The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671

Cells in focus

Fibroblasts and myofibroblasts: Their source,

function and role in disease
Robin J. McAnulty ∗
Centre for Respiratory Research, University College London, Rayne Building, 5 University Street,
London, WC1E 6JJ, United Kingdom
Received 2 October 2006; received in revised form 9 November 2006; accepted 10 November 2006
Available online 23 November 2006

Abstract
Fibroblasts are found in most tissues of the body. They exhibit several phenotypes including non-contractile fibroblasts, con-
tractile myofibroblasts, and intermediate phenotypes including the protomyofibroblast. Fibroblasts are metabolically active cells
which play critical roles regulating extracellular matrices, interstitial fluid volume and pressure, and wound healing. Fibroblast
numbers can be maintained or expanded by proliferation of resident populations but in addition, recent evidence indicates they
can also be derived through epithelial-mesenchymal transition or from circulating and tissue-derived mesenchymal stem cells.
Many diseases are associated with dysregulation of the injury repair response and fibroblast function, leading to increased or
decreased deposition of extracellular matrix proteins, altered tissue architecture, impaired function and in some cases signifi-
cant morbidity and mortality. There are currently no specific therapies that target fibroblast-associated pathology but increasing
knowledge of pathological mechanisms has led to development of new agents providing hope for improved treatment of these
diseases.
© 2006 Elsevier Ltd. All rights reserved.

Cell facts

• Transdifferentiates between non-contractile and contractile phenotypes

• Major cell involved in the synthesis of soft tissue extracellular matrix proteins
• Capable of producing 3.5 million molecules of collagen per cell per day
• Major producer of MMPs capable of degrading extracellular matrix
• Important role in regulating tissue hydration/osmotic pressure
• Contraction of wounds via generation of intracellular contractile forces

Keywords: Fibroblast; Myofibroblast; Mesenchymal cells; Epithelial-mesenchymal transition; Fibrocyte; Stem cells; Extracellular matrix; Fibrosis

1. Introduction

Fibroblasts are spindle shaped cells found in the

∗ Tel.: +44 207 679 6971; fax: +44 207 679 6973.
E-mail address: r.mcanulty@ucl.ac.uk.
majority of tissues and organs of the body associated
with extracellular matrix (ECM) molecules. Characteris-
tic features include expression of vimentin in the absence
of desmin and ␣-smooth muscle actin. When activated,

1357-2725/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biocel.2006.11.005
 R.J. McAnulty / The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671
fibroblasts exhibit an abundant endoplasmic reticulum
and prominent Golgi associated with the synthesis and
secretion of ECM molecules including collagens, pro-
teoglycans and fibronectin, as well as, proteases capable
of degrading the ECM. Cytoskeletal proteins in associa-
tion with cell surface integrins and the ECM facilitate cell
motility and the generation of contractile forces impor-
tant in tissue homeostasis and wound healing.
2. Cell origin and plasticity
Fibroblasts are embryologically of mesenchymal ori-
gin with a spectrum of phenotypic entities ranging
from the non-contractile fibroblast to the contractile
myofibroblast with a number of intermediate pheno-
types having been described (reviewed in Eyden, 2005)
including that of the protomyofibroblast (Desmouliere,
Darby, & Gabbiani, 2003). In addition to the fea-
tures of active fibroblasts, prototypical myofibroblasts
are distinguished by the presence of ␣-smooth mus-
cle actin containing stress fibres, linked in a linear
fashion through trans-membrane fibronexus junctions
to protruding filamentous fibronectin fibres, increased
expression of ED-A fibronectin and gap junctions (for
extensive reviews see Desmouliere et al., 2003; Eyden,
2005). Myofibroblasts are further distinguished from
smooth muscle cells by their general lack of smooth
muscle markers including desmin and smooth muscle
myosin. Myofibroblasts may arise from the transdif-
ferentiation of fibroblasts and smooth muscle cells.
However, whether myofibroblast-like cells derived from
fibroblasts and smooth muscle cells form similar or dis-
tinct phenotypic populations is debatable and whether
fibroblasts can differentiate into smooth muscle cells and
vice versa is uncertain, although recent studies suggest
that fibroblasts can differentiate into myofibroblast-like
cells with induction of protein expression patterns pre-
viously thought to be characteristic of smooth muscle
cells (Chambers, Leoni, Kaminski, Laurent, & Heller,
2003). Traditionally it was thought that replacement
or expansion of fibroblast/myofibroblast populations
homeostatically and in wound healing or disease settings
was from resident tissue populations of cells. However,
over the last 10–15 years mounting evidence suggests
that fibroblasts/myofibroblasts, at least following injury
and in fibrotic disease, may be derived from a variety
of sources. These include dedifferentiation of epithe-
lial cells by a process known as epithelial-mesenchymal
transition (EMT), as well as, bone marrow- and tissue-
derived mesenchymal stem cells (Fig. 1). However, the
relative contributions of each of these sources are cur-
rently a topic of intense debate due to the potential
667
implications for therapy in wound healing, cancer and
fibrosis.
2.1. Epithelial-mesenchymal transition
EMT is widely believed to occur during development
and in cancer progression, however its role in the tissue
response to epithelial stress or injury, at least in vivo,
is more controversial (reviewed in Zavadil & Bottinger,
2005). The sequence of molecular events involved in
EMT has recently been extensively reviewed by Zavadil
and Bottinger (2005). Briefly, EMT requires the organ-
ised dedifferentiation of epithelial cells with loss of
polarity, adherans and tight junctions through downreg-
ulation of proteins associated with the maintenance of
these structures including ZO1, cadherins and desmo-
plakin through the upregulation of the Snail/Slug family
of transcriptional repressors and switching from epithe-
lial ␣6␤4 to mesenchymal ␣5␤1 integrin expression.
This leads to the release of non-polarized epithelial
cells with a remodelled mesenchymal stress fibre pat-
tern of actin localisation rather than the epithelial cortical
pattern of cytoskeleton. To allow transitioning cells to
migrate into the interstitium, metalloproteinases (MMP),
such as MMP2 and MMP9 are induced to digest the base-
ment membrane. A number of extracellular stimuli have
been shown to be involved in the induction and pro-
gression of EMT including, TGF-␤, FGF-2, EGF and
IGF-II (reviewed in Kalluri & Neilson, 2003). Whilst
EMT has clearly been demonstrated to occur in vitro, it
has been more difficult to prove in vivo. Until recently, in
vivo evidence for EMT has relied on the demonstration
of loss and gain of epithelial and mesenchymal mark-
ers, respectively, in transitioning cells. Whilst there are
good markers for epithelial dedifferentiation (e.g. ZO-1,
E-cadherin, desmoplakins, cytokeratin 18 and MUC1),
fibroblast markers, such as vimentin, FSP1 and ␣-smooth
muscle actin are less specific, also being expressed in
other cells types or only expressed in a sub-population
of fibroblasts/myofibroblasts. However, recent studies in
the lungs of mice where ␤-galactosidase was specifically
expressed in epithelial cells has provided strong evidence
of transitioning of these cells into fibroblasts during the
development of lung fibrosis and that these cells repre-
sented the majority of the increased number of fibroblasts
in the lung, suggesting that EMT is an important source
of fibroblasts, at least in the lung (Kim et al., 2006).
2.2. Bone marrow-derived stem cells
A number of studies have demonstrated the poten-
tial for bone marrow-derived circulating fibrocytes to
668 R.J. McAnulty / The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671

Fig. 1. The source and function of fibroblasts in normal and pathological states. Origin and plasticity: Fibroblasts exist as several morphological
phenotypes ranging from the extremes of the non-contractile fibroblast to the ␣-smooth muscle actin stress fibre containing contractile myofibroblast
together with an intermediate phenotype which has been termed the protomyofibroblast. Fibroblasts can transdifferentiate into myofibroblasts and
there is some evidence to suggest the process may be reversible to at least some extent. Fibroblast populations can be maintained or expanded
by proliferation of existing populations, or derived from epithelial-mesenchymal transition, circulating bone marrow-derived fibrocytes or from
tissue-derived stem cells. There is also evidence that fibroblasts can undergo mesenchymal-epithelial transition and it has recently been shown that
genetic programmes can be induced in fibroblasts to convert them into pluripotent stem cells. Function: Major functions of fibroblasts/myofibroblasts
include: synthesis and degradation of the multitude of glycoproteins which make up the specialised extracellular matrices of tissues and organs of the
body which contribute to their specific functions; regulation through cell–matrix interactions of interstitial fluid volume, pressure and appropriate
levels of tissue contraction for optimum function; playing a critical role in wound healing through cell–cell and cell–matrix interactions, production
and response to mediators, modulation of extracellular matrix metabolism, wound contraction and scar resolution. Pathology: Dysregulated or
inappropriate fibroblast function is associated with pathologies in which diminished or excess extracellular matrix deposition, or inappropriate tissue
contraction is a feature. Such conditions affect almost all tissues and organs of the body, examples of which are included in the figure.
 R.J. McAnulty / The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671
enter tissues following injury and contribute to wound
healing and pathological scarring (Abe, Donnelly, Peng,
Bucala, & Metz, 2001; Bucala, Spiegel, Chesney, Hogan,
& Cerami, 1994; Quan, Cowper, Wu, Bockenstedt, &
Bucala, 2004). Fibrocytes represent approximately 0.5%
of the peripheral blood leukocyte population that have
an adherant spindle shape morphology in culture. They
express markers of haematopoietic cells (CD34), leuko-
cytes (CD11b, CD13 and CD45) as well as fibroblast
products (collagens I, III, and fibronectin) and are dis-
tinguished from monocytes/macrophages, dendritic cells
and B cells by their lack of specific markers for these cell
types. They appear to be derived from the differentia-
tion of CD14+ peripheral blood mononuclear cells (Yang
et al., 2002) largely under the control of TGF-␤ which
together with endothelin-1 also stimulates proliferation
and differentiation of fibrocytes to myofibroblast-like ␣-
smooth muscle actin positive cells (Li & Huard, 2002;
Schmidt, Sun, Stacey, Mori, & Mattoli, 2003; Yang et
al., 2002). However, this does not appear to be the case
in all situations as Hashimoto, Jin, Liu, Chensue, & Phan
(2004) found that bone marrow-derived lung fibroblasts
were unresponsive to TGF-␤ and failed to differentiate
into myofibroblasts. The contribution of bone marrow-
derived stem cells to increased fibroblast/myofibroblast
number during wound healing and fibrosis is uncertain
with estimates ranging from a few percent up to approx-
imately 80%.
2.3. Tissue-derived mesenchymal stem cells
Studies in several tissues have also suggested that
mesenchymal stem cells reside in tissues (Gharzi,
Reynolds, & Jahoda, 2003; Li & Huard, 2002) and one
recent extensive study suggests they may be localised to
vessel walls (da Silva Mereilles, Chagastelles, & Nardi,
2006). These cells lack haematopoietic and leukocyte
markers but express ␣SMA, a marker associated with
myofibroblasts and smooth muscle cells. Furthermore,
previous studies in the lung have suggested that
following injury myofibroblasts may originate from
perivascular and peribronchial sources (Zhang, Rekhter,
Gordon, & Phan, 1994). Whether these cells derive
from a population of mesenchymal stem cells similar
to those described by Mereilles and co-workers is not
known.
Together these findings demonstrate a high degree
of plasticity and a diversity of origins of fibrob-
last/myofibroblast populations. This diversity may also
begin to explain the heterogeneous phenotypic character-
istics of fibroblast/myofibroblast populations observed
both between tissues and within tissues.
669
3. Functions
One of the major functions of fibroblasts is the pro-
duction and homeostatic maintenance of the ECM of the
tissue or organ in which they reside. They are metabol-
ically highly active cells, being capable of synthesising
and secreting most ECM components, including col-
lagens, proteoglycans, fibronectin, tenascin, laminin
and fibronectin. Fibroblasts continually synthesise ECM
proteins and it has been estimated that each cell
can synthesise approximately 3.5 million procollagen
molecules/cell/day (McAnulty, Campa, Cambrey, &
Laurent, 1991). However, the amount they secrete is
regulated by lysosomal enzymes, such as cathepsins B,
D and L, with between 10% and 90% of all procolla-
gen molecules being degraded intracellularly prior to
secretion, depending on tissue and age. Regulation of
this process appears to provide a mechanism for rapid
adaptation of the amount of collagen secreted following
injury (McAnulty & Laurent, 1995). In addition, fibrob-
lasts produce matrix metalloproteinases (MMP) and
their inhibitors, tissue inhibitors of metalloproteinase
(TIMP), which regulate extracellular degradation of the
ECM. Fibroblast ECM metabolism is regulated by com-
plex mechanisms including cell–cell and cell–matrix
interactions, as well as a multitude of stimulatory and
inhibitory mediators, which may be present in their
local environment (McAnulty & Laurent, 2002). These
include mediators derived from other resident cells in the
local environment, fibroblasts themselves and mediators
derived from the circulation or infiltrating inflammatory
cells.
Fibroblasts also play an important role in regulating
tissue interstitial fluid volume and pressure by interac-
tion of ␤1 integrin receptors which anchor them to ECM
proteins, and particularly the collagen- and laminin-
binding ␣2␤1 integrin via intracellular forces generated
through the cytoskeleton (Wiig, Rubin, & Reed, 2003).
In vitro modelling of these cell–matrix interactions indi-
cate that these processes can be modulated by PDGF
and endothelin which enhance contraction and IL-1
and TNF-␣ which reduce contraction. Consistent with
this, interstitial fluid pressure has been shown to be
increased in vivo by PDGF-BB and ␣-trinositol, and
decreased by TNF-␣, nicotinomide and dexametha-
sone.
Following tissue injury fibroblasts/myofibroblasts
play a central role in wound healing and repair (reviewed
in Desmouliere et al., 2003). The initial processes follow-
ing injury include clot formation and platelet degranu-
lation, releasing mediators to attract inflammatory cells
to the wound site which produce additional mediators
670 R.J. McAnulty / The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671
involved in the recruitment of fibroblastic cells derived
from several potential sources as described above. The
fibroblastic cells present in this early phase are highly
active synthetically replacing the provisional matrix with
a more mature ECM including collagens and fibronectin
under the control of mediators produced by inflamma-
tory cells, injured and regenerating epithelial cells, and
fibroblasts themselves. As granulation tissue deposition
proceeds the fibroblasts develop characteristics of myofi-
broblasts, including the appearance of ␣-smooth muscle
actin containing stress fibres. The appearance of these
myofibroblasts correlates with contraction and closure of
the wound through focal adhesions between myofibrob-
lasts and the extracellular matrix. During the final phases
of remodelling and resolution the production of MMPs
and TIMPs by cells including fibroblasts changes from a
balance favouring ECM deposition to a matrix degrading
environment and myofibroblasts are removed by apopto-
sis. Remaining fibroblasts exhibit a more quiescent, non-
contractile phenotype which may have reverted from a
myofibroblast phenotype or be derived from a source of
cells not involved in differentiation into myofibroblasts.
Dysregulation of the injury repair response may lead to
ineffective or over exuberant and pathological wound
healing.
4. Associated pathologies
Many diseases associated with diminished or excess
deposition of ECM are likely to be related to dysregula-
tion of the injury repair response and fibroblast function.
In this context ‘injury’ is broad ranging including envi-
ronmental, infectious, cancerous, traumatic/mechanical,
autoimmune and drug-induced insults. Thus, diseases
in which fibroblasts, in their various phenotypic guises,
play a central role may affect almost all tissues and
organs of the body (illustrated in Fig. 1). Their impor-
tance is further highlighted by the suggestion that almost
half of all deaths are associated with fibrosing conditions.
Diseases associated with either increased or decreased
ECM deposition, or contraction of tissues result in dis-
torted tissue architecture, impaired function and in many
cases, particularly where the vital organs are involved,
significant morbidity and mortality. Dysregulation of
several phases of the injury repair response, including
chronic or repetitive injury, an inappropriate inflamma-
tory response, an altered balance of ECM metabolism
and deposition, altered phenotypic profiles or persis-
tence of myofibroblasts contribute to aberrant tissue
repair.
At present there are no treatments which specifically
target fibroblast-associated pathologies. Current thera-
peutic strategies primarily revolve around the use of anti-
inflammatory corticosteroids, immunosuppressants and
treatment of tissue or disease specific symptoms. How-
ever, at best these have limited therapeutic effects. Over
the last 30 years a number of approaches to modulate
extracellular matrix synthesis or degradation, including
use of prolyl-4-hydroxylase inhibitors to limit collagen
synthesis and TIMP inhibitors to promote ECM degra-
dation have been developed, although none have yet
progressed the clinic. The rapid expansion of our knowl-
edge over the last 15–20 years of mediators involved in
the regulation of the normal injury repair process and
in the pathogenesis of diseases associated with aberrant
repair has identified novel therapeutic targets and led
to the development of a number of specific inhibitors
for mediators or their receptors. These include small
molecule antagonists and biological inhibitors target-
ing TGF␤, endothelin-1, interferon-␥, EGF, and IL-13
which are currently in or about to enter clinical trials.
For example, inhibitors of TGF-␤ activity including neu-
tralizing antibodies and antisense vaccines are currently
undergoing clinical trials and small molecule receptor
antagonists are in pre-clinical development (reviewed in
Howell & McAnulty, 2006). These are likely to impact
on a number of processes, including inhibition of the
conversion of fibrocytes to myofibroblasts, EMT, and
modulation of ECM metabolism and deposition. In addi-
tion, the recent development of siRNA technologies may
allow for more rapid drug development with the potential
to dramatically reduce the time from target identifica-
tion to clinical trials. For example, siRNAs developed
for use in other disease settings by Sirna Therapeutics
(Sirna-027, which targets vascular endothelial growth
factor receptor 1, VEGFR-1) and Alnylam (ALN-
RSV01, which targets respiratory syncytial virus) took
less than 2 years from development to Phase I clinical
trials.
There is therefore renewed optimism that increased
knowledge of the pathogenesis of disease, which has led
to an influx of compounds in development or in clini-
cal trials across the spectrum of diseases associated with
aberrant fibroblast function, together with the potential
for more rapid development of drugs against newly iden-
tified targets, will lead to improved treatments in the not
too distant future.
Acknowledgements
RJMs research is supported by grants from the
Wellcome Trust, British Lung Foundation and Asthma
UK.
 R.J. McAnulty / The International Journal of Biochemistry & Cell Biology 39 (2007) 666–671
References
Abe, R., Donnelly, S. C., Peng, T., Bucala, R., & Metz, C. N. (2001).
Peripheral blood fibrocytes: Differentiation pathway and migration
to wound sites. Journal of Immunology, 166, 7556–7562.
Bucala, R., Spiegel, L. A., Chesney, J., Hogan, M., & Cerami,
A. (1994). Circulating fibrocytes define a new leukocyte sub-
population that mediates tissue repair. Molecular Medicine, 1,
71–81.
Chambers, R. C., Leoni, P., Kaminski, N., Laurent, G. J., & Heller, R.
A. (2003). Global expression profiling of fibroblast responses to
transforming growth factor-␤1 reveals the induction of inhibitor of
differentiation-1 and provides evidence of smooth muscle cell phe-
notypic switching. American Journal of Pathology, 162, 533–546.
da Silva Mereilles, L., Chagastelles, P. C., & Nardi, N. B. (2006).
Mesenchymal stem cells reside in virtually all post-natal organs
and tissues. Journal of Cell Science, 119, 2204–2213.
Desmouliere, A., Darby, I. A., & Gabbiani, G. (2003). Normal and
pathologic soft tissue remodelling: Role of the myofibroblast, with
special emphasis on liver and kidney fibrosis. Laboratory Investi-
gation, 83, 1689–1707.
Eyden, B. (2005). The myofibroblast: A study of normal, reactive and
neoplastic tissues, with an emphasis on ultrastructure. Part 1 –
Normal and reactive cells. Journal of Submicroscopic Cytology
and Pathology, 37, 109–204.
Gharzi, A., Reynolds, A. J., & Jahoda, C. A. B. (2003). Plasticity of hair
follicle dermal cells in wound healing and induction. Experimental
Dermatology, 12, 126–136.
Hashimoto, N., Jin, H., Liu, T., Chensue, S. W., & Phan, S. H. (2004).
Bone marrow-derived progenitor cells in pulmonary fibrosis. Jour-
nal of Clinical Investigation, 113, 243–252.
Howell, J. E., & McAnulty, R. J. (2006). TGF-␤: Its role in asthma and
therapeutic potential. Current Drug Targets, 7, 547–565.
Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal tran-
sition and its implications for fibrosis. Journal of Clinical
Investigation, 112, 1776–1784.
Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M.
G., Brumwell, A. N., Sheppard, D., & Chapman, H. A. (2006).
Alveolar epithelial cell mesenchymal transition develops in vivo
during pulmonary fibrosis and is regulated by the extracellular
matrix. Proceeding of the National Academy of Sciences USA, 103,
13180–13185.
671
Li, Y., & Huard, J. (2002). Differentiation of muscle-derived cells into
myofibroblasts in injured skeletal muscle. American Journal of
Pathology, 161, 895–907.
McAnulty, R. J., & Laurent, G. J. (1995). Pathogenesis of lung fibrosis
and potential new therapeutic strategies. Experimental Nephrology,
3, 96–107.
McAnulty, R. J., & Laurent, G. J. (2002). Fibroblasts. In P. Barnes, J.
Drazen, S. Rennard, & N. Thomson (Eds.), Asthma and COPD:
Basic mechanisms and clinical management (pp. 139–144). Lon-
don: Academic Press.
McAnulty, R. J., Campa, J. S., Cambrey, A. D., & Laurent, G. J. (1991).
The effect of transforming growth factor ␤ on rates of procollagen
synthesis and degradation in vitro. Biochimica et Biophysica Acta,
1091, 231–235.
Metz, C. N. (2003). Fibrocytes: A unique cell population impli-
cated in wound healing. Cellular and Molecular Life Sciences,
60, 1342–1350.
Quan, T. E., Cowper, S., Wu, S.-P., Bockenstedt, L. K., & Bucala,
R. (2004). Circulating fibrocytes: Collagen-secreting cells of the
peripheral blood. International Journal of Biochemistry and Cell
Biology, 36, 598–606.
Schmidt, M., Sun, G., Stacey, M. A., Mori, L., & Mattoli, S. (2003).
Identification of circulating fibrocytes as precursors of bronchial
myofibroblasts in asthma. Journal of Immunology, 170, 380–
389.
Wiig, H., Rubin, K., & Reed, R. K. (2003). New and active role of
interstitium in control of interstitial fluid pressure: Potential ther-
apeutic consequences. Acta Anaesthesiologica Scandinavica, 47,
111–121.
Yang, L., Scott, P. G., Giuffre, J., Shankowsky, H. A., Ghahary, A.,
& Tredget, E. E. (2002). Peripheral blood fibrocytes from burn
patients: Identification and quantification of fibrocytes in adherent
cells cultured from peripheral blood mononuclear cells. Laboratory
Investigation, 82, 1183–1192.
Zavadil, J., & Bottinger, E. P. (2005). TGF-␤ and epithelial-to-
mesenchymal transitions. Oncogene, 24, 5764–5774.
Zhang, K., Rekhter, M. D., Gordon, D., & Phan, S. H. (1994).
Co-expression of ␣-smooth muscle actin and type I collagen
in fibroblast-like cells of rat lungs with bleomycin-induced pul-
monary fibrosis: A combined immunohistochemical and in situ
hybridization study. American Journal of Pathology, 145, 114–
125.