Fibroblast is the characteristic and most abundant cell type of the connective proper tissue. Its main function is to produce and maintain the extracellular matrix. Although the suffix "blast" is generally used for undifferentiated cells, and the suffix "cyte" for differentiated cells, fibroblasts are differentiated cells, but showing a high proliferation capability. Thus, fibroblast and fibrocyte are two physiological states of the same cell type, being fibroblast the most active and fibrocyte more quiet. Many authors suggest that fibroblasts are young metabolically active and proliferating cells, whereas the term fibrocyte should be used for old and low secretory cells. However, the term fibroblast is commonly applied to both cell types.
Currently, fibroblast is a thoroughly studied cell type in regenerative research and has been used in cell cultures since long time ago. In 2006, embryo and adult mouse fibroblasts were transformed into cells showing embryo stem cell features by using retrovirus that modified only 4 transcription factor genes. They were named IPSc (induced pluripotent stem cells). In 2007, IPSc were obtained from human fibroblasts. These results opened new paths for tissular regeneration, different than therapeutic cloning.
Fibroblasts show variable morphology, both in shape and size, depending on the organ they are found and on the cellular activity level. Generally, they are elongated (Figures 1 and 2) or star-like cells, with cytoplasmic projections that can be short and wide, or long, thin and branched. These last cell protrusions allow physical contact between close fibroblasts. Gap junctions can be found in these contacts. They can also physically contact other cells like neurons, muscle cells, endothelium, leukocytes, and others. Fibroblast also communicate with other cells through the extracellular matrix and by releasing molecules.
Fibroblasts usually show an elongated nucleus and scarce cytoplasm. Fibroblasts normally have a well-visible nucleolus, whereas fibrocytes do not, which may be a landmark to distinguish both cell stages. At transmission electron microscopy (Figures 3 and 4), fibroblasts do not usually show well-developed organelles. However, active fibroblasts are larger, with more cytoplasm and abundant organelles (Golgi apparatus, endoplasmic reticulum and ribosomes) involved in extracellular matrix components synthesis.
Fibroblasts show a well-differentiatated cytoskeleton. Actina and alpha-actinin are found in the cell periphery, where myosin is also present. Alpha-actinin makes possible the anchoring of actin filaments to the plasma membrane through integrin-type transmembrane proteins. Integrins connect the cytoskeleton with collagen and fibronectins of the extracellular matrix. It is a weak binding that can be formed and removed easily. All these structural components may allow fibroblasts to move at around 1 µm/min speed through the extracelular matrix.
2. Origin, distribution and diversity
The morphological diversity of fibroblasts is specified by the embryonic origin and the environment where they are found. Fibroblasts are characterized by the expression of mesenchymal cellular markers like vimentin, and type I collagen. Furthermore, they lack molecular markers found in other cell linages. During embryo development, fibroblasts may be generated from ectoderm (neural crests) and mesoderm. However, fibroblasts with the same embryonic origin form a heterogeneous population.
The most deeply study fibroblasts are probably those found in the dermis. The gene expression pattern of dermal fibroblasts is different from fibroblasts of other parts of the body. Gene expression profiles appear to be inherited as a result of their embryonic origin, remarkably influenced by Hox genes, that provide positional information. Hox genes have been related with growth, differentiation, cell migration, extracellular matrix production and lipidic metabolism. Two types of heterogeneity can be distinguished in dermal fibroblasts.
Fibroblasts form different populations according to the body location: rostral or caudal, ventral or dorsal. The position is important for fibroblast function, and they somehow know the spatial location. For example, fibroblasts are thought to be involved in the induction of hair follicles, sweat glands, and feathers in birds. All these structures show different distribution, density and features in different positions of the body. Furthermore, fibroblasts in different places are derived from particular embryonary structures. Face dermal fibroblast develop from neural crests (ectoderm), back dermal fibroblasts from the somitic mesoderm, ventral dermal fibroblasts from lateral mesoderm. Even coming from the same embryonic source, the final position influences fibroblast functioning, dermal regionalization and fibroblast morphology.
There is local heterogeneity as well. Dermis is divided in an upper papilar region and deeper reticular region. Papilar fibroblasts are different from reticular fibroblasts in physiology and regarding the extracellular matrix molecules they synthesize and release. In papilar dermis there are more thin and scatered collagen fibers, more type I and III collagens and more decorin than in the reticular dermis. In addition, fibroblasts associated to hair follicles form a third population that in turn can be divided in two sub-populations: those in the interior of the hair follicle and contribute to the bulb size, follicle length and diameter, and those surrounding the basal membrane of the follicle epithelium.
Fibroblasts are involved in many functions. The most common is synthesizing and maintaining many components of the extracellular matrix, such collagen, reticular and elastic fibers, as well as ground substance including gycosaminoglycans, proteoglycans and glycoproteins. Thanks to this feature, they are essential during wound healing by forming groups in the edges of the wounds and releasing extracellur matrix to form scars. They appear to be involved in other less known functions. Fibroblasts participate in the first stages of the immune response and influence the structural organization of the tissue during embryonic development. There are subtle differences in the functions of fibroblasts located in same region.
Fibroblast plasticity makes this cell type easily cultured in vitro, and therefore very interesting for research purposes. Fibroblast culture is extensively used in cosmetic industry. For example, face wrinkles are a consequence of collagen lost. Collagen, elastin and proteoglycans are more slowly synthesized during aging. Fibroblast culture provides those molecules that can be injected in the skin. A recent innovation is the injection of fibroblasts in the skin. For that, fibroblasts are obtained from a skin biopsy, usually from the region behind the ears, the cells are grown in culture, and the fibroblasts are injected in the chosen region of the same individual.
Sriram G, Bigliardi PL, Bigliardi-Qi M. 2015. Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. European journal of cell biology. 94: 483-512.