Myofibroblasts. I. Paracrine cells important in health and disease

Abstract

Myofibroblasts are a unique group of smooth-muscle-like fibroblasts that have a similar appearance and function regardless of their tissue of residence. Through the secretion of inflammatory and anti-inflammatory cytokines, chemokines, growth factors, both lipid and gaseous inflammatory mediators, 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. Platelet-derived growth factor (PDGF) and stem cell factor are two secreted proteins responsible for differentiating myofibroblasts from embryological stem cells. These and other growth factors cause proliferation of myofibroblasts, and myofibroblast secretion of extracellular matrix (ECM) molecules and various cytokines and growth factors causes mobility, proliferation, and differentiation of epithelial or parenchymal cells. Repeated cycles of injury and repair lead to organ or tissue fibrosis through secretion of ECM by the myofibroblasts. Transforming growth factor-beta and the PDGF family of growth factors are the key factors in the fibrotic response. Because of their ubiquitous presence in all tissues, myofibroblasts play important roles in various organ diseases and perhaps in multisystem diseases as well.

Full text

invited review
Myofibroblasts. I. Paracrine cells important
in health and disease
D. W. POWELL, R. C. MIFFLIN, J. D. VALENTICH,
S. E. CROWE, J. I. SAADA, AND A. B. WEST
University of Texas Medical Branch at Galveston, Departments of Internal
Medicine, Physiology, and Biophysics and Pathology, Galveston, Texas 77555
Powell, D. W., R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I.
Saada, and A. B. West. Myofibroblasts. I. Paracrine cells important in
health and disease. Am. J. Physiol. 277 (Cell Physiol. 46): C1–C19,
1999.—Myofibroblasts are a unique group of smooth-muscle-like fibro-
blasts that have a similar appearance and function regardless of their
tissue of residence. Through the secretion of inflammatory and anti-
inflammatory cytokines, chemokines, growth factors, both lipid and
gaseous inflammatory mediators, as well as extracellular matrix proteins
andproteases,they playan importantrole inorganogenesis and oncogen-
esis, inflammation, repair, and fibrosis in most organs and tissues.
Platelet-derived growth factor (PDGF) and stem cell factor are two
secreted proteins responsible for differentiating myofibroblasts from
embryological stem cells. These and other growth factors cause prolifera-
tion of myofibroblasts, and myofibroblast secretion of extracellular ma-
trix (ECM) molecules and various cytokines and growth factors causes
mobility, proliferation, and differentiation of epithelial or parenchymal
cells. Repeated cycles of injury and repair lead to organ or tissue fibrosis
through secretion of ECM by the myofibroblasts. Transforming growth
factor-␤and the PDGF family of growth factors are the key factors in the
fibrotic response. Because of their ubiquitous presence in all tissues,
myofibroblasts play important roles in various organ diseases and
perhaps in multisystem diseases as well.
platelet-derived growth factor; stem cell factor; transforming growth
factor-␤; wound repair; fibrosis; inflammation; immunophysiology
A GROWING BODY OF LITERATURE over the last decade has
made it evident that there is phenotypic heterogeneity
among fibroblasts and that some express features of
smoothmuscledifferentiation(73,136, 214,216).These
smooth-muscle-like cells, or myofibroblasts as they
were termed by Gabbiani (82, 83) who pioneered this
field, take part in the growth, development, and repair
of normal tissue as well as the diseases affecting many
different organs. These cells belong to a unique class,
and, even allowing for specific functions for those cells
in a given organ or tissue, there is an amazing similar-
ity in their morphology, function, and biochemical
repertoire regardless of their location. Nonetheless, in
a given tissue, they may express some specific appear-
ances and functions, i.e., phenotypic and functional
heterogeneity. Because of this propensity and their
location next to epithelial or parenchymal cells, we
have suggested they might be termed ‘‘juxtaparenchy-
mal cells’’ (247).
In this review, we give an overview of myofibroblasts,
illustrating similarities and differences in their bio-
chemical/physiological/immunologic properties, and we
indicate the role that these cells play in specific disease
states. The major soluble factors secreted by these cells
are discussed, and important receptors on myofibro-
blasts are listed. We have slanted the discussion to-
ward the intestinal myofibroblasts (247): the intersti-
tial cells of Cajal (ICC) and the subepithelial intestinal
myofibroblast. This review is not meant to be entirely
comprehensive of the field of myofibroblasts. It focuses
on recently discovered information about the interac-
tions of myofibroblasts with epithelial and parenchy-
mal cells and the molecules that mediate these interac-
tions. Furthermore, we have purposely referenced
review articles when possible to amplify the reference
base.
ROLES IN HEALTH AND DISEASE
Table 1 lists various tissue myofibroblasts and what
is thought to be their normal function. Some of these
functions are well proven, and others can be inferred
from the known properties of myofibroblasts in other
0363-6143/99 $5.00 Copyright r1999 the American Physiological Society C1

tissues. In general, there are several common normal
activities of myofibroblasts. First, through mesenchy-
mal-epithelialinteractions,myofibroblasts arekey com-
ponents of organogenesis or morphogenesis, i.e., the
growth and differentiation of the tissue or organ (227).
They do so through the secretion of soluble mediators of
inflammation and growth factors (Table 2) and expres-
sion of their receptors (Table 3) and through secretion
and formation of interstitial matrix and/or basement
membrane molecules (Table 4) (20, 73, 82, 247). Myofi-
broblasts also play a fundamental role in many disease
states, either through activation and proliferation or
through deletion (Table 5) (51, 214, 216). They play a
central role in wound healing, presumably as an exten-
sion or accentuation of their role in normal growth and
differentiation (82, 83, 99, 120, 136). They appear to be
involved in the formation and repair of the extracellu-
lar matrix (ECM) and proliferation and differentiation
of epithelial (or parenchymal), vascular and neurogenic
elements (50, 215, 250, 262).
Healing is facilitated by the fact that the myofibro-
blasts are contractile, which aids in reducing the
amount of denuded surface area of wounded tissue
(163, 192, 242). An extension of this contractile capabil-
ity allows these cells to participate in the ejection of
fluid from the gastric glands (237) and in the motility of
intestinal villi (120). Their relationship to myoepithe-
lial cells, which have this function in the breast lobule
(204) and the seminiferous tubules of the testis (106), is
unclear. The contractile property of pericytes and spe-
Table 1. Myofibroblasts: possible functions
Tissue or Organ Function
Skin
Granulation tissue Epithelial growth and differentiation; wound repair (41, 51, 81, 99)
Pericyte* Angiogenesis; regulation of local blood flow (216)
Mouth
Periodontal ligament Attachment of teeth (136, 214, 216)
Gingival myofibroblasts Structure of gum (136, 214, 216)
Palatal mucosa Structure of palate (27)
Eye
Orbital fibroblast Glycosaminoglycan secretion for cushioning eye in orbit (9, 221, 254)
Retinal myofibroblast Angiogenesis and wound healing; connective tissue matrix formation (253)
Anterior capsule of lens Lens formation (172, 217)
Corneal myofibroblast Wound healing (184)
Heart and pericardium Structure of cardiac valve; repair after myocardial infarction (258)
Kidney
Mesangial cell Glomerular growth and differentiation; regulation of glomerular blood flow (185, 239)
Interstitial cell Tubule growth and differentiation (136, 177, 239)
Liver
Perisinusoidal stellate cell (Ito cell) Endothelial and sinusoid structure and function; regulation of blood flow; vitamin Astorage
(72, 88, 150)
Pancreas
Periacinar stellate cell Growth and development of the acinus (4, 8)
Lung
Interstitial contractile cell Alveolus formation (26, 105)
Stomach and intestine
Interstitial cell of Cajal Regulation of motility, ‘‘pacemaker’’ activity (212, 243)
Subepithelial myofibroblast Epithelial growth and differentiation; contraction of gastric glands and intestinal villi;
regulation of intestinal absorption and secretion (120, 152, 153, 180, 247)
Brain
Astrocyte Substrate pathways for neural growth; formation of blood-brain barrier; secrete mitogens
and growth factor for neurons (166)
Breast
Stromal myofibroblast Epithelial growth and differentiation; possibly contraction and expulsion of milk (204)
Bone marrow
Stromal cell Nurture stem cells and promote hematopoiesis (182, 218)
Joint
Synoviocyte Lines joint space (11)
Uterus
Endometrial myofibroblasts Regeneration of endometrium after menses (40, 76)
Placental myofibroblasts Structure of placental stem villus (134)
Ovary
Theca cells Meiosis and ovulation (49, 136)
Prostate
Stromal cells Growth and differentiation of prostate gland (98, 125, 181)
Testicular
Peritubular myoid cells Growth and differentiation of seminiferous tubules; ? contraction and expulsion of sperm
(104, 106)
Leydig cells Androgen secretion (136)
Capsule cells Contraction of capsule (85)
*Pericytes exist in all organs and presumably have the same functions at each site. Some of the myofibroblasts listed in this table (e.g.,
hepatic stellate cell and renal mesangial cell) are also ‘‘pericytes.’’ Numbers in parentheses are reference numbers.
C2 INVITED REVIEW

cialized pericytes such as the hepatic stellate (Ito) cell,
the mesangial cell of the kidney, and the glomus cell of
peripheral vessels gives these myofibroblasts the abil-
ity to locally autoregulate blood flow (122, 124, 160,
177, 216, 247). The ability to accumulate and extrude
calcium causes cyclic increases and decreases in cal-
cium concentration in these cells, permitting actin-
myosin contraction (77). This process is probably the
same as or similar to the one responsible for the ability
of the ICC to perform a pacemaker function in the
intestine (212). Because myofibroblasts are intercon-
nected through gap junctions (120, 212, 246), the
electrical signals created by cyclic ion movements can
betransmittedthrough thesyncytium andthusthrough
the length of the resident organ.
Myofibroblasts play a major role in the inflammatory
response. These cells are avid producers of both chemo-
kines and cytokines (105, 178, 179, 227, 235, 267) and
are capable of augmenting or downregulating the in-
flammatory response by the secretion of these soluble
mediators of inflammation (Table 2). They also synthe-
size prostaglandins, expressing both the constitutive
cyclooxygenase-1 (COX-1 or PHS-1) gene product and
the inducible COX-2 (PHS-2) protein (19, 69, 102, 105,
167, 240, 241, 259). In some tissues they make both
nitric oxide and carbon monoxide, gases known or
proposed to be important neurotransmitters and regu-
lators of motility and inflammation (1, 14, 39, 69, 162,
167, 202, 240, 241). When activated, myofibroblasts
also express adhesion molecules such as intracellular
adhesion molecule-1, vascular cell adhesion molecule,
and neural cell adhesion molecule (100, 133, 151, 178,
192). Thus lymphocytes, mast cells, and neutrophils
may dock on the myofibroblasts and participate in
organized immunological and inflammatory reactions
(31, 48, 67, 105, 201, 236). Myofibroblasts also express
␣and ␤integrins that are part of the adhesion mecha-
nismofmyofibroblasts tomatrix proteins(192).Through
these or other properties, myofibroblasts participate in
theformation of tissuegranulomas (208, 247). Granulo-
mas themselves are impressive factories of cytokines
and other inflammatory mediators (87, 114).
Last, production of matrix molecules such as colla-
gen, glycosaminoglycans, tenascin, and fibronectin in
the interstitial space or basement membrane (Table 4)
is part of the structure, growth, differentiation, and
wound healing function of myofibroblasts (20, 227).
These processes, when unchecked, deranged, or re-
peated, can result in tissue fibrosis (4, 25, 71, 72, 88,
138, 150). Therefore, fibrotic disease is a major patho-
logicalend point of activatedandproliferating myofibro-
blasts in most, if not all, tissues.
Diseasestatesnot mentioned in Table3 are inflamma-
tory pseudotumors of the lung, liver, or stomach (64)
Table 2. Cytokines, growth factors, and inflammatory mediators secreted by myofibroblasts
Cytokines Growth Factors Chemokines Inflammatory Mediators
IL-1 (178, 185, 240, 246)
IL-6 (178, 179, 185)
TNF-␣(185)
IL-10 (178)
TGF-␤(17, 25)
CSF-1 (185)
GM-CSF (178, 185)
PDGF-AA (26, 185)
PDGF-BB (141, 142)
bFGF (17)
IGF-I (144, 162, 185)
IGF-II (144, 226)
NGF (185)
KGF (37, 207)
HGF (28, 84)
SCF (132)
IL-8 (36, 178, 185)
MCP-1 (36, 185, 236)
GRO-1␣(36)
MIP-1␣(36)
MIP-2 (235)
RANTES (36)
ENA-78 (5, 36)
PhospholipaseA2activating protein (185)
PGE2(19)
Prostacyclin (262)
HETEs (185)
PAF (247)
NO (39, 69, 151, 167, 185, 202)
CO (1, 14, 162)
H2O2,O
⫺(19, 185)
IL, interleukin; TNF-␣, tumor necrosis factor-␣; TGF-␤, transforming growth factor-␤; MCP-1, monocyte chemoattractant protein-1; CSF-1,
colony-stimulating factor I; GM-CSF, granulocyte/macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; bFGF, basic
fibroblast growth factor; IGF, insulin-like growth factor; NGF, nerve growth factor; KGF, keratinocyte growth factor; HGF, hepatocyte growth
factor; SCF, stem cell factor; VEGF, vascular endothelial growth factor; MIP, macrophage protein; RANTES, regulated, upon activation,
normal T cell expressed and secreted; ENA-78, epithelial neutrophil-activating peptide 78; GRO-1␣, melanoma growth-stimulatory activity;
HETEs, hydroxyeicosatetraenoic acids; PAF, platelet activating factor.
Table 3. Receptors expressed by myofibroblasts
Cytokines Growth Factors Inflammatory
Mediators Neurotransmitters
and Paracrine Mediators Adhesion
Proteins
IL-1 (139, 178)
IL-1Ra (102)
TNF-␣(100, 101)
IL-6 R (179)
IL-8 R (31)
IL-4 R (128, 156)
IL-11 R (143)
TGF-␣/EGFR (138, 214)
TGF-␤RI and RII (25, 58, 159, 203)
PDGF-␣(26, 111, 263)
PDGF-␤(111, 141, 234)
c-kit (18, 109, 174)
aFGF and bFGF R (111)
IGF-IR (144)
Thrombin receptor (15, 151)
FGFR-II
Prostaglandins (19)
HETEs (210) Acetylcholine (102)
Histamine (19)
Serotonin (19)
Bradykinin (19)
Endothelin (80, 142, 246)
Atrial natriuretic factor (246)
Aldosterone or ANG II (34, 258)
ICAM-1 (100, 178)
VCAM-1 (178)
NCAM (133)
MCP-1 (151, 235)
␣1␤1integrin (192)
CD18 (31)
EGFR, epidermal growth factor receptor; ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; NCAM-1,
neural cell adhesion molecule-1; RI and RII, types I and II receptors.
C3INVITED REVIEW

and neoplastic transformation of the myofibroblasts
themselves. Recent evidence indicates that stromal
tumors of the gastrointestinal tract are derived from
c-kit mutationsin gastrointestinal myofibroblasts (103).
Another benign neoplasm of myofibroblasts is the des-
moid tumor, which can occur in any tissue but develops
most commonly in the mesentery of the gut (92).
Although desmoids can and do occur sporadically, they
are particularly common (increased 850 times) in the
familial adenomatous polyposis (FAP) syndrome. FAP
is a hereditary malignancy presenting as colonic polyps
and colorectal carcinoma (233) that is due to mutations
in the adenomatous polyposis coli gene (92). Malignant
myofibroblasts are also observed in clearly aggressive
tumorssuch as angiosarcomas, fibrosarcomas, histiocy-
tomas, and mesotheliomas (46, 216). Myofibroblasts
are also responsible for the desmoplastic reaction seen
in many cancers, i.e., the proliferation of fibrotic tissue
withinor adjacent to the tumor itself. Thisis most often
observed in breast carcinoma, carcinoid tumors,
Hodgkin’s disease, and malignant melanomas (70, 153,
204, 218, 264). The role of myofibroblasts in both
hereditary and nonhereditary colon cancer is discussed
in more detail later in part II of this review [which will
appear in the August issue (191)] (see also Ref. 131).
DEFINITION OF A MYOFIBROBLAST
Myofibroblasts may be defined morphologically and
immunologically through identification of expressed
cytoskeletalproteins (214, 216). The simplestdefinition
of a myofibroblast is that they are smooth-muscle-like
fibroblasts. Some investigators choose to call them
smooth-muscle-like cells or activated smooth muscle
cells (159, 163, 237). Others refer to them as lipocytes
because of their propensity to store retinoids (vitamin
A) or as stellate cells, because of a shape change of
transiently differentiated myofibroblasts (see below).
Myofibroblasts may well represent an intermediate
state between fibroblasts and smooth muscle cells. This
is best demonstrated in the prostate (98, 125, 181), in
the pericytes surrounding the fetal vessels of the
placentalstem villus (134), andin the stromal myofibro-
blasts of the breast (204).
In both cell culture in vitro and native tissues in situ,
myofibroblasts possess several distinguishing morpho-
logical characteristics, some of which are present in
fibroblasts or smooth muscle cells (Fig. 1). They display
prominent cytoplasmic actin microfilaments (stress
fibers), and they are connected to each other by ad-
herens and gap junctions (51, 239). These cells are also
in contact with the ECM by focal contacts once known
as the fibronexus, a transmembrane complex made up
ofintracellular contractile microfilaments andthe ECM
protein fibronectin (65). Both fibronexus formation and
stress fiber assembly are regulated by Rho, a newly
described member of the RAS superfamily of small
guanosine triphosphatases (GTPases) (94), specifically
in mammalian cells by Rho A. These small, monomeric
GTP-binding proteins also regulate myofibroblast mor-
phology (191, 265). Often, an incomplete basal lamina
surrounds the myofibroblasts. Gap junctions couple
some myofibroblasts to the tissue smooth muscle, and
the cells are commonly in close apposition to varicosi-
ties of nerve fibers (134, 212, 243).
In some tissues, e.g., the liver (Ito cells) (88), intes-
tine[both the ICC (243) and the subepithelial myofibro-
blasts] (78, 246), the orbital myofibroblast (195, 254),
the synoviocyte of the joint space (11), and brain
(astrocyte) (15, 166, 193), the myofibroblasts exist in
two distinct morphological states (Fig. 2): 1) the ‘‘acti-
vated’’ myofibroblast, as described above, and 2) the
stellate-transformed myofibroblast, which is consid-
ered to be a transiently differentiated myofibroblast.
This generalization, correlating appearance and func-
tion, has not been verified in every tissue where such
morphological heterogeneity has been seen. Agents
(e.g., prostaglandins, cholera toxin, vasoactive intesti-
nal polypeptide) that increase the cAMP content of
activated myofibroblasts and cell-soluble cAMP ana-
logs themselves induce stellate transformation in vitro
within 24 h (78) and stop myofibroblast proliferation (5,
119).
Immunohistochemical characterization of myofibro-
blasts is based on antibody reactions to two of the three
filament systems of eukaryotic cells (75, 116). These
three systems are composed of 1) actin, a component of
the microfilaments; 2) vimentin, desmin, lamin, or glial
fibrillary acidic protein (GFAP), members of the inter-
mediate filament system; and 3) the tubulins of the
microtubules. Myofibroblasts have not been character-
ized with regard to tubulins. The ␤and ␥actins are
expressed by all cells, including myofibroblasts, which
may also express ␣-smooth muscle (␣-SM) actin (214,
216). Myofibroblasts stain negatively for ␣-cardiac and
␣-skeletal actin (216). Myofibroblasts are not well
characterized with regard to the newly defined myosin
isoforms (75, 161, 217). In some tissues, such as the
intestine and reticular cells of lymph nodes and spleen,
Table 4. Matrix molecules important in growth
differentiation and wound repair
Collagens (20, 96, 138, 154, 168, 220, 227, 268)
Types I–VI, XVIII*
Glycoproteins (20, 96, 138, 154, 220, 227, 251)
Laminins
Entactin/nidogen
Fibronectin
Tenascin
Sparc/BM40
Thrombospondin
Proteoglycans (20, 96, 138, 154, 220, 227)
Glycosaminoglycans (GAGS)
Hyaluronic acid (HA-type)
Heparan sulfate (HS-type)
Chondroitin sulfate (CS-type)
Perlecan†
Matrix modifying proteins (16, 146)
Matrix metalloproteinases (MAPs)
Tissue inhibitor of metalloproteinases (TIMPs)
*Collagen types I, III, IV, and VI are secreted by myofibroblasts;
typeIV is the basement membrane collagen. †Perlecan is a proteogly-
can secreted by epithelial cells.
C4 INVITED REVIEW

myofibroblasts stain positive for smooth muscle heavy
chain myosin or tropomyosin (old terminology) (216,
243).
Vimentin, desmin, and ␣-SM actin are the three
filaments most often used to classify myofibroblasts
(161). Expression of these proteins may vary with the
tissue studied within species and is subject to environ-
mental factors, e.g., whether the cells are studied in
situ or in culture and, even within a given tissue,
whether the cells are activated by hormonal or cytokine
treatment or by disease (191). Based on immunohisto-
chemical staining of these filaments in a given tissue, a
classification system has been proposed (134, 216).
Myofibroblasts that express only vimentin are termed
V-type myofibroblasts, those that express vimentin and
desmin are called VD-type, those that express vimen-
tin, ␣-SM actin, and desmin are called VAD-type, those
that express vimentin and ␣-SM actin are called VA-
type, and those that express vimentin and myosin are
called VM-type.
Table 5. Tissue myofibroblasts: diseases
Tissue or
Organ Activation/
Proliferation Deletion or
Damage
Skin
Granulation tissue Scleroderma; keloid; Dupuytren’s contracture
(73, 213, 224); ? psoriasis (63)
Pericyte Atherosclerosis and restenosis (149, 159); hyper-
tension (208) Microaneurysms, edema, and hemorrhage (26,
239)
Mouth
Periodontal ligament Periodontal disease (136, 214)
Gingival myofibroblasts Gingival hypertrophy secondary to drugs (cyclo-
sporin and Dilantin) (135, 136, 212, 214, 216)
Eye
Orbital fibroblast Exophthalmos (proptosis) of Grave’s disease (9,
221, 254)
Retinal myofibroblast Proliferative vitreoretinopathy (253) Diabetic microaneurysm (26, 142, 239)
Anterior capsule of lens Anterior capsular cataract (172, 217)
Corneal myofibroblast Corneal scarring (184)
Heart and pericardium Myocardial fibrosis, atherosclerosis, and coro-
nary artery restenosis (35, 149, 159, 258)
Kidney
Mesangial cell Proliferative and sclerosing glomerulonephritis
(108, 184, 239) Absence of glomerular structure (141, 234)
Interstitial cell Renal tubulointerstitial fibrosis (171, 177, 198,
239)
Liver
Perisinusoidal stellate (Ito cell) Fibrosis and cirrhosis (72, 88, 150)
Ischemia-reperfusion injury of hepatic trans-
plantation (206)
Necrotizing hepatitis (62)
Pancreas
Periacinal stellate cell Pancreatic fibrosis (4, 8)
Lung
Interstitial contractile cell Pulmonary interstitial fibrosis, idiopathic and
drug-induced; sarcoidosis (105, 209, 214) Emphysema (25)
Diffuse alveolar damage disease (176)
Pulmonary hypertension (123)
Stomach and intestine
Interstitial cell of Cajal ? Abnormal intestinal motility; hypertrophic
pyloric stenosis; Hirschsprung’s disease;
megacolon of piebaldism; idiopathic pseudo-
obstruction (33, 52, 115, 183, 212, 243, 248,
249)
Subepithelial myofibroblast Collagenous colitis; villous atrophy and crypt
hyperplasia; polyp formation; ? fibrosis of
Crohn’s disease (2, 86, 114, 131, 153)
Healing gastric ulcer (170)
Brain
Astrocyte Produce glial scar tissue (166) Human immunodeficiency virus-associated cog-
nitive motor disease; spongiform encepha-
lopathy (166)
Breast
Stromal myofibroblast Fibrocystic disease; desmoplastic reaction to
breast cancer (73, 214)
Bone marrow
Stromal cell Fibrosis in myelodysplasia and neoplastic dis-
eases (182, 218) Aplastic anemia (182, 218)
Joint
Synoviocyte Rheumatoid pannus formation (11)
C5INVITED REVIEW

In the intestine, the ICC express immunoreactive
vimentin, ␥-SM actin, and smooth muscle tropomyosin,
suggesting that they are members of the V or VM (243)
class of myofibroblasts. However, we have not been able
to find references indicating that ICC have been ex-
plored with antibodies to ␣-SM actin. The intestinal
subepithelial myofibroblasts (ISEMFs) stain positive
for vimentin and ␣-SM actin and negative (or weakly)
Fig. 1. A: transmission electron micro-
graph of a cultured lumen intestinal
subepithelialmyofibroblast (18Co). The
cell membrane displays numerous ca-
veolae. Stress fibers (bundles of actin
microfilaments) are prominent. The cy-
toplasm is rich in rough endoplasmic
reticulum, Golgi apparatus, and mito-
chondria. B: nucleus of an activated
myofibroblast shows multiple indenta-
tions. Adherens (C) and gap junctions
(D) are present between myofibro-
blasts. [From Valentich et al. (246).]
Fig. 2. Phase-contrast micrographs (A
and B) and scanning electron micro-
graphs (Cand D) of stellate 18Co cells.
The stellate myofibroblast displays a
highly refractile cell body on phase-
contrast microscopy and possesses a
highly arborized array of cell processes
with several orders of bifurcation. The
cell processes are devoid of microvilli,
whereas the cell body shows a dense
array of long microvilli, giving it a
shaggy appearance. [From Valentich et
al. (246).]
C6 INVITED REVIEW

for desmin (VA-type). They also express smooth muscle
myosin (thus may be called VAM-type myofibroblasts),
although expression of myosin is less than that seen in
corresponding smooth muscle cells in the same tissue
(120, 153, 246). It is possible that both intestinal
myofibroblasts, the ICC and ISEMF, could be the
VA(M)-type.
Specific monoclonal antibodies have been developed
to identify myofibroblasts in certain tissues. For ex-
ample,themonoclonal antibody Gb42 recognizesplacen-
tal myofibroblasts (134). The 8E1 monoclonal antibody
reacts with many of the stellate-shaped myofibroblasts,
such as GFAP-positive astrocytes, and both intestinal
myofibroblasts, the ICC and ISEMF (79). Anti-GFAP
serum stains astrocytes, pancreatic periacinar stellate
cells, and hepatic stellate (Ito) cells (30). The PR2D3
antibody stains subepithelial myofibroblasts in the
stomach and intestine, lung myofibroblasts, periductu-
lar myofibroblasts of the kidney, testes, and breast, Ito
cells of the liver, umbilical cord stellate myofibroblasts,
and both vascular and tissue smooth muscle of most
organs (199). Antibodies against the protooncogene
c-kit, the receptor for stem cell factor (SCF or steel
factor),react with ICC (109, 132,244) and possibly with
pulmonary alveolar myofibroblasts (61). No systematic
studies have been reported concerning the reactivity of
all the other myofibroblasts to c-kit antibodies.
In many of the studies quoted above, only a subset of
the (myo)fibroblasts stain with ␣-SM actin antibodies
in vivo or in vitro (culture). In vivo, not all fibroblastic-
appearing cells are myofibroblasts. In culture, treat-
ment with transforming growth factor-␤(TGF-␤) may
induce uniform ␣-SM actin staining of all the cells,
providing the cells are of a single clone (226). Further-
more, activation to an ␣-SM actin-expressing pheno-
type may require both TGF-␤and a specific cell-matrix
interaction (118, 222) (see ACTIVATION,PROLIFERATION,
AND MIGRATION OF MYOFIBROBLASTS).
ORIGIN OF MYOFIBROBLASTS AND ROLE IN GROWTH
AND DEVELOPMENT
It is unclear whether myofibroblasts originate from
progenitor stem cells (possibly neuroepithelial stem
cells) (24, 157) from the neural crest (117) or simply
transdifferentiate from resident tissue fibroblasts (81)
or from tissue (e.g., vascular, intestinal, or uterine)
smooth muscle cells (204). The close anatomic relation-
ship of pericytes to vascular smooth muscle and of
intestinal myofibroblasts to intestinal smooth muscle
suggests a bidirectional route of transdifferentiation.
These various possibilities are depicted in Fig. 3. It has
recently been suggested that renal tubular cells (a cell
of endoderm origin) might differentiate into myofibro-
blasts (mesenchymal cells) under noxious stimuli (171,
177, 198). However, it is equally likely that the peritu-
bular interstitial myofibroblasts are proliferating un-
der these circumstances and simply replacing apoptotic
tubular cells in these disease states.
Two soluble factors have been shown to promote
differentiation from embryonic stem cells: PDGF and
SCF. PDGF has two chains, A and B, and exists as a
homodimer (PDGF-AA or PDGF-BB) or as a het-
erodimer (PDGF-AB). Each form acts on separate
receptors: ␣receptors that are nondiscriminatory and
can bind AA, BB, andAB dimers or ␤receptors that are
specific for the B chain (126). After ligand binding,
there are two separate intercellular signaling path-
ways for the PDGF receptor: a mitogen-activated pro-
tein kinase (MAPK) path and one involving phosphati-
dylinositol 3-kinase (PI3K). Depending on the cell
types, one pathway may be required for cell activation
and/or proliferation and the other pathway for cell
motility (migration) (3, 72, 150). For example, smooth
muscle cells proliferate in response to the MAPK
cascade and migrate in response to the PI3K path,
whereas hepatic stellate cells and endothelial cells
respond with both proliferation and migration via the
PI3K (72).
Disruption of the PDGF-AA gene in mice is lethal in
50% of affected animals (26). The surviving animals are
almost completely devoid of lung alveolar myofibro-
blasts (also called pulmonary contractile interstitial
cells) and develop emphysema due to failure of lung
septation. In contrast, animals born with disruption of
the PDGF-BB gene have a virtual absence of renal
mesangial cells and failure of the formation of the
complex structure of the glomerulus (141, 234). The
PDGF-BB-deficient animals also lack pericytes and
thus develop microaneurysms, reminiscent of those
seen in the diabetic retina, and leaky vessels that cause
tissue edema and hemorrhage (142). Intestinal subepi-
thelial myofibroblasts (119) and hepatic stellate cells
(147) proliferate in response to low concentrations of
PDGF-BB, suggesting that this growth factor is impor-
tant in the growth and development of these cells.
The protooncogene c-kit is the transmembrane glyco-
protein tyrosine kinase (III) receptor (160 kDa molecu-
lar mass) for SCF, a growth factor secreted by epithelial
cells, white blood cells, and (myo)fibroblasts. SCF is
also a member of the PDGF family, and the tyrosine
kinase type III family also includes receptors for granu-
locyte/macrophage colony-stimulating factor (GM-
CSF). Intestinal ICC (in situ and in culture) express
c-kit as detected by rat anti-kit (ACK2) monoclonal
antibodies (18, 109, 132, 174, 244). Mutations in the
c-kit locus, the W mutants, result in abnormalities in
the number, structure, and function of the ICC (18, 52,
174, 212, 249). Furthermore, mutants of the ligand
SCF, steel (Sl) mutants, also show morphological and
functional abnormalities of the ICC (257). Thus the
PDGF family of growth factors seems crucial for the
embryological development of myofibroblasts. Unfortu-
nately, no systematic study of the various different
tissue myofibroblasts has been reported in PDGF or
SCF knockout mice or in mutants of their respective
receptors.
TGF-␤, PDGF, insulin-like growth factor II (IGF-II),
and interleukin-4 (IL-4) appear to be the most impor-
tant growth factors for the transdifferentiation of fibro-
blasts to myofibroblasts or of stellate-transformed myo-
fibroblasts into activated myofibroblasts (45, 61, 145,
211, 239). When myofibroblasts from the intestine (74),
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breast (203), skin (17, 111, 263), liver (88), lung (214),
prostate (181), nose (256), and joint synovium (214) are
treated with TGF-␤in serum-containing media, they
express ␣-SM actin, reduce the number of vitamin A
lipid droplets, and expand the rough endoplasmic retic-
ulum, i.e., they take on the morphology of an activated
myofibroblast.Conversely,interferon (IFN)-␣and IFN-␥
(56, 90) decrease the expression of ␣-SM actin in
myofibroblasts. It is not clear whether they do so by
transdifferentiating myofibroblasts back to the fibro-
blast state, inducing them to undergo stellate transfor-
mation, or simply downregulating the amount of ␣-SM
actin in the cell.
ACTIVATION, PROLIFERATION, AND MIGRATION
OF MYOFIBROBLASTS
Fibroblasts or stellate-transformed myofibroblasts
become activated and proliferate when cultured on
plasticin serum-containing growth culturemedia, espe-
cially when seeded at low cell density (74, 155). In vivo
activation, as signified by the development of ␣-SM
actin positivity, may be separable from proliferation.
Whereas many fibrogenic cytokines [IL-1, tumor necro-
sis factor (TNF)-␣, PDGF, fibroblast growth factor
(FGF), and TGF-␤] have been incriminated in this
process (138), TGF-␤appears to be the most important
cytokine causing the development of ␣-SM actin stain-
ingand an activated phenotype (25, 45, 88,97, 155, 165,
223,238) capable ofcollagen secretion (25,45, 165). The
source of TGF-␤in damaged tissue may be from white
blood cells, parenchymal or epithelial cells, or from the
myofibroblast itself in an autocrine fashion (22, 25, 45,
88). Recently, it has been determined that the activa-
tion of the myofibroblast requires the presence of
matrixmolecules, specifically,the ED-A(EIIIA) domain
of fibronectin (118, 222). Tissue injury gives rise to this
specific ED-A domain splice variant of fibronectin.
ED-A is the binding site for cell membranes and for
other matrix molecules. It has been shown in both skin
granulation tissue (222) and hepatic (118) models that
this fibronectin ED-A domain is necessary for TGF-␤to
trigger ␣-SM actin expression and collagen secretion by
myofibroblasts. Following activation of the myofibro-
blast, PDGF or connective tissue growth factor (CTGF),
Fig. 3. Proposed scheme depicting the origin, transdifferentiation, activation, and stellate transformation of
myofibroblasts. PDGF, platelet-derived growth factor; TLP, tethered ligand protein; TGF-␤, transforming growth
factor-␤; IL-1, interleukin-1; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; IGFI, insulin-like
growth factor I; CTGF, connective tissue growth factor.
C8 INVITED REVIEW

a member of the PDGF family (29), appears to be the
factorprimarily responsible formyofibroblast prolifera-
tion (71, 72, 89, 119, 147). TGF-␤was once considered
the prime factor (88, 214, 216), but it is now thought
that TGF-␤acts predominantly through the induction
of PDGF receptors on or synthesis of CTGF by the
myofibroblasts (72, 89, 111, 112, 263). Thus TGF-␤is
predominantly a cytodifferentiating rather than a pro-
liferating growth factor.
The TGF-␤s are a large superfamily of soluble factors
important in growth, development, and fibrogenesis
(149). TGF-␤1, TGF-␤2, and TGF-␤3 are encoded from
three separate genes. TGF-␤1 is the isoform usually
upregulated in the presence of tissue injury. It is
secreted in a latent form after cleavage from a large
promolecule and then noncovalently binds to another
peptide on the cell membrane called the latency-
associated peptide, which, in turn, is formed from the
cleavage fragments of the TGF-␤precursor. This latent
TGF-␤is stored on the surface of the cell or on the
extracellular matrix, awaiting conversion by unknown
mechanisms to active TGF-␤. In contrast to their
apparent (but probably indirect) proliferative effect on
myofibroblasts (see above), TGF-␤s cause G1phase cell
cycle arrest of epithelial and smooth muscle cells and
may even induce apoptosis (25). TGF-␤acts through a
superfamily of serine-threonine kinase cell surface
receptors.All threeTGF-␤s bind firstto the typeII (RII)
receptor that assembles and phosphorylates the type I
(RI) receptor, activating this serine-threonine kinase
and transducing the signal (25). Microsatellite (ge-
nomic) instability due to defects in DNA mismatch
repairsystems of the TGF-␤receptors has been incrimi-
nated in the unregulated growth of cancer and in
vascular atherosclerosis/restenosis (159). This raises
the question of a role for myofibroblasts in these two
diseases [see part II of this review (191)].
TGF-␣(138), a member of the epidermal growth
factor(EGF) family,as well asEGF itself (138,214, 216,
226), GM-CSF (25), both acidic and basic FGF (aFGF
and bFGF, respectively) (25, 119, 185, 214, 216, 226),
and IGF-I and IGF-II (25, 226) are candidate growth
factors promoting myofibroblast proliferation (see more
details in Growth Factors). Proinflammatory cytokines
such as TNF-␣, IL-1, IL-6, and IL-8 may also cause
activation and proliferation (119, 138, 177, 185, 246) as
does IL-4, a protein generally thought of as an anti-
inflammatory cytokine (61, 156, 211).
ANG II or aldosterone, thrombin, and endothelin are
also important soluble factors reported to promote
myofibroblast activation (15, 34, 35, 77, 246, 258).
Endothelin is capable of rapidly transdifferentiating
the stellate morphology of intestinal myofibroblasts to
the activated phenotype within 30 min of addition to
cell culture media (78, 80, 246). After it activates the
myofibroblasts, endothelin may subsequently inhibit
their proliferation (147, 148).
Cocultures of fibroblasts and myofibroblasts with
cancercells of several differenttypes induce transdiffer-
entiation of fibroblasts to myofibroblasts and activation
and proliferation of myofibroblasts (13, 19, 46, 70, 136,
149, 153, 204, 246, 264). This property of neoplastic
cells, perhaps via secretion of growth hormones such as
TGF-␤, may well be responsible for the desmoplastic
reaction (excessive fibrosis) seen in many cancers.
ROLE IN WOUND REPAIR
Theprocess of woundhealing is ahighly orchestrated
event that entails the release of proinflammatory cyto-
kines, eicosanoids of the cyclooxygenase, lipoxygenase,
and cytochrome P-450 family, nitric oxide, and a host of
growth factors; the secretion of collagen and other
matrix proteins; the elaboration of angiogenic, angio-
static, and nerve growth factors; and, finally, if it is a
deep or open wound, the formation of granulation
tissue that then becomes a scar (fibrosis) (20, 57, 187,
208, 214, 247, 252). Myofibroblasts appear to be key
cells in these various events. They become activated
and proliferate in the early stages of wounding. They
respond to proinflammatory cytokines with elaboration
of matrix proteins and additional growth factors and
then disappear by apoptosis following repair or scar
formation (51, 54, 55, 113, 164, 266).
Repair Processes
Epithelialtissues such as the intestine or stomach, in
contrast to organs such as the liver, kidney, or lung, do
not commonly sustain widespread injury that leads to
uniform fibrosis. However, gastrointestinal epithelial
tissues are often superficially injured. In fact, exfolia-
tionof the epithelium is viewed as a defenseresponse to
certain noxious insults such as toxins, microbiological
invasion, or gut anaphylaxis (163). The process of
repair of the epithelium occurs through two separate
mechanisms (252). If the basement membrane underly-
ing the sloughed epithelium is intact, residual epithe-
lial cells at the edges of the wound become motile and
move along the basement membrane until they meet
advancing epithelial cells from the other side of the
wound and form new tight junctions. This process is
calledrestitution(189, 225). Prostaglandins fromCOX-1
or COX-2 activation are key factors promoting restitu-
tion (23) and preserving the epithelial cells from dam-
age (47). Myofibroblast-secreted growth factors such as
TGF-␤, TGF-␣, EGF, aFGF, and bFGF and inflamma-
tory cytokines such as IL-1␤and IFN-␥also promote
restitution (58, 59, 189, 190, 200).
Conversely, if the wound is deep, the subepithelial
tissues that contain interstitial substance, blood ves-
sels, nerves, and fibroblasts must be reconstituted. If
the basement membrane has been destroyed by the
noxious stimulus, epithelial cells and mesenchymal
elementsforma new basement membrane(252).Epithe-
lial stem cells then undergo mitosis and proliferate and
migrate along the newly formed basement membrane.
This latter process is a coordinated event involving
secretion of matrix proteins and growth factors. Thus
myofibroblasts appear to play roles both in the restitu-
tion and repair processes.
A key event in the process of wound repair by either
restitutionor proliferation is contractionof the underly-
ing granulation tissue or gastrointestinal lamina pro-
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pria to limit the exposed surface area of the wound (51,
120, 163, 192, 208, 242). Myofibroblasts contain smooth
muscle myosin isoforms in addition to ␣-SM actin, the
requisite machinery for contraction and/or motility.
The ability of myofibroblasts to carry out these pro-
cesses depends on changes in the cellular cytoskeleton
as well as in the Rho-regulated fibronexus and on the
expression of integrins that allow attachment of the
myofibroblasts to the extracellular matrix (192, 242).
The fibronexus, discovered and characterized by Ey-
den (65) and Singer and colleagues (228–232) connects
the myofibroblast to the extracellular matrix through a
transmembrane ␣␤ integrin complex that joins the
actin stress fiber of the myofibroblast to ECM fibronec-
tin (32, 192). The Rho family of small GTPases includes
Rac 1–3, Cdc 42, and Rho A–H, which respond to
PDGF, TNF-␣or bradykinin, or lipopolysaccharide A,
respectively. In mammals, Rho A acts on the actin
cytoskeleton to cause myofibroblast shape change or
motility (6, 265).
ECM
The ECM is a complex mixture of collagen, other
glycoproteins, and proteoglycans distributed in each
organ or tissue in unique proportions (220, 227). These
matrix proteins have several general functions: they
arethescaffoldfor tissue formation and growth;through
binding to cell receptors (integrins), they initiate inter-
cellular signaling events; and they bind to growth
factors and thus supply sustained concentration of
these factors for epithelial or parenchymal cell migra-
tion, proliferation, and differentiation (20, 219, 227).
There are at least 19 different collagens in the collagen
superfamily, with types I, III, IV, and VIII being
secreted by myofibroblasts (154, 168). Proteoglycans
are proteins with large sulfated polysaccharide side
chains of several types (Table 4). The major glycopro-
teins secreted by the myofibroblasts are the various
laminins, which include fibronectin (see ACTIVATION,
PROLIFERATION,AND MIGRATION OF MYOFIBROBLASTS) and
tenascin. Laminin is a constituent of the basement
membrane along with type IV collagen, entactin, and
chondroitin sulfate (all of mesenchymal origin) and
perlecan, a large, low-density proteoglycan composed of
heparan sulfate side chains of epithelial cell origin (20,
227). Basement membranes and matrix are degraded
by a family of Zn2⫹-dependent matrix metalloprotein-
ases (MMPs 1–3) also secreted by myofibroblasts (146,
251). They are classified by the substrates they de-
grade: MMP 1 digests types I, II, and III collagen; MMP
2 (gelatinase A) digests denatured collagens I and III
and native collagen IV; and MMP 3 (stromelysin)
degrades laminin, fibronectin, proteoglycans, type IV
collagen, and casein (16, 251). These MMPs are inhib-
ited by tissue inhibitors of metalloproteinases (TIMPs)
(16). Growth factors may bind to heparan sulfate
proteoglycans or collagen, thus controlling their avail-
ability both temporally and spatially, and so modify
their biological activity (20, 219, 227, 242).
Growth Factors
The growth factors secreted by myofibroblasts have
three general functions as follows: 1) they initiate or
increase cell mobility, 2) they induce proliferation, i.e.,
they are paracrine mitogens for epithelial or parenchy-
mal cells and perhaps autocrine mitogens for them-
selves, or 3) they induce terminal differentiation of
these cells, even driving the cells to apoptosis. Some
growth factors seem to have all three effects.
Individual growth factors may be produced by the
epithelial cells alone (trefoil proteins), by mesenchymal
cells such as myofibroblasts or inflammatory cells,
particularly macrophages and lymphocytes, and some
byboth cell types (67).Furthermore, the various inflam-
matory cytokines, eicosanoids, and growth factors re-
leased during tissue damage may directly affect the
epithelium or parenchymal cell of the injured tissue, or
these agents may act more proximally on myofibro-
blasts to induce these cells to secrete additional cyto-
kines, eicosanoids, or growth factors (67). Thus an in
vivoepithelial proliferative responsecould be the result
of a cytodifferentiating effect of mediators on the myofi-
broblasts, inducing them to express receptors for other
factors or to secrete specific epithelial proliferating
growth factors. Examples of this are TGF-␤1, which
induces the expression of PDGF receptors on or CTGF
secretion by the myofibroblasts, causing them to prolif-
erate in response to PDGF (137), or the secretion of
hepatocyte growth factor (HGF) or keratinocyte growth
factor (KGF) by myofibroblasts in response to IL-1 (37)
or immune stimulation (10, 66).
IL-1 (60), IL-6 (261), IL-15 (196), and TNF-␣(121,
139) have also been identified as being involved in
tissue repair and have been shown to be mitogenic for
several mesenchymal and epithelial cell lines. Further-
more, combinations of cytokines and growth factors
may have offsetting effects on epithelial proliferation,
so the ultimate consequence of these various factors in
vivo can be quite complicated.
Factors secreted by myofibroblasts such as EGF and
TGF-␣(12, 188), IGF-I and IGF-II (144, 145), HGF (28,
84, 173), and members of the FGF family, including
aFGF, bFGF (also known as FGF-2) (110), KGF (also
known as FGF-7) (107, 207), and IL-11 (38, 175, 194),
have been demonstrated to be the major paracrine
growth factors for epithelial and parenchymal cells.
The trefoil peptides, secreted by the epithelial cells
themselves, have similar effects through autocrine
stimulation(186). These factors mayalso have nonmito-
genic effects on intestinal cells as well, e.g., they may
regulate secretory and contractile processes as well as
regulate blood flow (245).
The trefoil peptides are so named because of a
distinctive pairing of six cysteine residues that results
in three interchained loops, thus giving a ‘‘three leaf’’
trefoil shape (38, 186). There are three such trefoil
proteins that are small, highly stable molecules se-
creted principally by the goblet (mucus)-secreting cells
of the epithelium and not by myofibroblasts. The stom-
ach secretes peptide pS2 in the fundus and spasmolytic
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polypeptide (SP) in the antrum, whereas the breast
epithelium secretes only pS2 and the pancreas secretes
only pancreatic SP (pSP) (129). In contrast, the intesti-
nal epithelium secretes only intestinal trefoil factor
(ITF).Targetedgene disruption of ITFcauses abnormal
epithelial cells and increased susceptibility to various
models of injury, resulting in a colitis-like picture (7,
130). Exogenous administration of ITF repairs the
damage susceptibility in this knockout model and also
protects the gastric mucosa against other injuries such
as those induced by ethanol or chronic indomethacin
administration (7). PS2 gene knockout mice have a
different disease phenotype; they develop extensive
neoplastic adenomas in the antrum of the stomach,
which then progress to carcinoma in situ (140).
TGF-␣,EGF, and the EGF human homologue urogas-
trone (EGF/URO) are members of the same family of
polypeptides and act on a common cell membrane
receptor (12, 188). The TGF-␣/EGF receptor appears to
be upregulated in the mucosa of injured intestine and
other organs. TGF-␣is expressed in epithelial cells,
myofibroblasts, and monocytes/macrophages, whereas
EGF seems to be produced primarily by the epithelial
cells of the salivary gland and Brunner’s glands of the
duodenum. TGF-␣is synthesized as a 160-amino acid
precursor molecule that spans the cell membrane.
Proteases release the soluble 50-amino acid form. It is
unclear whether the membrane-bound form is active as
a growth factor for adjacent cells. The soluble factor is
trophic (mitogenic) for a number of cell lines in vitro
and intestinal epithelial cells in vivo. It may well have
differentiating functions as well. Ulceration of the
human gastrointestinal mucosa causes the develop-
ment of a specific cell lineage from epithelial stem cells
that bud from the crypts next to an ulcer and then
ramify to form a small gland. These budding glands
secreteEGF/URO,which stimulates epithelial prolifera-
tion and promotes ulcer healing (260).
The FGF family (aFGF and bFGF) are important
mitogens for myofibroblasts and have powerful neuro-
trophic and angiogenic properties that are important
for tissue healing (68, 110). Other angiogenic factors
secreted by myofibroblasts include the CXC family of
cytokines such as IL-8 and epithelial neutrophil-
activating peptide (ENA-78) (5, 127, 178). Cell-to-cell
contact such as that occurring in restitution or wound
healing has its antiapoptotic action via the adhesion
molecule N-cadherin. When the adjacent cells touch,
there is homophilic binding of N-cadherin molecules,
which activate the FGF family of receptors. In this way,
cell contact mimics the antiapoptotic effect of bFGF
(91).
IGF-I and IGF-II are structurally related polypep-
tides that have various metabolic, proliferative, and
differentiating effects through endocrine, autocrine,
and paracrine mechanisms (144, 145). The effects are
mediated by IGF-I receptors and insulin receptors.
There is an IGF-II receptor, but its role in signal
transduction is unclear. IGF is present in the circula-
tion (from liver) and is also secreted in a paracrine
fashion by myofibroblasts adjacent to epithelial and
parenchymal cells (144). The IGF actions are deter-
mined by the availability of free IGF, the form that
interacts with its receptors. In turn, the amount of free
IGF is modulated by the level of high-affinity IGF-
binding proteins (IGFBPs), of which six have been
identified (42–44). These IGFBPs not only regulate the
bioavailability of IGF but also inhibit or enhance its
action on target tissues. Although the IGFs are weakly
mitogenic for epithelial and parenchymal cells, they
seem to be powerfully mitogenic for myofibroblasts
(226) and other smooth muscle cells (255).
A new member of the family of factors stimulating
epithelial growth is IL-11, a multifunctional cytokine
originally derived from bone marrow stromal cells (175,
194). It regulates the growth of hematopoietic and
lymphoid cells by acting on the IL-6 family of cytokine
receptors. It stimulates proliferation of small intestinal
crypts and accelerates recovery of the intestinal mu-
cosa from models of damage (143). It also has trophic
effects on neurons, preadipocytes, and myofibroblasts
of the lung (175). TGF-␤and IL-1 are potent stimulants
of IL-11 production. Paradoxically, IL-11 has been
shown to inhibit epithelial cell proliferation in the lung
by altering phosphorylation of the retinoblastoma pro-
tein (194). Thus it is possible that the proliferative
effect of IL-11 on epithelia occurs via activation of
myofibroblasts, with subsequent secretion of epithelial
proliferating factors by these cells, rather than being a
direct effect of IL-11 on the epithelium itself.
KGF is a member of the FGF family (FGF-7) (107,
207). This factor is unique because, unlike other mem-
bers of the FGF family, it does not appear to have
activityon fibroblasts, endothelial cells,or other nonepi-
thelial targets. This is a consequence of the epithelial
cell expression of the KGF receptor (KGFR), a trans-
membrane tyrosine kinase that binds KGF and aFGF
with high affinity and binds bFGF much more poorly.
The KGFR is nearly identical to the FGF receptor type
II, except for alterations in a 49-amino acid residue in
one of its extracellular loops. FGFR-II does not bind
KGFbut shows a high affinityfor both aFGF and bFGF.
KGFR expression is limited to epithelial cells, whereas
FGFR-II is present in a variety of tissues including
fibroblasts. KGF, initially isolated from lung fibro-
blasts, appears to be a myofibroblast-secreted epithe-
lialgrowth factor with specificroles in epithelialgrowth
and differentiation. The KGFR is expressed on the
epithelial cells, and KGF has been shown to induce
proliferation and differentiation of a host of epithelial
and parenchymal cells, including intestinal epithelial
cells, type II pneumocytes, hepatocytes, and keratino-
cytes of the skin. Its expression and secretion are
regulated by IL-1 (37). Its synthesis is significantly
upregulated in the lamina propria of inflamed intestine
(66). Thus KGF represents a prime example of a
mediator causing a specific mesenchymal-epithelial
interaction.
HGF, also known as scatter factor because it induces
cell migration as well as proliferation, is synthesized
and secreted by fibroblasts and myofibroblasts (28, 84).
HGF is a glycoprotein heparin-binding heterodimer
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related to plasminogen, consisting of a heavy ␣chain
and a light ␤chain held together by disulfide bonds
(84). It is produced as a single-chain precursor protein
and proteolytically cleaved to form HGF. The HGF
receptor, prominently expressed by epithelial cells, is
encoded by the protooncogene c-met. This receptor is a
heterodimeric glycoprotein of 190 kDa linked with two
disulfide bonds; the ␣chain is extracellular, while the
membrane-spanning ␤chain has the cytoplasmic do-
main of a tyrosine kinase. C-met also is regulated by
proteases that cleave both chains from a 178-kDa
common precursor. Thus HGF is only active if the
correct proteases are present. Like TGF-␤, HGF has
effects on cell division, motility, and apoptosis and
appears to have angiogenic activity (28). Its synthesis
is stimulated by IL-1 (28). Not only does it cause
proliferation of epithelial cells but it also affects paren-
chymalcells such as liver andbone (28). Thus HGF,like
KGF, is a major mediator of epithelial-mesenchymal
interactions and epithelial morphogenesis (207).
The process of repair is completed by the terminal
differentiation of epithelial and parenchymal cells and
by apoptosis of the ␣-SM actin myofibroblasts (51, 81,
216). The factors that terminate the repair process are
poorly understood. The role of IL-10, INF-␥, and INF-␣
ineither the downregulation (90, 197) of myofibroblasts
or induction of their apoptosis (95, 128) needs further
investigation.
ROLE IN FIBROSIS
With repeated cycles of injury and repair or if, for
unclear reasons, there is loss of the signals that discon-
tinue the healing process, organ fibrosis occurs. The
important functions of the myofibroblasts in the fibro-
sis of tissues such as the skin, lung, pancreas, and
kidney are well described (see references in Table 4).
The effects of PDGF, TGF-␤, and other growth factors
in the fibrotic process have been studied in detail (72,
93, 167, 214, 239) and are beyond the scope of this
review (see Refs. 20 and 96 for detailed reviews of
fibrosis).
Factors that act on myofibroblasts are important in
tissue fibrosis. Recently, the key role of TGF-␤in
fibrosis has been accentuated by the finding of fibrosis
of multiple organs, including the liver, kidney (both
renal interstitium and glomerulus), and adipose tissue
in a transgenic mouse overexpressing TGF-␤(45).
PDGF-BB causes fibrosis in the kidney (239), and,
given the propensity of TGF-␤to upregulate PDGF
receptors, an equally important role for PDGF cannot
be ruled out. IGF-I has been shown also to induce
collagen mRNA and IGF binding protein-5 mRNA in
ratintestinal smooth muscle (269), raising the question
of an important role for this growth factor in organ
fibrogenesis (268). IL-1, IL-6, INF-␥, TNF-␣, and bFGF
have also been incriminated as fibrogenic cytokines
(101, 205). Potential abnormalities in matrix secretion,
degradation of matrix by MMPs, and inhibition of
MMPs by TIMPs (see above) that might result in
fibrosis are under investigation (21, 96, 154). An under-
standing of these processes and the development of
effective pharmacological or biological inhibitors would
be important advances in the treatment of disease.
CONCLUSIONS AND SPECULATION
Myofibroblastsare ubiquitous cells withsimilar prop-
ertiesand functions that play important roles ingrowth
and development, wound repair, and disease. Either
their absence or their activation and proliferation in a
given tissue or organ can lead to specific diseases as
outlined in Table 3. However, because they are present
in virtually every tissue, it is possible that they may
play a role in multisystem diseases as well. For ex-
ample, do abnormalities in pericytes account for some
of the multifocal effects of chronic hypertension (208)?
Are the multiple abnormalities of diabetes mellitus due
to stimulation of or damage to vascular, renal, intesti-
nal, and skin myofibroblasts? It is intriguing that high
glucose concentrations induce TGF-␤1 production by
the glomerular mesangial cell (135), and PDGF and
bFGF improve wound healing in genetically diabetic
animals (87). What is the role of myofibroblasts in
aging, a condition in which myofibroblasts are reported
to be morphologically abnormal (169)? These are but a
few of the intriguing questions raised by this unique
family of pleiotropic cells.
We thank Terri Kirschner for excellent editorial expertise.
We acknowledge the support of National Institute of Diabetes and
Digestive and Kidney Diseases Grant 2 R37 DK-15350, a grant from
the Crohn’s and Colitis Foundation of America, and support from The
Keating Fund for Research Prevention of Cancer, administered by
the University of Texas Medical Branch (UTMB) Small Grants
Program, UTMB at Galveston.
Address for reprint requests and other correspondence: D. W.
Powell, Dept. of Internal Medicine, Univ. of Texas Medical Branch at
Galveston, 4.108 John Sealy Annex 0567, 301 Univ. Blvd., Galveston,
TX 77555-0567 (E-mail: dpowell@utmb.edu).
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