Fibroblast

Fibroblasts (from fibra=fiber and blastos=germ or former) are motile, spindle- or star-shaped, actively dividing cells of the connective tissue. Their cell nucleus is oval, relatively large with a loosely condensed chromatin structure and distinct nucleoli (high metabolic activity). Fibroblasts are of mesenchymal origin and generally express the fiber protein vimentin, which can be used as a marker for their mesenchymal origin.

Fibroblasts are a major component of the connective tissue of the organism and play an important role in the synthesis of the intercellular substance required to build up the so-called extracellular matrix. After a maturation process, fibroblasts develop further into fibrocytes. This renders them immobile. Fibroblasts and fibrocytes are therefore the same cell type with different states of activity and maturity. The products of fibroblasts mainly include collagen (especially types I, III and V) and structural proteins such as fibronectin, laminin and elastin. Fibroblasts also produce basic substances such as glycosaminoglycans (e.g. hyaluronic acid) and proteoglycan complexes. Collagens ensure the high strength of the extracellular matrix. Fibroblasts have other functions in addition to their supporting function.

Distribution: Fibroblasts are primarily specific localized cells of the connective tissue. Connective tissue is found throughout the body and provides support, firmness and elasticity to organs. Fibroblasts are also found in the lungs. There they are found in a highly complex, multicellular environment, which is normally closely adjacent to the epithelium or endothelium. However, fibroblasts can also develop from differentiated connective tissue cells, such as bone or cartilage. This happens in response to stimuli, e.g. injuries. In certain situations, epithelial cells can also transform into fibroblasts, which is known as "epithelial-mesenchymal transition (EMT)". Conversely, fibroblasts can also transform into epithelial cells (mesenchymal-epithelial transition - MET).

Migration: Fibroblasts can move through the tissue, especially in the case of injury.

Tissue-specific differences: Fibroblasts in skin, tendons or lungs differ in their gene expression and ECM composition. Like lymphocytes, they consist of different subpopulations with different phenotypes and functions. Subpopulations with different phenotypes and functions.

Lung fibroblasts: Lung fibroblasts exhibit heterogeneity with regard to the expression of surface markers, proliferation and collagen production.

Periodontal fibroblasts: Periodontal fibroblasts also show heterogeneity, differing in collagen production, morphology and glycogen stores.

Dermal fibroblasts: Their population consists of heterogeneous and different cell types. Dermal fibroblasts secrete various signaling molecules that are involved in the regulation of ongoing cell proliferation, but also in inflammation. They influence the functions of immune cells, keratinocytes, endothelial cells and mast cells through direct cell-cell communication as well as through autocrine and paracrine interactions (Stunova A et al. 2018). There are clear differences between fetal and adult dermal extracellular matrix (ECM). Fetal dermal extracellular matrix (ECM) contains higher proportions of type III collagen, chondroitin sulphate and hyaluronic acid than adult ECM. Elastin is present in the adult but not in the fetal dermis.

Myofibroblasts: A special form of fibroblasts are myofibroblasts, which were discovered in experimental studies on inflammation and wound healing. They are responsible for wound closure. This initially involves the proliferation of fibroblasts and their consecutive modulation into myofibroblasts. Myofibroblasts are characterized by their production of alpha-smooth muscle actin. Collagen type 3 is also expressed. Myofibroblasts have a fine structural similarity to smooth muscle cells, as they contain microfibrils, microtendons and cell-cell channels. Myofibroblasts have also been detected in human granulation tissue, in palmar fibromatosis and in the reactive stroma of invasive carcinomas.

Angiogenesis: Fibroblasts play a special role in angiogenesis. In this process, endothelial cells first migrate to the point where blood vessels develop. There they form thin capillaries. In vitro angiogenesis models show that fibroblasts release growth factors, which in turn initiate the formation of blood vessels by endothelial cells.

Wound healing: Damage to the skin surface, for example, stimulates fibroblasts to proliferate ("fibroblast proliferation"). This activation increases the release of cytokines and growth factors (e.g. TGF-beta, FGF, VEGF), which in turn has a positive effect on the repair of the injury. Fibroblasts therefore also play a central role in wound healing.

Fibroblasts in fetal skin: The cluster formation in fetal skin shows eight different fibroblast populations with developmental stage-specific frequencies:

• Fibroblasts of the dermal papillae: The appearance of fibroblasts of the dermal papilla (PRDM1+) and the hair follicles (SLC26A7+) coincides with the maturation of the hair follicles.
• ^GRP+fibroblasts: predominate in the papillary dermis 9-13 weeks after conception.
• Apolipoprotein E-positive fibroblasts: This fibroblast species is specifically associated with blood vessels. They increase in frequency as the vessels develop.
• ^HOXC5+ post-embryonic fibroblasts: 7-8 weeks after conception, a fibroblast cluster expressing HOXC5 is most abundant. ^HOXC5+ fibroblasts were decreased 9-13 weeks after conception and subsequently undetectable (Morioka N et al. 2025).
• ^PLAT+ fibroblast species decreases with the same kinetics.
• ^ASPN+fibroblasts form the largest cluster in the reticular dermis 14-16 weeks after conception (Morioka N et al. 2025).
• ^HOXC5+ fibroblasts are closely associated with papillary and hair follicle fibroblasts, while PLAT+ fibroblasts were associated with reticular and vascular fibroblasts.

Fibroblasts associated with pathological functions:

• Skin aging: Senescence inducers, including stressors (ROS, DNA damage, radiation exposure), telomere shortening and mitochondrial dysfunction, increase the activity of proteins that inhibit the activity of cyclin-dependent kinases (CDK), leading to fibroblast cell cycle arrest. Compared to young skin (18-29 years), the total number of fibroblasts in aged skin (> 80 years) is reduced by about 35%, while the number of senescent fibroblasts increases with age (significant increase in p16INK4a, a marker for senescent cells encoding an inhibitor of CDK4/6). (Ogata et al. 2021). The number of p16INK4a-positive cells also correlates with wrinkling and elastic morphological changes. Other classical senescence biomarkers such as p21CIP1, p53 and β-galactosidase (SA-β-Gal) are upregulated in aged or UV-irradiated fibroblasts, while lamin B1 is downregulated. Senescent fibroblasts (like other cells) undergo proliferation arrest but remain in the stroma due to their low propensity for apoptosis and inefficient removal. Excessive accumulation of senescent fibroblasts contributes significantly to skin aging, as these fibroblasts cause loss of cell identity and dysfunction of ECM homeostasis. As a result, senescence spreads from cell to cell and accelerates the process of skin aging (Zhang J et al. 2024).
• Carcinoma-associated fibroblasts: Fibroblasts are the main component of the tumor stroma. Cancer-associated fibroblasts (CAFs) are diverse cells with numerous functions. They play a key role in shaping the tumor microenvironment with functions in tumor promotion and inflammation as well as in the maintenance and remodeling of the extracellular matrix (Cords L et al. 2023). Furthermore, they can interact with tumor-infiltrating immune cells and modulate the immunological state of the tumor microenvironment (TME) (Yamamoto Y et al. 2023). Different CAF subpopulations have been described in different types of cancer. Animal experiments have demonstrated four different CAF phenotypes in breast cancer, which have been termed vascular CAFs, matrix CAFs, cyclic CAFs and developmental CAFs (Cords L et al. 2023). Further CAF phenotypes with anti-inflammatory and immunoregulatory functions, ECM-producing functions, protein folding functions and antigen-presenting functions have been described in mouse models. In human breast cancer, the CAF-S1 subtype is associated with an immunosuppressive environment and cancer cell migration. This CAF species likely promotes metastasis. CAF subsets have been identified and associated with prognosis or response to therapy in patients with many types of cancer, including pancreatic ductal adenocarcinoma (PDAC), urothelial carcinoma of the bladder, melanoma and lung cancer. This underlines their importance for cancer research. (Cords L et al. 2023)
• PRRX1-positive fibroblasts: In these fibroblast species (pulmonary fibrosis, liver cirrhosis, sclerosis of the skin (morphea, keloids, systemic sclerosis), the proportion of PRRX1-positive fibroblasts (PRRX1 stands for "paired related homeobox 1") increases from fetal skin to postnatal skin (PS) and further in keloids. (Dou S et al. 2025)
• Tumor microenvironment: CAFs = carcinoma-associated fibroblasts: CAFs play a central role in the tumor microenvironment (TME) in solid tumors and influence the progression of the tumor parenchyma and metastasis (Sahai E et al. 2020). CAFs consist of distinct fibroblast populations that presumably exhibit different activated fibroblast states and tumor-promoting phenotypes in a tumor, suggesting intratumoral heterogeneity of these fibroblasts. They may arise from resident tissue fibroblasts, from mesenchymal cells recruited from the bone marrow, or from adipocyte-derived progenitor cells, endothelial cells, mesothelial cells or pericytes. This heterogeneity is reflected in the variety of roles that fibroblasts play in tumor progression and metastasis, including the promotion of cancer cell growth, angiogenesis and remodeling of the extracellular matrix (ECM). In addition, CAFs coordinate tumor-promoting inflammation and modulate the immunological microenvironment towards immunosuppression (Lavie D et al. 2022; Mezawa Y et al. 2022). The heterogeneity of CAF subpopulations is likely due to their origins and differentiations, which depend on autocrine and paracrine signaling in the TME (α-SMA+ or FAP+ CAFs are the two predominant CAF markers). S100 calcium-binding protein A4 (S100A4), also known as fibroblast-specific protein 1 (FSP1), also marks tumor cells that have undergone EMT. It has been shown that FSP1 is only expressed in a subset of CAFs and that there is minimal overlap between the expression of FSP1 and αSMA.

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