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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 2  |  Page : 91-95

Myofibroblasts in oral health and odontogenic lesions


Department of Oral and Maxillofacial Pathology, SRM Dental College, Chennai, Tamil Nadu, India

Date of Web Publication19-May-2016

Correspondence Address:
Srikanth Ramarao Prabakar
Department of Oral and Maxillofacial Pathology, SRM Dental College, Chennai, Tamil Nadu
India
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DOI: 10.4103/0976-433X.182665

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  Abstract 

Myofibroblasts (MFs) are the cells that are not only essential for the integrity of the human body by virtue of its role in physiological tissue repair (wound healing), but can also threaten it by its ability to promote tumor development. Under physiological conditions, after wound healing, MFs disappear by apoptosis, but when there is continued insult, these MFs persist in the tissue and result in dysfunctional repair mechanisms causing excessive secretion of extracellular matrix with resultant fibrosis and scarring. MFs are phenotypically altered fibroblasts and are a unique group of smooth muscle-like fibroblasts that have a similar appearance and function regardless of their tissue of residence. MFs originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells, and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of MFs when local fibroblasts are not able to satisfy the requirement for these cells during repair. Apart from pathological remodeling of tissues, they play an important role in organogenesis and oncogenesis, inflammation, repair, and fibrosis. Because of their ubiquitous presence in all tissues, MFs play important roles in various organ diseases and perhaps in multisystem diseases as well. In the light of such severe consequences of MF appearance and dysfunction, the necessity of more profoundly understanding the molecular mechanisms of MF formation and function is essential. This article highlights the overview of MFs and their role in oral health and disease particularly in relation to odontogenic lesions.

Keywords: Myofibroblasts, wound healing, odontogenic lesions


How to cite this article:
Prabakar SR, Kumar T D, Krishnan R, Prakash S S. Myofibroblasts in oral health and odontogenic lesions. SRM J Res Dent Sci 2016;7:91-5

How to cite this URL:
Prabakar SR, Kumar T D, Krishnan R, Prakash S S. Myofibroblasts in oral health and odontogenic lesions. SRM J Res Dent Sci [serial online] 2016 [cited 2020 Oct 22];7:91-5. Available from: https://www.srmjrds.in/text.asp?2016/7/2/91/182665


  Introduction Top


Myofibroblasts (MFs), by simple definition, are specialized fibroblasts, with smooth muscle like features characterized by the presence of contractile apparatus.[1] They are unique cells and are essential for the integrity of the mammalian body by virtue of its role in wound healing, but it can also threaten it by its ability to promote tumor development. Through the secretion of inflammatory and anti-inflammatory cytokines, chemokines, growth factors, as well as extracellular matrix proteins and proteases, they play an important role in organogenesis and oncogenesis, inflammation, repair and fibrosis in most organs and tissues. It is an almost universal cellular component in mammalian lesions, but not a typical component of normal untraumatized tissues.

The concept of collagen, being the main element responsible for contraction of wound, changed in 1950. It was discovered that specialized fibroblasts were present in the granulation tissues. Microscopic studies revealed that these specialized cells are similar to that of smooth muscle cells which are capable of contraction. Later, these smooth muscle-like cells is termed as MFs, by Gabbiani in 1971.[2]

Partly because of its absence in normal tissues, it has not been a part of conventional histologic teaching and has contributed difficulties in explaining the nature of these ubiquitous cells and in defining it. This article reviews on some important hallmarks related to its structure, immunophenotypes, origin and fate, its role in normal, and in pathologic situations.


  Structure Top


MFs have several unique morphological characteristics, few of which are present in fibroblast as well as smooth muscle cells. They are spindle-shaped cells [Figure 1] with numerous cytoplasmic extensions containing actin microfilaments called as stress fibers, and they are connected to each other by adherens and gap junctions and are connected to extracellular matrix (ECM) by a transmembrane complex known as fibronexus.[3]
Figure 1: Myofibroblasts in stromal cells (Courtesy: Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, Kato Y, Muguruma K, Sawada T, Hirakawa K. Myofibroblasts are associated with the progression of scirrhous gastric carcinoma. J Exp Ther Med 2010;547-51)

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Transmission electron microscopy shows, the cell membranes display numerous invaginations. The cytoplasm is rich in well-developed rough endoplasmic reticulum (RER), Golgi apparatus, mitochondria, and indented nucleus[Figure 2].
Figure 2: Transmission electron microscopy showing tubular epithelial-myofibroblast transdifferentiation (Courtesy: Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. J Int Soc Nephrol 1996;56:1455-67)

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Since MFs share features with fibroblasts (RER and Golgi apparatus) and with smooth muscle cells (myofilaments), it is seen that MF's are devoid of lamina – a structure seen in smooth muscle cells.

Further, α-smooth muscle actin (α-SMA) is present in other cells other than MFs such as pericytes, endothelial cells, myoepithelial cells, and one should not rely only on expression of α-SMA alone in identification or in distinguishing MFs. Hence, electron microscopy plays an important role in distinguishing MFs from other cells.


  Immunphenotypes Top


Almost all MFs express α-SMA, an actin isoform present in most of the types of smooth muscle cells. It is considered to be the main immunohistochemical (IHC) marker in identifying MFs.[4]

Apart from α-SMA, they also express desmin, myosin, and vimentin [Figure 3]. Based on these expressions, MFs disclose five immunophenotypes: (a) Phenotype V, cells expressing vimentin alone; (b) phenotype VA, those expressing vimentin and α-SMA; (c) phenotype VD, those expressing vimentin and desmin; (d) phenotype VAD, those expressing vimentin, α-SMA and desmin; and (e) phenotype VAM, those cells expressing vimentin, α-SMA, and myosin.
Figure 3: Myofibroblasts expression in stromal cells (Courtesy: Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, Kato Y, Muguruma K, Sawada T, Hirakawa K. Myofibroblasts are associated with the progression of scirrhous gastric carcinoma. J Exp Ther Med 2010, 547-51)

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Origin, differentiation of myofibroblast

Their occurrence in various physiological and pathological situations makes it difficult to think about its exact source of origin. It is uncertain that the origin of MF is from the progenitor stem cells (possibly neuroepithelial stem cells), from the neural crest, or simply transdifferentiate from the resident tissue fibroblasts, or from tissue smooth muscle cells.[5]

In normal conditions, fibroblastic cells exhibit few or no actin-associated cell to cell, and cell to matrix contacts, and little ECM production.[1]

After tissue injury, they become activated to migrate into the damaged tissue and to synthesize ECM components [6] by cytokines locally released from the inflammatory and resident cells.[7] Another important stimulus for this transition is the change of the mechanical micro environment. In response to this mechanical challenge, fibroblasts gain contractile stress fibers that are composed of cytoplasmic actins,[1] hallmarking them as “Protomyofibroblats.”

The term protomyofibroblast are termed for those fibroblasts with stress fibers that do not express α-SMA. For the transformation of protomyofibroblasts into mature MFs, mechanical stresses along with certain cytokines are necessary.

Cytokines necessary for myofibroblasts differentiation

Various cytokines and growth factors have roles in MF differentiation.[8] Among these, especially, the transforming growth factor (TGF)-β1 [Figure 4], is the major growth factor and a potent inducer of MFs differentiation.[8]
Figure 4: Differentiation of fibroblast into myofibroblast (Courtesy: Boris H. Formation and function of the myofibroblast during tissue repair. J Invest Derm 2007;127:526-37)

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Platelet-derived growth factors play an important role in the differentiation of fibroblasts into protomyofibroblasts.[9] TGF-β1 and ED-A FN (a variant of fibronectin) are key players in the differentiation of protomyfibroblasts into mature MFs. Other factors such as granulocyte-macrophage colony stimulating factor and integrins also play a role.[9]In vitro studies have shown heparin to have a minor role in the differentiation of MFs by stimulating the expression of α-SMA.[8]

Certain cytokines have been indicated to reduce the adverse effects of MFs, by inhibiting their differentiation such as interferon (IFN)-γ, basic fibroblast growth factor (bFGF), and prostaglandin E2 (PGE2). IFN-γ and PGE2 have been found to downregulate its differentiation by inhibiting the TGF-β1 induced MF differentiation.[10],[11] bFGF has a role in inhibiting the differentiation by reducing the expression of α-SMA (Ishiguro et al., 2009) and also induces apoptosis of MFs.[12]

Myofibroblasts in physiological situations

Morphogenesis and organogenesis

Through epithelial-mesenchymal interactions, MFs are the main components of morphogenesis and organogenesis.[5] They do so by the discharge of soluble mediators of inflammation and growth factors and expression of their receptors and by the production of interstitial matrix and molecules of basement membrane.[5]

Normal wound healing and wound contraction

Immediately after injury, the healing process allowing to restoration of the injured tissue occurs. According to the morphological changes in the course of the healing process, there occur three phases of events described as (a) inflammatory phase, (b) proliferative phase, for the development of granulation tissue, and (c) regenerative phase for maturation, scar formation, and re-epithelialization.[13]

MFs appear to be key cells in the process of wound healing and are found more numerous in the exudates layer of granulation tissue. PGs synthesized by these cells promotes healing by restoration of the epithelium. Contraction of the wound is because of the presence of α-SMA filaments in the cytoplasm of these cells.[14]

The ECM, which is a mixture of collagen and ground substances and enzymes such as matrix metalloproteinases, required for tissue remodeling are also secreted by these cells.

Hence, they play a key role in the wound healing, seemingly as an addition to their function in normal growth and differentiation.[5]

Myofibroblasts in odontogenic lesions

In general stromal reactions to epithelial neoplasm is marked by the appearance of MFs.[15] In support of this, it has been proved that there is the presence of MF's at the invasion front of a variety of malignant tumors involving various organs such as liver, lung, pancreas, prostate as well as in odontogenic lesions.[16]

Previously, it was thought that the presence of MF's at the invasive front of the malignant tumors was a host reaction to prevent invasion of malignant cells. Later, it was proved with abundance of evidence that their presence at the invasion front is not part of the host defense mechanism against invasion, but actually promotes it, by the production of angiogenic factors, ECM components.[17]

Presence of MFs has been reported in the stroma of odontogenic cysts and tumors. Electron microscopic studies have demonstrated the presence of MFs in the stromal component of ameloblastoma [Figure 5] and it has been proposed that the presence of these cells could contribute to its aggressive behavior.[18]
Figure 5: Higher α-smooth muscle actin immunoreactivity in ameloblastoma (Courtesy: Shruthi DK, Tegginamani AS, Karthik B. A possible role of myofibroblast in biological behavior of odontogenic keratocyst and ameloblastoma: A comparative study. Univ Res J Dent 2014;4:115-7)

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Various studies have been conducted on odontogenic cysts and tumors and has revealed that MFs were particularly more in lesions with locally aggressive behavior such as odontogenic keratocyst (OKC) and a solid variant of ameloblastoma.[19]

Studies conducted using IHC to demonstrate α-SMA in odontogenic cysts reported that a variable proportion of the cyst wall fibroblasts showed expression for α-SMA. The results of these study demonstrated that MFs contribute to cyst wall elasticity and also help in cyst wall expansion.[20]

Vered et al. evaluated quantitatively the expression of MFs in different odontogenic cysts and tumors, and the results showed that the mean number of MF, in well recognized aggressive odontogenic lesions (ameloblastoma and OKC) was high and did not differ significantly from that seen in squamous cell carcinoma. In contrast, known nonaggressive lesions (unicystic ameloblastoma, ameloblastic fibro-odontoma, orthokeratinized odontogenic cyst, and dentigerous cyst) showed significantly lower results compared to ameloblastoma and OKC. They suggested a positive link, that is when more MFs are present in the stroma, more aggressive behavior of the odontogenic cyst/tumor can be anticipated.[11]


  Conclusion Top


MFs are ubiquitous cells with similar properties and functions that play significant roles in morphogenesis, organogenesis, and wound healing as well as in odontogenic lesions. As they are present in virtually all tissues, it is possible that they may play a role in multisystem diseases. Understanding the role of the stromal cells and ECM will allow us to identify more precise prognostic markers and potentially device new therapeutic options and prevent various diseases caused by these miraculous multipotential cells. Studies can help us to use only beneficial effects of MFs and control their activation wherever they are hyperactive.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002;3:349-63.  Back to cited text no. 1
    
2.
Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971;27:549-50.  Back to cited text no. 2
    
3.
Hinz B, Gabbiani G. Cell-matrix and cell-cell contacts of myofibroblasts: Role in connective tissue remodeling. Thromb Haemost 2003;90:993-1002.  Back to cited text no. 3
    
4.
Vered M, Shohat I, Buchner A, Dayan D. Myofibroblasts in stroma of odontogenic cysts and tumors can contribute to variations in the biological behavior of lesions. Oral Oncol 2005;41:1028-33.  Back to cited text no. 4
    
5.
Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 1999;277(1 Pt 1):C1-9.  Back to cited text no. 5
    
6.
Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127:526-37.  Back to cited text no. 6
    
7.
Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83:835-70.  Back to cited text no. 7
    
8.
Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993;122:103-11.  Back to cited text no. 8
    
9.
van Beurden HE, Von den Hoff JW, Torensma R, Maltha JC, Kuijpers-Jagtman AM. Myofibroblasts in palatal wound healing: Prospects for the reduction of wound contraction after cleft palate repair. J Dent Res 2005;84:871-80.  Back to cited text no. 9
    
10.
Tanaka K, Sano K, Yuba K, Katsumura K, Nakano T, Tanaka K, et al. Inhibition of induction of myofibroblasts by interferon gamma in a human fibroblast cell line. Int Immunopharmacol 2003;3:1273-80.  Back to cited text no. 10
    
11.
Garrison G, Huang SK, Okunishi K, Scott JP, Kumar Penke LR, Scruggs AM, et al. Reversal of myofibroblast differentiation by prostaglandin E(2). Am J Respir Cell Mol Biol 2013;48:550-8.  Back to cited text no. 11
    
12.
Ishiguro S, Akasaka Y, Kiguchi H, Suzuki T, Imaizumi R, Ishikawa Y, et al. Basic fibroblast growth factor induces down-regulation of alpha-smooth muscle actin and reduction of myofibroblast areas in open skin wounds. Wound Repair Regen 2009;17:617-25.  Back to cited text no. 12
    
13.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008;453:314-21.  Back to cited text no. 13
    
14.
Pinisetti S, Manyam R, Suresh B, Aparna V. Myofibroblasts in oral lesions: A review. J Oral Maxillofac Pathol 2014;18:52-7.  Back to cited text no. 14
[PUBMED]  Medknow Journal  
15.
De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol 2003;200:429-47.  Back to cited text no. 15
    
16.
Pousti SB, Izadi F, Jalessi M, Hoseini A. Gorlin's syndrome presenting as recurrent mandibular cyst infection. Iran Red Crescent Med J 2008;10:124-6.  Back to cited text no. 16
    
17.
Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 2003;83:337-76.  Back to cited text no. 17
    
18.
Rothouse LS, Majack RA, Fay JT. An ameloblastoma with myofibroblasts and intracellular septate junctions. Cancer 1980;45:2858-63.  Back to cited text no. 18
    
19.
Mashhadiabbas F, Moghadam SA, Moshref M, Elahi M. Immunohistochemical detection and ultrastructure of myofibroblasts in the stroma of odontogenic cysts and ameloblastoma. Iran Red Crescent Med J 2010;12:453-7.  Back to cited text no. 19
    
20.
Lombardi T, Morgan PR. Immunohistochemical characterisation of odontogenic cysts with mesenchymal and myofilament markers. J Oral Pathol Med 1995;24:170-6.  Back to cited text no. 20
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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Introduction
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