Cell review: organ specificity and medical application of fibroblasts
Original Cell Press CellPress cell science
life sciences
Life science
Fibroblasts are diverse interstitial cells, which create signal niches by producing complex extracellular matrix and biophysical and biochemical clues, and participate in tissue balance and diseases. Fibroblasts have diverse lineages and a wide range of uses, but our understanding of these cells, which fill a considerable part of the human body, is still not comprehensive. Next, let’s understand the mysterious and fascinating fibroblasts from four aspects and embark on a human journey across time and space.
Definition of fibroblast
The term "fibroblast" refers to the following kinds of cells: (1) cells that secrete many macromolecules with the same structure and signal as the extracellular space of tissues; (2) Adopting the phenotype of myofibroblasts that contract instantaneously when dealing with tissue injury; (3) signal niche cells as resident stem cells; (4) As the progenitor cells of specialized differentiated interstitial cells, they are sometimes called mesenchymal stem cells (Lemos and Duffield, 2018; Pittenger et al. , 1999, 2019)。
Fibroblasts create and maintain anatomically diverse connective tissue rich in extracellular matrix (ECM) to support a wide range of basic organ functions, such as resisting blunt and sharp skin injuries, stretching and elastic retraction in the organ range of lung, etc. In addition to producing connective tissue, fibroblasts serve as the progenitor cells of specialized interstitial cell types during embryonic development, adult homeostasis, injury, repair and remodeling, such as osteoblasts forming bones or fat cells filled with lipids.
The origin and development of fibroblasts
In 1858, German pathologist Rudolf Virchow first described fibroblasts as a unique cell type, which he called "Spindelzellen des Bindegewebes"-"Spindle cells of connective tissue" (Virchow, 1858;; Fig. 2A). Ernst Ziegler first put forward the term "fibroblast" to describe cells that produce new connective tissue after healing (Ziegler, 1895;; Fig. 2B), this observation was replicated by Santiago Ramón y Cajal, who observed that "célula fusiforme" or "fibro-células" are important producers of granulation tissue in skin wound healing and scar (Cajal, 1986;; Fig. 2C). The appearance of in vitro technology developed in the 1900 s promoted the research of fibroblasts. These methods allow primary fibroblasts from embryonic chicken heart explants to be cultured, and these cells can easily propagate before other cell types after passage (Burrows and Neymann, 1917; Carrel, 1912; Ebeling, 1913; Hogue, 1919; Fig. 2D). More than 50 years later, 3T3 fibroblast cell line from mouse embryo was established (Todaro and Green, 1963; Todaro and others,1964) further promoted our understanding of the biological and genealogical potential of fibroblasts. These findings include the identification of fibroblast growth factor (FGFS) (Gospodarovicz, 1974); Multi-line differentiation of cultured fibroblasts into bone, cartilage and fat cells (Junker et al., 2010); And the key role of fibroblasts in the production, remodeling and contraction of ECM.
Although there are a lot of studies on fibroblasts in vitro, the in vivo correlation of these cells is still unclear, and the real characteristics of fibroblasts and their pedigree potential in the in vivo primary environment have only recently been deeply explored. New evidence shows that fibroblasts have promoted major changes in the tumor-related environment, which has been widely reviewed elsewhere (Sahai et al., 2020).
Organ specificity of fibroblasts
The existence of tissue-specific fibroblast function and lineage can support the development, homeostasis and repair needs of specific organs. During embryonic development, multiple cell lines coalesce to form fibroblasts, which are filled with organs from all three somatic germ layers, such as skin and breast derived from ectoderm, skeletal muscle or myocardium derived from mesoderm, and lungs derived from endoderm. When fibroblasts proliferate in specific organs, they will produce unique microstructure, biophysical and biochemical components of connective tissue.
In organs rich in epithelial cells (for example, skin and lungs), fibroblasts in the skin produce a mechanically elastic, viscous and elastic structural foundation, which supports the epithelial cells of the outward layered epidermis and its many appendages, mainly hair follicles and sweat glands. Fibroblasts and other mesenchymal cell lines in the skin have established three anatomically different layers: papillary dermis, reticular dermis and dermal white adipose tissue (dWAT) (Figure 5A). Skin epithelial cells are derived from ectoderm, which has a unique level of connectivetissue. In contrast, lung epithelium originated from endoderm, forming a highly branched tree and eventually forming an inflatable sac called alveoli. The gas exchange function of lung depends on the close physical connection between alveolar epithelium and extensive capillary network, and on the repeated and rapid expansion and contraction ability of lung. These functions require the reticular ECM of the lung, which has the best viscoelasticity, but is strong enough to withstand the change of air pressure and prevent alveolar rupture and potentially fatal air pressure trauma. With the maturity of the lung, the lung mesenchymal progenitor cells assume different spatial positions and functions, including smooth muscle cells around bronchi and blood vessels, pericytes, numerous interstitial fibroblasts, adipocytes supporting lung cells and mesothelial cells of visceral pleura (Peng et al., 2013; Fig. 5B).
In interstitial organs (such as skeletal muscle and heart), unlike skin and lung, skeletal muscle has no epithelial structure, but is composed of large, highly differentiated and multinucleated muscle fibers arranged in parallel, and its main function is to generate strength through contraction. The connective tissue in muscle has a complex layered tissue. Its innermost layer is called endocardium, which surrounds a single muscle fiber and contains a special basement membrane rich in laminin and collagen IV. Laminin acts through its transmembrane receptor, helping the mechanical force to be transmitted from the intracellular contraction device to the inner muscle layer rich in collagen I and III (Chapman et al., 2016). Muscle fiber group is called bundle, surrounded by perimuscular layer, which forms a continuum with tendon, and is rich in so-called perimuscular layer "cable", that is, thick connective tissue bundle mainly composed of closely arranged type I and type III collagen III fibers. Finally, the whole muscle is wrapped by the connective tissue layer of the adventitia (Chapman et al., 2016). Myocardium is an anatomically and physiologically complex contractile organ. Its main cell group, cardiomyocytes, are connected with each other, and an electrically coupled tissue is formed through the sandwich disc that constitutes its middle layer, which is called myocardium. The heart is also rich in fibroblasts, which produce and reshape a powerful ECM network, which is very important for conductivity and heartbeat rhythm. In addition to myocardium, fibroblasts also exist in the outermost epicardium, which contains specialized adipose tissue, and the innermost endocardium, with a layer of endothelial cells at its edge.Unlike most other organs’ fibroblasts, which originated from mesenchymal progenitor cells through gradual standardization, most cardiac fibroblasts are formed through EMT, and fibroblasts located in interventricular septum and right ventricle are products of EndMT (Gittenberger-de Groot et al., 1998; Fig. 5D).
Application of fibroblasts in diseases
At present, the approved anti-fibrosis therapy is aimed at the activation of fibroblasts in established diseases and cannot restore the structure and function of diseased tissues. Therefore, developing strategies to promote the repair of damaged tissues will greatly promote the development of this field.
Although the plasticity of fibroblasts may be problematic in the context of fibrotic diseases, it also provides opportunities for regenerative intervention. Recently, this understanding has promoted the development of in-situ reprogramming into fibroblasts by molecular strategy to restore tissue anatomy and function (including direct reprogramming). In skin wounds, the innate ability of fibroblasts to support hair follicle regeneration can be induced by transcription reprogramming.
Examples have proved that the principle of therapeutic reprogramming of fibroblasts in vivo can be realized in liver and heart, such as transferring transcription factors such as Foxa3, Gata4, Hnf1a and Hnf4a to myofibroblasts in liver through viruses, reprogramming them into hepatocyte-like cells, and reducing the signs of liver fibrosis in mouse models (Rezvani et al., 2016; Song et al., 2016). The above examples clearly emphasize the therapeutic potential of reprogramming tissue-resident fibroblasts directly into "working" cells, and suggest it as a new scar replacement strategy. However, there are still several important problems to be solved, including the efficiency of reprogramming factor delivery using non-integrated vectors and high fibroblast specificity (if not exclusiveness), in order to transform this attractive method into safe clinical application.
Conclusion and prospect
In the past decades, our understanding of fibroblast biology under different organs and conditions has made remarkable progress. New methods and techniques have made this field develop from phenotypic study of cultured cells more than a century ago to complex genetic and functional observation in vivo. These advances reveal that fibroblasts from different organs (such as skin, lung, heart and skeletal muscle) have unexpected similarities and unique characteristics, so they are currently used to treat human diseases.
While great progress has been made, many problems and opportunities still exist. For example, the ongoing efforts to adopt single-cell omics and space genomics technologies will provide key insights into the heterogeneity of fibroblasts within and between tissues, and their ability to assume multiple functional States for physiological or disease triggers. With our understanding of the basic function of fibroblasts far beyond the scope of ECM synthesis, in-situ regulation of fibroblasts can bring new therapeutic possibilities for a wide range of diseases characterized by aging, pathological remodeling and tissue fibrosis. New research fields, including cross-regulation between wound fibroblasts, immune cells and peripheral nervous system, are very important for understanding how to restore tissues to their pre-injury state. Finally, effective clinical transformation will require rigorous verification in local human tissues and human-like models, such as organotypic cultures, xenotransplantation and organs derived from pluripotent cells. These advances will make it possible to prevent, treat and even reverse fibrosis through proper and controlled repair.
Related paper information
The original paper was published in Cell, a periodical of CellPress Cell Press. Click "Read the original" to view the paper.
▌ Paper title:
Fibroblasts: Origins, definitions, and functions in health and disease
▌ Website of the paper:
https://www.cell.com/cell/fulltext/S0092-8674(21)00792-3
▌DOI:
https://doi.org/10.1016/j.cell.2021.06.024
Read the original text