Editing Fibroblast (section)

== Function ==
Fibroblasts make [[collagen]] fibers, [[glycosaminoglycan]]s, [[reticular fiber|reticular]] and [[elastic fibers]]. The fibroblasts of growing individuals divide and synthesize ground substance. Tissue damage stimulates fibrocytes and induces the production of fibroblasts.<ref>{{Cite journal |last=Pilling |first=Darrell |last2=Vakil |first2=Varsha |last3=Cox |first3=Nehemiah |last4=Gomer |first4=Richard H. |date=2015-09-22 |title=TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation |url=https://pnas.org/doi/full/10.1073/pnas.1507387112 |journal=Proceedings of the National Academy of Sciences |language=en |volume=112 |issue=38 |pages=11929–11934 |doi=10.1073/pnas.1507387112 |issn=0027-8424 |pmc=4586854 |pmid=26351669}}</ref>

===Inflammation===
Besides their commonly known role as structural components, fibroblasts play a critical role in an immune response to a tissue injury. They are early players in initiating inflammation in the presence of invading microorganisms. They induce chemokine synthesis through the presentation of receptors on their surface. Immune cells then respond and initiate a cascade of events to clear the invasive microorganisms. Receptors on the surface of fibroblasts also allow regulation of [[Hematopoietic stem cell|hematopoietic cells]] and provide a pathway for immune cells to regulate fibroblasts.<ref>{{cite journal | vauthors = Smith RS, Smith TJ, Blieden TM, Phipps RP | title = Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation | journal = The American Journal of Pathology | volume = 151 | issue = 2 | pages = 317–322 | date = August 1997 | pmid = 9250144 | pmc = 1858004 }}</ref>

===Tumour mediation===
Fibroblasts, like [[Cancer-associated fibroblast |tumor-associated host fibroblasts]] (TAF), play a crucial role in immune regulation through TAF-derived ECM components and modulators. TAF are known to be significant in the inflammatory response as well as immune suppression in tumors. TAF-derived ECM components cause alterations in ECM composition and initiate the ECM remodeling.<ref name=":0">{{cite journal | vauthors = Silzle T, Randolph GJ, Kreutz M, Kunz-Schughart LA | title = The fibroblast: sentinel cell and local immune modulator in tumor tissue | journal = International Journal of Cancer | volume = 108 | issue = 2 | pages = 173–180 | date = January 2004 | pmid = 14639599 | doi = 10.1002/ijc.11542 | s2cid = 10936034 | doi-access =  }}</ref> ECM remodeling is described as changes in the ECM as a result of [[enzyme]] activity which can lead to degradation of the ECM. Immune regulation of tumors is largely determined by ECM remodeling because the ECM is responsible for regulating a variety of functions, such as proliferation, differentiation, and morphogenesis of vital organs.<ref>{{cite journal | vauthors = Bonnans C, Chou J, Werb Z | title = Remodelling the extracellular matrix in development and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 12 | pages = 786–801 | date = December 2014 | pmid = 25415508 | pmc = 4316204 | doi = 10.1038/nrm3904 }}</ref> In many tumor types, especially those related to the epithelial cells, ECM remodeling is common. Examples of TAF-derived ECM components include Tenascin and Thrombospondin-1 (TSP-1), which can be found in sites of chronic inflammation and carcinomas, respectively.<ref name=":0" />

Immune regulation of tumors can also occur through the TAF-derived modulators. Although these modulators may sound similar to the TAF-derived ECM components, they differ in the sense that they are responsible for the variation and turnover of the ECM. Cleaved ECM molecules can play a critical role in immune regulation. Proteases like matrix [[Metalloproteinase|metalloproteineases]] and the uPA system are known to cleave the ECM. These proteases are derived from fibroblasts.<ref name=":0" />

===Use of fibroblasts as feeder cells===
[[Mouse embryonic fibroblast]]s (MEFs) are often used as supportive "feeder cells" in research using human embryonic stem cells,<ref>{{cite journal |last1=Llames |first1=S. |last2=García-Pérez |first2=E. |last3=Meana |first3=A. |last4=Larcher |first4=F. |last5=del Río |first5=M. |title=Feeder Layer Cell Actions and Applications |journal=Tissue Eng Part B Rev. |date=2015 |volume=21 |issue=4 |pages=345–353 |doi=10.1089/ten.teb.2014.0547 |pmid=25659081 |pmc=4533020 }}</ref> induced pluripotent stem cells and primary epithelial cell culture.<ref>{{cite journal |last1=Hynds |first1=R.E. |last2=Bonfanti |first2=P. |last3=Janes |first3=S.M. |title=Regenerating human epithelia with cultured stem cells: feeder cells, organoids and beyond |journal=EMBO Molecular Medicine |date=2018 |volume=10 |issue=2 |pages=139–150 |doi=10.15252/emmm.201708213 |pmid=29288165 |pmc=5801505 }}</ref> However, many researchers are trying to phase out MEFs in favor of culture media with precisely defined ingredients in order to facilitate the development of clinical-grade products.<ref>{{cite journal |last1=Hagbard |first1=L. |last2=Cameron |first2=K. |last3=August |first3=P. |last4=Penton |first4=C. |last5=Parmar |first5=M. |last6=Hay |first6=D.C. |last7=Kallur |first7=T. |title=Developing defined substrates for stem cell culture and differentiation. |journal=Philosophical Transactions of the Royal Society B |date=2018 |volume=373 |issue=1750 |doi=10.1098/rstb.2017.0230 |pmid=29786564 |pmc=5974452 }}</ref>

In view of the potential clinical applications of stem cell-derived tissues or primary epithelial cells, the use of human fibroblasts as an alternative to MEF feeders has been studied.<ref>{{cite journal | vauthors = Desai N, Rambhia P, Gishto A | title = Human embryonic stem cell cultivation: historical perspective and evolution of xeno-free culture systems | journal = Reproductive Biology and Endocrinology | volume = 13 | issue = 1 | pages = 9 | date = February 2015 | pmid = 25890180 | pmc = 4351689 | doi = 10.1186/s12958-015-0005-4 | doi-access = free }}</ref> Whereas the fibroblasts are usually used to maintain pluripotency of the stem cells, they can also be used to facilitate development of the stem cells into specific type of cells such as cardiomyocytes.<ref>{{cite journal | vauthors = Matsuda Y, Takahashi K, Kamioka H, Naruse K | title = Human gingival fibroblast feeder cells promote maturation of induced pluripotent stem cells into cardiomyocytes | journal = Biochemical and Biophysical Research Communications | volume = 503 | issue = 3 | pages = 1798–1804 | date = September 2018 | pmid = 30060947 | doi = 10.1016/j.bbrc.2018.07.116 | doi-access = free }}</ref>

=== Host immune response ===
Fibroblasts from different anatomical sites in the body express many genes that code for [[Cytokine|immune mediators]] and proteins.<ref name=":1">{{cite journal | vauthors = Krausgruber T, Fortelny N, Fife-Gernedl V, Senekowitsch M, Schuster LC, Lercher A, Nemc A, Schmidl C, Rendeiro AF, Bergthaler A, Bock C | display-authors = 6 | title = Structural cells are key regulators of organ-specific immune responses | journal = Nature | volume = 583 | issue = 7815 | pages = 296–302 | date = July 2020 | pmid = 32612232 | doi = 10.1038/s41586-020-2424-4|pmc=7610345  | bibcode = 2020Natur.583..296K | s2cid = 220295181 | doi-access = free }}</ref> These mediators of immune response enable the [[Cell signaling|cellular communication]] with hematopoietic immune cells.<ref>{{cite journal | vauthors = Armingol E, Officer A, Harismendy O, Lewis NE | title = Deciphering cell-cell interactions and communication from gene expression | journal = Nature Reviews. Genetics | date = November 2020 | volume = 22 | issue = 2 | pages = 71–88 | pmid = 33168968 | pmc = 7649713 | doi = 10.1038/s41576-020-00292-x }}</ref> The immune activity of non-hematopoietic cells, such as fibroblasts, is referred to as “structural immunity”.<ref name=":1" /><ref>{{cite journal | vauthors = Minton K | title = A gene atlas of 'structural immunity' | journal = Nature Reviews. Immunology | volume = 20 | issue = 9 | pages = 518–519 | date = September 2020 | pmid = 32661408 | doi = 10.1038/s41577-020-0398-y | s2cid = 220491226 | doi-access =  }}</ref> In order to facilitate a fast response to immunological challenges, fibroblasts encode crucial aspects of the structural cell immune response in the [[epigenome]].{{Cn|date=May 2021}}