Fibroblasts and CAFs
What are fibroblasts?
Fibroblasts are a ubiquitous spindle-shaped cell type in the human body. They not only provide scaffold and structure to the tissues but also actively communicate with other cells in the tissue in both normal homeostasis and repair. They survive severe stress that is usually lethal to all other cells, and the only normal cell type that can be live-cultured from post-mortem and decaying tissue. They have a 60-day lifespan in chicken embryo. Even though fibroblasts are studied the most, very little is still understood about them. They’re heterogenous in function and form based on the source and tissue and activation state. They have active roles in wound repair, fibrosis, cancer and fibro-inflammatory diseases.
What is meant by the term fibroblasts?
Fibroblasts are the cells residing in the connective tissues of the body and synthesize collagen fibers. They are embedded in the interstitial space or fibrillar extracellular matrix (ECM) or near a capillary. Fibroblasts are non-epithelial, non-immune cells with a likely mesenchymal lineage origin. Fibroblasts exhibit classic spindle-shape morphology with a potential for planar polarity. Thus, they are termed fibroblasts (fiber + blasts), meaning ECM (fiber) resident/producing cells which are metabolically active (blasts) like MSCs.
What is the difference between normal, activated, and senescent fibroblasts?
Fibroblasts in normal tissue are in the resting or quiescent state and share features with mesenchymal stem cells (MSCs). They are typically fusiform with actin cytoskeleton and vimentin intermediate filaments. They interact with their environment with the α1β1 integrins. Fibroblast specific protein-1 (FSP-1 or S100A4) is expressed by non-proliferating normal fibroblasts [1]. However, in wound healing, chronic inflammation, fibrosis, they can become activated. Activated fibroblasts have enhanced proliferation and ECM synthesis. In this state, they become highly contractile and are called myofibroblasts and express a-smooth muscle actin (αSMA or ACTA2). Their ECM proteins include collagen 1, fibronectin and tenascin C. Some molecules that drive this activated state are transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF), monocyte chemotactic protein (MCP-1) and interleukin-6 (IL-6). They also form the basement membrane which separates the epithelium from the stroma by secreting laminin and type IV collagen. Once activated, the fibroblasts not only secrete ECM but generate cytokines and chemokines, matrix proteases (MMPs), recruiting immune cells and exerting physical forces to modify tissue architecture [2]. They can also become adipocytes, endothelial or chondrocyte-like cells, and can be induced to become induced pluripotent stem cells (iPSCs). They can also induce angiogenesis by production of vascular endothelial growth factor A (VEGFA). Senescent fibroblasts are larger than normal or activated fibroblasts with a stable cell cycle arrest but highly metabolic in terms of their secretory phenotype, including matrix proteases, growth factors, IL-6, chemokines. For more details, please refer this article: https://medium.com/@narainradhika17/senescence-and-its-role-in-cancer-2644305c90d2
What are some fibroblast markers?
Fibroblasts are identified by expression of some markers but still lack specific markers. They include FSP1 or S100A4, vimentin, αSMA, fibroblast activated protein (FAP), PDGF receptor-α (PDGFRα), PDGFRβ, and desmin [3]. FSP1, which is expressed by quiescent fibroblasts, also identifies macrophages and possibly other immune cells and is expressed by some cancer cells [4,5]. FAP is expressed by activated fibroblasts but is also present in a subset of CD45+ immune cells [6]. Desmin and PDGFRβ are also expressed in perivascular cells [7]. αSMA is expressed by myofibroblasts but also serves as a general marker for mesenchymal cells such as smooth muscle cells and pericytes of blood vessels [8]. These markers may also not be expressed all at the same time. Therefore, fibroblasts are often defined by combination of their morphology, location, lack of epithelial, endothelial and leukocyte markers. The exact correlation between fibroblast markers and function is unknown. Resting fibroblasts can also differentiate into different subsets with diverse functions. Usually, researchers use multiple markers to identify each subset.
What are cancer-associated fibroblasts (CAFs)
Activated fibroblasts associated with tumors are called CAFs and are a dominant component of the tumor stroma [9]. They are recruited from multiple sources and are a heterogeneous population. The fibroblasts from various sources are programmed by cancer cells and other cells in the tumor microenvironment (TME) by physical and chemical signals. CAFs can, in turn, modulate the cancer cells by both biochemical and biomechanical signals to support many aspects of tumorigenesis. They lack mutations found in cancer cells [10] but influence the rate and extent of cancer progression. They are defined by the same markers that generally apply to fibroblasts [11]. However, other cells in the TME like adipocytes or pericytes may share the markers.
What are the sources of CAFs and how are they reprogrammed?
CAF heterogeneity might be due to the numerous potential cellular sources of CAFs. CAFs can be derived from normal resident tissue fibroblasts that are activated by the neighboring tumor cells. For example, quiescent pancreatic stellate cells and hepatic stellate cells, resident fibroblasts in the pancreas and liver, can acquire a myofibroblast-like phenotype upon de novo activation [12]. Cancer cells secrete TGFβ [13], PDGF [14], fibroblast growth factor (FGF) [15], for proliferation and/or differentiation of normal fibroblasts to CAFs. Initial activation of fibroblasts is also thought to be a host defense mechanism to restrain cancer progression [9]. Some other contributors are cancer-derived exosomes [16], reactive oxygen species (ROS), and hypoxia [17]. They also undergo transcriptional or epigenetic changes to adopt a different metabolome/secretome, maintaining the CAF state through autocrine signaling and affecting cancer cells through paracrine signaling [18]. Thus, they are considered as CAFs in pancreatic and liver cancers, respectively. Fibrocytes, can also be recruited from the bone marrow to be incorporated in the tumor stroma, as in breast cancer [19]. MSCs are another CAF source and the best-studied. Bone-marrow-derived MSCs (BM-MSCs) can differentiate into CAFs in cancers such as prostate [20] and breast [21]. Other sources of CAFs are epithelial or endothelial cells that are adjacent to cancer cells and undergo epithelial-to-mesenchymal transition (EMT) [22] or endothelial-to-mesenchymal transition (EndMT) [23], respectively. The less common CAF sources are cells that undergo transdifferentiation, such as adipocytes [24], pericytes [25], and smooth muscle cells [26]. Mechanical stretching can also convert normal tissue-resident fibroblasts to CAFs by triggering complex biochemical signaling through an increased expression of PDGFRα [27].
References:
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