myofibroblasts in health and disease

MYOFIBROBLASTS IN HEALTH AND DISEASEPALLAVI D. SHIROL, DAYANAND D. SHIROL

International Journal of Oral & Maxillofacial Pathology. 2012;3(1):23-27

Dr. RUCHI SHARMA

Myofibroblasts are a unique group of smooth

muscle like fibroblasts which play a significant role

in oncogenesis, inflammation, repair,

organogenesis and fibrosis in various organs and

tissues by the secretion of inflammatory and anti-

inflammatory cytokines, both lipid and gaseous

inflammatory mediators, chemokines, growth

factors as well as extracellular matrix proteins and

proteases.

2

INTRODUCTION

Powell DW, Miffin 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.

Because of their location next to epithelial or

parenchymal cells, myofibroblasts might also be

termed ‘‘JUXTAPARENCHYMAL CELLS’’.

They are present in organs with a high remodelling

capacity such as kidneys, lungs and the periodontal

ligament or during increased remodelling, such as

in growth, development, inflammatory responses

and the contraction of healing wounds.

3



DEFINITION

Myofibroblasts (MFs) are specialized fibroblasts

with smooth muscle-like features characterized by

the presence of contractile apparatus.

4

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.

For years it was believed that collagen is the main

element responsible for wound contraction.

This concept changed in 1950 and it was found that

fibroblasts, under certain conditions, were capable of

contraction in vitro suggesting that cells were central

to wound contraction.

5

THE PREVIOUS CONCEPT

Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible

role in wound contraction. Experientia 1971;27:549-50.

Myofibroblasts were first discovered by electron

microscopy in granulation tissue by Guilio Gabbiani

et al.

6

Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible

role in wound contraction. Experientia 1971;27:549-50.

The granulation tissue

revealed numerous

bundles and aggregates of

microfilaments similar to

smooth muscle cells and

the term MF was

proposed.

DISCOVERY

large, spindle-shaped /stellate cells

long cytoplasmic extensions

amphophilic cytoplasm

indented nucleus

conspicuous nucleoli.

7

STRUCTURE

Schurch W, Seemayer TA, Hinz B, Gabbiani G. Myofibroblast. In: Mills SE, editor. Histology for Pathologists.

Philadelphia: Lippincott-Williams and Wilkins Publishers; 2007. p. 123-164.

ULTRASTRUCTURE

irregular, stellate cellular outlines with long cytoplasmic

extensions

8

Valentich J. D., Popov V., Saada J. I., Powell D. W.(1997) Phenotypic characterization of an intestinal

subepithelial myofibroblast cell line. Am. J. Physiol. 272(Cell Physiol. 41):C1513–C1524

9

numerous and often dilated cisternae of RER

cytoplasmic actin microfilaments(Stress Fibers),

sometimes arranged in discrete

bundles beneath the plasma membrane



slender fusiform and smooth, contoured nucleus

nucleus of activated myofibroblasts shows multiple

indentations

10

Mills, S E. Histology for Pathologists. Lippincott Williams & Wilkins, 3rd Edition

11

well-developed Golgi area

scattered mitochondria

Drobnik J et al. Experimental hypothyroidism increases content of collagen and glycosaminoglycans in the heart. J

Physiol Pharmacol. 2009 Sep;60(3):57-62

12

intercellular gap junctions and adherens junctions



connected to the ECM by cell-to-stroma attachment

sites through fibronexus

13



14

www.pathresidents.com

15

Mills, S E. Histology for Pathologists. Lippincott Williams & Wilkins, 3rd Edition

CLASSIFICATION

16

Schmitt-Graff, A., A. Desmouliere, and G. Gabbiani. Heterogeneity of myofibroblast phenotypic features:

an example of fibroblastic cell plasticity. Virchows Arch. 425: 3–24, 1994.

Vimentin (V)

Vimentin and Desmin (VD)

Vimentin, α-SM actin and Desmin (VAD)

Vimentin and Myosin (VM)

Vimentin and α-SM actin (VA)

ORIGIN AND DIFFERENTIATION OF

MYOFIBROBLASTS

It is uncertain that the origin of myofibroblasts is

from progenitor stem cells (possibly

neuroepithelial stem cells), from the neural crest

or simply transdifferentiate from resident tissue

fibroblasts or from tissue smooth muscle cells.

17



18

Scotton C J, Chambers R C. Molecular targets in pulmonary fibrosis -The myofibroblast in focus. CHEST

132- 4 (Oct 2007).

19

PROTO-MYOFIBROBLASTS DIFFERENTIATION FROM

FIBROBLASTS AND SUBSEQUENTLY INTO MATURE

MYOFIBROBLASTS.

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.

FUNCTIONS OF MYOFIBROBLASTS

Tissue or Organ Function

EPITHELIUM

Granulation tissue Epithelial growth and

differentiation; wound repair

Pericyte Angiogenesis; regulation of local

blood flow

ORAL CAVITY

Periodontal ligament Attachment of teeth

Gingival myofibroblasts Structure of gingiva

Palatal mucosa Structure of palate

20



ROLE OF MYOFIBROBLASTS IN HEALTH AND

DISEASE

Through epithelial-mesenchymal interactions,

myofibroblasts are main components of

morphogenesis or organogenesis i.e. the growth

and development of the tissue or organ.

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 or molecules of basement membrane.

21



CYTOKINES, GROWTH FACTORS, AND INFLAMMATORY

MEDIATORS SECRETED BY MYOFIBROBLASTS

CYTOKINES GROWTH FACTORS CHEMOKINESINFLAMMATORY

MEDIATORS

IL-1

IL-6

TNF-a

IL-10

TGF-b

CSF-1

GM-CSF

PDGF-AA

PDGF-BB

bFGF

IGF-I

IGF-II

NGF

KGF

HGF

SCF

IL-8

MCP-1

GRO-1a

MIP-1a

MIP-2

RANTES

ENA-78

Phospholipase A2

activating protein

PGE2

Prostacyclin

HETEs

PAF

NO

CO

H2O2, O2

22



RECEPTORS EXPRESSED BY MYOFIBROBLASTS

CYTOKINES GROWTH

FACTORS

INFLAMMATORY

MEDIATORS

NEUROTRANSMITTERS

AND PARACRINE

MEDIATORS

ADHESION

PROTEINS

IL-1 TGF-a/EGFR Prostaglandins Acetylcholine ICAM-1

IL-1Ra TGF-b RI and RII HETEs Histamine VCAM-1

TNF-a PDGF-a Serotonin NCAM

IL-6 R PDGF-b Bradykinin MCP-1

IL-8 R c-kit Endothelin a1b1 integrin

IL-4 R aFGF and bFGF R Atrial natriuretic factor CD18

IL-11 R IGF-IR Aldosterone or ANG II

Thrombin receptor

FGFR-II

23



They play a key role in the wound healing,

seemingly as an addition to their function in normal

growth and differentiation.

They are also involved in the formation and repair

of the extracellular matrix (ECM) and proliferation

and differentiation of epithelial (or parenchymal),

vascular and neurogenic elements.

24

ROLE OF MYOFIBROBLASTS IN WOUND HEALING

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(10):871-80.

Myofibroblasts also express α and β integrins that

are part of the adhesion mechanism of

myofibroblast to matrix protein. They produce

matrix molecules such as collagen, glycosamino-

glycans, tenascin and fibronectin in the interstitial

space or basement membrane and play important

role in growth, differentiation and wound healing

which if deranged or separated can result in tissue

fibrosis.

25



MATRIX MOLECULES IMPORTANT IN GROWTH

DIFFERENTIATION AND WOUND REPAIR

26

•Types I–VI, XVIIICOLLAGENS

• Laminins

• Entactin/nidogen

• Fibronectin

• Tenascin

• Sparc/BM40

• Thrombospondin

GLYCOPROTEINS

• Glycosaminoglycans (GAGS)

• Hyaluronic acid (HA-type)

• Heparan sulfate (HS-type)

• Chondroitin sulfate (CS-type)

• Perlecan

PROTEOGLYCANS

• Matrix metalloproteinases (MAPs)

• Tissue inhibitor of metalloproteinases (TIMPs)

MATRIX MODIFYING PROTEINS



27

PHASES OF WOUND HEALING

INFLAMMATORY PHASE

Following injury, vasoconstriction reduces

haemorrhage and favours platelet aggregation.

Almost simultaneously, vasodilatation enables

inflammatory cells to enter the site of injury and

clean the wound.

Neutrophils and macrophages migrate into the

wound to prevent the invasion and proliferation of

micro-organisms.

Platelet aggregation and coagulation result in the

formation of a provisional fibrin clot that covers the

wound.

28



2005;84(10):871-80.

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2005;84(10):871-80.

Myofibroblasts have an important position in theinflammatory response.

They produce both cytokines and chemokines and arecapable of augmenting or down regulating theinflammatory response by the secretion of these solublemediators of inflammation.

They also synthesise prostaglandins, expressing bothCOX-1 and the inducible COX-2 protein.

On activation, myofibroblasts also express molecules foradhesion like intracellular adhesion molecule-1, vascularadhesion molecule and neural cell adhesion molecule.

Thus lymphocytes, mast cells and neutrophils may dockon the myofibroblasts and participate in organisedimmunological and inflammatory reactions.

30



2005;84(10):871-80.

ROLE OF MYOFIBROBLASTS IN THE INFLAMMATORY

PHASE

PROLIFERATORY PHASE

This phase starts with the migration of fibroblasts intothe wound area and their propagation.

These fibroblasts start to produce granulation tissuecomponents such as fibronectin, collagen andhyaluronic acid.

Some fibroblasts differentiate into myofibroblasts, whichare principally responsible for tissue contraction, butalso produce extracellular matrix components.

Simultaneously, re- epithelisation occurs by proliferationand migration of epithelial cells from the wound edges.

Soon after re-epithelialisation,wound contraction stopsand myofibroblasts start to disappear, probably throughapoptosis.

31



2005;84(10):871-80.

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2005;84(10):871-80.

PHASE OF REMODELLING

The number of blood vessels decline and apoptosis

of myofibroblasts results in scar tissue with a low

cell density.

Eventually the scar contains only some fibroblasts

having well developed rough endoplasmic

reticulum.

Myofibroblasts may exist in pathological conditions,

such as hypertrophic scars.

33



2005;84(10):871-80.

34



2005;84(10):871-80.

ROLE OF MYOFIBROBLASTS IN WOUND

CONTRACTION

Initially tractional forces are exerted by migrating

fibroblasts on the adjacent collagen matrix.

This mechanical tension stimulates fibroblasts to

differentiate into proto-myofibroblasts by the

development of stress fibres.

Fibroblasts under tension via the extracellular

matrix also express TGFβ1.

35



2005;84(10):871-80.

The last maturation phase will last for several

months and will result in the final scar.

This phase begins early, during the formation of the

granulation tissue, with progressive reorganisation

of the matrix under the influence of myofibroblasts.

These cells contract their microfilament bundles

which are bonded to the extracellular matrix,

causing compaction of the collagen network and

contraction of the wound.

36



2005;84(10):871-80.

Proto- myofibroblasts generate contractile fibreswithout the expression of α-SM actin.Proto- myofibroblasts can also synthesise andorganise fibronectin and form small fibronexi. Proto-myofibroblasts can differentiate into maturemyofibroblasts in response to specific factors likeTGβ1, ED-A fibronectin (ED-A FN) and mechanicaltension.

Mature myofibroblasts express α- SM actin in stressfibers and form large fibronexi.

Once the wound is repaired, mature myofibroblastsdisappear through apoptosis or by dedifferentiation.

37



2005;84(10):871-80.

MYOFIBROBLASTS IN PATHOLOGIC TISSUES

• GIANT CELL GRANULOMA

• GIANT CELL FIBROMA

• PHENYTOIN-INDUCED GINGIVAL HYPERPLASIA

INFLAMMATORY AND REACTIVE LESIONS

• NODULAR FASCIITIS

• BENIGN MYOFIBROBLASTOMA

• FIBROMATOSIS

• SARCOMAS

PROLIFERATIVE MYOFIBROBLASTIC LESIONS

• AMELOBLASTOMA

• ODONTOGENIC KERATOCYST

• ODONTOGENIC MYXOMAODONTOGENIC LESIONS

• ORAL SUBMUCOUS FIBROSIS

• SQUAMOUS CELL CARCINOMA

PRECANCEROUS AND CANCEROUS LESIONS

38

Pinisetti S, Manyam R, Suresh B, Aparna V. Myofibroblasts in oral lesions: A review. J

Oral Maxillofac Pathol 2014;18:52-7.

ODONTOGENIC KERATOCYST

39

Pinisetti S, Manyam R, Suresh B, Aparna V. Myofi broblasts in oral lesions: A review. J


FOLLICULAR AMELOBLASTOMA

40



UNICYSTIC AMELOBLASTOMA

41



SQUAMOUS CELL CARCINOMA

42



ROLE OF MYOFIBROBLASTS IN FIBROSIS

After tissue injury, fibroblasts differentiate intocontractile and secretary myofibroblasts which helpin tissue repair during wound healing, but this canseverely disturb the organ function whencontraction and extracellular matrix proteinsecretion become excessive, such as inscleroderma, hypertrophic scars, kidney, lung andheart fibrosis.

Myofibroblasts play significant roles in promotingECM deposition, release of inflammatory mediatorsand epithelial injury, which are believed to beimportant factors in perpetuating the cycle of injuryof fibrosis.

43

Hinz boris, Phan Sem H, Thannickal Victor J, Galli Andrea, Bochaton-Piallat Marie-Luce, Gabbiani Giulio.

The myofibroblast – One Function, Multiple Origins. Am J Pathol 2007;170(6):180716.

44

de Haan and Arslan: Highlights of Keystone symposium ‘Fibrosis : from bench to bedside’ Fibrogenesis

& Tissue Repair 2014, 7:11

The fate of activated myofibroblasts in injured

tissues may eventually decide whether there will be

normal healing or progression to the end-stage

fibrosis.

Resolution with myofibroblast apoptosis would

terminate progression; however, this would be

countered by persistence of TGFβ1 expression and

ECM deposition, which promote the pro-survival or

antiapoptotic phenotype.

45



It is shown in recent studies that during fibrotic

situations, myofibroblasts develop the ability of

creating a long-lasting tension essentially regulated

at the level of RhO/RhO kinase-mediated inhibition

of myosin light chain phosphatase, compared with

the usual contraction-relaxation activity depending

on Ca2+ induced phosphorylation of myosin light

chain kinase taking place in smooth muscle cells-

SMCs.

46



In one study it was shown that Oral Sub Mucous

Fibrosis (OSMF) may possibly represent an

abnormal healing process in response to chronic

mechanical and chemical irritation due to areca nut

chewing as exhibited by the increased incidence of

myofibroblasts in this disease.

Also it was seen that there was progressive

increase in myofibroblasts from early to advanced

stages.

Hence to control fibrosis it is essential to stop

myofibroblast activities.

47

Angadi PV, Kale AD, Hallikerimath S. Evaluation of myofibroblasts in oral submucous fibrosis: correlation

with disease severity. J Oral Pathol Med 2011;40(3):208-13.

ROLE OF MYOFIBROBLASTS IN ORAL CANCER

It is well known fact that many epithelial tumours

are characterised by the local accumulation of

connective tissue cells and extracellular material;

this phenomenon has been called the stroma

reaction.

In stroma reaction, the myofibroblast is one of the

cellular components.

Myofibroblasts interact with epithelial cells and

other connective tissue cells and may thus control

such phenomena as tumour invasion and

angiogenesis.48

Gabbiani G. The Evolution of the Myofibroblast Concept: a Key Cell for Wound Healing and fibrotic diseases. G

Gerontol 2004;52:280-2.

Cancer invasion progresses by ECM degradation at

the cancer-stroma interface, loss of epithelial

morphology and acquisition of mesenchymal

characteristics, referred to as the epithelial-

mesenchymal transition (EMT), are typical for

invasive carcinoma cells and predispose tumours to

a more advanced state of progression.

49

Kawashiri S, Tanaka A, Noguchi N, Hase T, Nakaya H, Ohara T, et al. Significance of Stromal Desmoplasia

and Myofibroblast appearance at the invasive front in Squamous Cell Carcinoma of the Oral Cavity. Head

Neck 2009;31(10):1346-53.

In normal mucosa, physiological turnover of the epithelium is the only stimulus for a stromalreaction.

In contrast, cancer cells invade the stroma by altering the stromal microenvironment via the destruction of normal tissue.

Although both the synthesis and degradation of the ECM occur during wound healing, cancer invasion may progress when ECM degradation exceeds its synthesis, preventing complete healing.

The mesenchymal cells that mediate proteolyticactivity in the stroma could be myofibroblasts. The fibrous stroma in oral SCC is a desmoplasticresponse.

50



Neck 2009;31(10):1346-53.

In many types of solid tumour SMA-positive

myofibroblasts (Peritumour fibroblasts, carcinoma-

associated fibroblasts) are found within the stromal

compartment.

Most commonly, myofibroblasts have been

described as differentiating locally from fibroblasts.

However, it is now evident that a number of other

cell types may undergo myofibroblastic

transdifferentiation.

51



Neck 2009;31(10):1346-53.

These include other locally-derived mesenchymal

cells such as adipocytes, stellate cells and

pericytes, as well as circulating mesenchymal stem

cells, monocytes in bone marrow and epithelial

cells, but it is not possible to identify which cells in

cancer tissue transit myofibroblasts.

Cancer cell derived transforming growth factor

(TGF) stimulation may activate fibroblasts, leading

to their transdifferentiation into myofibroblasts.

52



Neck 2009;31(10):1346-53.

Transition of myofibroblast appearance in invasive

cancer and particularly tumour desmoplasia, is an

important reflection of the tumour-host interaction

especially in aggressive cancers.

Several cytokines including TGF-β, PDGF, IL-4 &

IGF-II have been reported to induce myofibroblastic

differentiation. TGF-β1 is a pleiotropic cytokine

which is over expressed in many carcinomas and

may be pro-oncogenic.

53



Neck 2009;31(10):1346-53.

In one study it was demonstrated that tumour cells

induced transdifferentiation of oral normal

fibroblasts to myofibroblasts via secretion of

transforming growth factor beta- 1 (TGF-β1).

In turn, myofibroblasts secreted factors that

stimulated OSCC cell proliferation as revealed by

Ki67 expression.

54

Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA, et al. Mutual paracrine effects of

oral squamous cell carcinoma cells and normal oral fibroblasts: Induction of fibroblast to myofibroblast

transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 2008;44(5):509-17.

Myofibroblasts also promote invasion by

remodelling the extracellular matrix and

metalloproteinases (MMPs) and their inhibitors

produced by both cancer and stromal cells are

known to play a role in altering the composition of

the tumour micro environment and are prognostic.

55


oral squamous cell carcinoma cells and normal oral fibroblasts: Induction of fibroblast to myofibroblast

transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 2008;44(5):509-17.

In another study, data demonstrated activin A

(growth factor) is required for the proliferative

effects of myofibroblasts on OSCC cells.

Myofibroblasts in the stroma of OSCC may

influence proliferation and invasion, resulting in

more aggressive tumour.

56

Sobral LM, Bufalino A, Lopes MA, Graner E, Salo T, Coletta RD. Myofibroblasts in the stroma of oral

cancer promote tumorigenesis via secretion of activin A. Oral Oncol 2011;47(9):840-6.

Studies conducted by Kellerman et al and

Moghadam et al revealed no statistically significant

difference in the mean number of myofibroblasts

between well, moderate and poorly differentiated

OSCC and suggested that transdifferentiation of

MFs occurs during the invasive stage of

carcinomatous epithelium and further loss of

tumoral differentiation does not affect the number

of cells.

57


oral squamous cell carcinoma cells and normal oral fi broblasts: Induction of fi broblast to myofi broblast

transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 2008;44:509-17.

58

Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA, et al. Myofibroblasts in the

stroma of oral squamous cell carcinoma is associated with poor prognosis. Histopathology 2007;51:849-53.

Morphologic characters of the invasive front may

better reflect the tumor prognosis than other parts

of the tumor. Few studies done in this regard,

reported high levels of collagen fibers and stromal

MFs at the invasive front and their number

increased with the increasing tumor invasiveness.

59

Vered M, Allon I, Buchner A, Dayan D. Stromal myofi broblasts accompany modifi cation in the epithelial

phenotype of tongue dysplastic and malignant lesions. Cancer Microenviron 2009;2:49-57.

The presence of MFs was also thought to be

associated with tumor prognosis.

Studies done in this regard showed that increased

MFs was associated with poor prognosis.

MFs in tongue cancer were associated with risk

score and prognosis.

60

Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, et al. Stromal features are predictive of

disease mortality in oral cancer patients. J Pathol 2011;223:470-81.

Patients whose specimens were weakly positive for

α-SMA had 5 year mean survival rate of 82%;

whereas, patients with samples that were strongly

positive with α-SMA had a mean survival rate of

38% indicating that the presence of more number of

MFs in the stroma is associated with poor

prognosis.

Thus, the presence of increased stromal MFs is an

effective predictor of oral squamous cell carcinoma

patient mortality.

61

Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, et al. Stromal features are predictive of

disease mortality in oral cancer patients. J Pathol 2011;223:470-81.

CONCLUSION

Myofibroblasts are ubiquituous cells with similar

properties and functions that play significant roles

in growth, development, wound repair as well as

disease.

As they are present in virtually every tissue, it is

possible that they may play a role in multisystem

diseases.

62

Understanding the role of the stromal cells and

extracellular matrix 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

myofibroblasts and control their activation wherever

they act hyperactive.

63

REFERENCES

64

Powell DW, Miffin RC, Valentich JD, Crowe SE, Saada JI, WestAB. Myofibroblasts. I. Paracrine cells important in health anddisease. Am J Physiol 1999;277(1 Pt 1):C1-9.

Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA.Myofibroblasts and mechano-regulation of connective tissueremodelling. Nat Rev Mol Cell Biol 2002;3:349-63.

Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblastsin granulation tissue and their possible role in wound contraction.Experientia 1971;27:549-50.

Schurch W, Seemayer TA, Hinz B, Gabbiani G. Myofibroblast. In:Mills SE, editor. Histology for Pathologists. Philadelphia:Lippincott-Williams and Wilkins Publishers; 2007. p. 123-164.

Valentich J. D., Popov V., Saada J. I., Powell D. W.(1997) Phenotypiccharacterization of an intestinal subepithelial myofibroblast cellline. Am. J. Physiol. 272(Cell Physiol. 41):C1513–C1524

Mills, S E. Histology for Pathologists. Lippincott Williams &Wilkins, 3rd Edition

Drobnik J et al. Experimental hypothyroidism increases content ofcollagen and glycosaminoglycans in the heart. J PhysiolPharmacol. 2009 Sep;60(3):57-62

www.pathresidents.com

Schmitt-Graff, A., A. Desmouliere, and G. Gabbiani.Heterogeneity of myofibroblast phenotypic features: an exampleof fibroblastic cell plasticity. Virchows Arch. 425: 3–24, 1994.

65

Scotton C J, Chambers R C. Molecular targets in pulmonary fibrosis -The myofibroblast in focus. CHEST 132- 4 (Oct 2007).

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 PalateRepair. J Dent Res 2005;84(10):871-80.

Pinisetti S, Manyam R, Suresh B, Aparna V. Myofibroblasts in orallesions: A review. J Oral Maxillofac Pathol 2014;18:52-7.

Hinz boris, Phan Sem H, Thannickal Victor J, Galli Andrea, Bochaton-Piallat Marie-Luce, Gabbiani Giulio. The myofibroblast –One Function, Multiple Origins. Am J Pathol 2007;170(6):180716.

66

myofibroblasts in health and disease

Health & Medicine