phase (Maturation phase), the longest phase, where granulation tissue matures by a series of collagen synthesis/resorption, reorganization, and scar tissue formation. In the skin, the type III collagen fibers, which are initially deposited in the early stage of wound healing, are replaced by the more predominant, type I collagen.

Read: Regeneration in humans – Finding the gene switch

Fibroblasts in the skin appear to play a significant part in healing wounds. Fibroblast activation occurs through four mechanisms:

• by growth factors through autocrine and paracrine stimulation, meaning via cell signaling from the cell  itself or from the surrounding cells
• by direct cell-cell contact
• by extracellular matrix, via the integrins
• by certain environmental conditions (such as hyperglycemia or hypoxia due to renal disease)

As a result of tissue damage, fibroblasts go to the injured site and deposit new collagen, speeding up the healing process. This is sometimes seen in the process fibroblasting where the skin is renewed.

There are variations in the quantity and phenotype of fibroblasts in chronic lung disorders such asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). The loss of typical tissue architecture and function brought on by these fibroblastic disorders is significantly influenced by these alterations. Although a lot of studies has been put into controlling leukocytic activity and inflammation, very few studies have looked at how existing or novel medicines affect fibroblast activity.

• Inflammation

In addition to their well-known function as structural elements, fibroblasts are essential for the immunological response to tissue damage. When invasive bacteria are present, they play a key role in the early stages of inflammation. They activate receptors on their surface, which causes chemokine production.
The invading bacteria are subsequently eliminated by a series of actions that are started by immune cells in response. A mechanism for immune cells to regulate fibroblasts is provided by receptors on the surface of fibroblasts, which also allow the regulation of hematopoietic cells.

• Tumor growth mediation

Through the extracellular matrix (ECM) components and modulators produced from tumor-associated host fibroblasts (TAF), fibroblasts, such as TAF, play a critical role in immune regulation or modulation. TAF are known to have a crucial role in tumor immune suppression as well as the inflammatory response. ECM components produced by TAF change the composition of the ECM and start the connective tissue remodeling process.

ECM remodeling is defined as changes in the ECM brought on by enzyme activity, which may result in ECM breakdown. ECM remodeling controls a multitude of processes, including the fibroblast cell proliferation, differentiation, and morphogenesis of important organs, which in turn controls how the immune system regulates malignancies. ECM remodeling is prevalent in many tumor forms, particularly those connected to epithelial cells. Instances include Tenascin and Thrombospondin-1 (TSP-1) of TAF-derived ECM elements that are present in locations of chronic inflammation and carcinomas, respectively.

The TAF-derived modulators can also influence how the immune system responds to malignancies. Although these modulators may have a similar sound to the ECM components obtained by TAF, they are distinct in that they are in charge of the ECM’s variety and turnover.

ECM molecules that have been cleaved can be extremely important for immunological control. The ECM is known to be cleaved by proteases such as matrix metalloproteinases (MMPs) and the uPA system. Fibroblasts are the source of these proteases.

Numerous ECM genes, including Col1a1, Col1a2, Col5a1, Loxl1, Lum, Fbln1, and Fbln2, as well as the cell surface receptors Cd34 and Pdgfra, were on the short list of common fibroblast markers.

• Secondary actions

Human embryonic stem cell research frequently employs mouse embryonic fibroblasts (MEFs) as “feeder cells”. However, a growing number of researchers are increasingly moving away from MEFs in favor of culture media that include precisely defined elements that are only derived from humans.

Furthermore, adopting “defined media” where the supplements are synthetic and meet the primary purpose of eradicating the possibility of contamination from derivative sources, is a common way to resolve the challenge of only employing human derivation for media supplements.

Human fibroblasts have been investigated as feeder cells in light of the therapeutic applications of tissues produced from stem cells. While fibroblasts are often utilized to keep stem cells pluripotent, they can also be employed to help the growth of stem cells into particular types of cells, such as cardiomyocytes.

• Host immune response

Numerous genes that code for immunological mediators and proteins are expressed by fibroblast tissue from various anatomical locations in the body. These immune response mediators allow cells to talk to hematopoietic immune cells.

“Structural immunity” refers to the immunological function of non-hematopoietic cells, such as fibroblasts. Fibroblasts encode important components of the structural cell immune response in the epigenome to enable a quick response to immunological challenges.

• Fibroblast Growth Factor

Fibroblast growth factors (FGFs), a class of cell-signaling proteins produced by macrophages, play a significant role in a number of functions, most notably the development of animal cells normally. Any deviations from normal function result in a variety of developmental abnormalities.

There are now 23 known members of the FGF family in humans, all of which are structurally similar signaling molecules. Fibroblast growth factor receptors are all bound by FGF1 through FGF10 members (FGFRs). Both FGF1 and FGF2 are sometimes referred to as acidic and basic fibroblast growth factors, respectively.

Specific Fibroblasts

Cancer-associated fibroblasts (CAFs) are an essential part of the tumor microenvironment and have a variety of roles, including matrix deposition and remodeling, extensive reciprocal signaling connections with cancer cells, and crosstalk with invading leukocytes. They are therefore a potential target for improving cancer therapy techniques.

A particular kind of fibroblast created from a mouse embryo is known as mouse embryonic fibroblasts (MEFs). When MEFs are cultivated in vitro, they take on the spindle structure that fibroblasts are known for. A constrained cell line is the MEF. After repeated transmissions, MEFs will eventually senescence and disappear.

There are many other kinds of special fibroblasts such as:

• Fibroblast-like synoviocyte
• Cardiac fibroblasts (which can lead to cardiac fibrosis)
• Cultured fibroblasts
• Fibroblast abdominal
• 3t3 fibroblasts
• Stromal fibroblasts
• Fap fibroblast
• Human gingival fibroblasts
• Interstitial fibroblasts in the kidney
• Tumor-associated fibroblasts
• Human diploid fibroblasts
• Keloid fibroblasts
• Reactive fibroblasts
• Senescent fibroblasts
• Adventitial fibroblasts
• Murine fibroblast
• Neonatal fibroblasts

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References

• Baur, P. S., Barratt, G. F., Brown, G. M., & Parks, D. H. (1979). Ultrastructural Evidence for the Presence of “Fibroclasts” and “Myofibroclasts” in Wound Healing Tissues. THE JOURNAL of TRAUMA: INJURY, INFECTION, and CRITICAL CARE, 19(10), 744–756. https://doi.org/10.1097/00005373-197910000-00006
• Dave, J. M., & Bayless, K. J. (2014). Vimentin as an integral regulator of cell adhesion and endothelial sprouting. Microcirculation (New York, N.Y.: 1994), 21(4), 333–344. https://doi.org/10.1111/micc.12111
• Dick, M. K., Miao, J. H., & Limaiem, F. (2022). Histology, Fibroblast. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK541065/
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