The emerging role of fibrocytes in ocular disorders
Zhang et al. Stem Cell Research & Therapy
The emerging role of fibrocytes in ocular disorders
Feng Zhang 0 1
Ke Liu 0 1
Han Zhao 0 1
Yan He 0 1
0 Hunan Clinical Research Center of Ophthalmic Disease , Changsha 410011, Hunan Province , China
1 Department of Ophthalmology, The Second Xiangya Hospital, Central South University , Changsha 410011, Hunan Province , China
The fibrocyte, which was first described in 1994, is a type of circulating mesenchymal progenitor cell in the peripheral blood. Fibrocytes play important roles in chronic inflammation, wound healing, tissue remodeling, and fibrosis. Emerging evidence indicates that fibrocytes are involved in a wide variety of ocular disorders associated with inflammation and fibrosis. In this review, we summarize recent advances regarding the general characteristic profile of fibrocytes, molecular mechanisms underlying the fibrocyte recruitment to target tissues, their differentiation into fibroblasts, and the potential role of fibrocytes in ocular disease. Given the critical role of fibrocytes in ocular disorders, fibrocytes may serve as a promising pharmaceutical target in the development of novel therapeutic strategies to treat ocular inflammation and fibrosis.
Fibrocytes; Mesenchymal progenitor cell; Fibrosis; Inflammation; Ocular disorders
Adult bone marrow contains a large number of distinct
stem or progenitor cells, including hematopoietic stem
cells, mesenchymal stem cells, endothelial progenitor cells,
and fibrocytes. It has been suggested that other progenitor
cells, as well as hematopoietic stem cells, could be
involved in the process of hematopoiesis support,
neovascularization, and tissue regeneration or wound healing,
supporting the blood cells [
]. Fibrocytes are among
these other progenitor cells, with the features of both
lymphocytes and fibroblasts, that have become
increasingly researched recently. Circulating fibrocytes were first
identified in 1994 in an in vivo study using an animal
model of wound repair and were defined by their unique
co-expression of hematopoietic and progenitor cell
markers (CD45 and CD34, respectively), together with the
production of extracellular matrix (ECM) [
]. In addition,
fibrocytes express a number of chemokine receptors and
adhesion molecules, some of which are critical for the
recruitment of fibrocytes to sites of tissue injury, fibrosis,
and inflammation [
Due to the properties of mesenchymal stem cells,
fibrocytes are capable of differentiating into several cell lineages,
such as classic trilineage cells (including adipocytes,
osteoblasts, and chondrocytes), fibroblasts, and myofibroblasts
]. The function of these cells has been shown to be
involved in several pathological processes encompassing
fibrosis, inflammation, neovascularization, and some
immunological diseases. A large number of in vitro and in
vivo studies have revealed distinct roles of fibrocytes in a
wide variety of ocular disorders. In this review, we will
focus on the latest advances regarding the emerging roles
of fibrocytes in ocular disease and the therapeutic potential
of specific treatments targeting fibrocytes.
Origin and phenotypic characteristics
The term fibrocyte, which combines the term fibroblast
with leukocyte, thrombocyte, and erythrocyte, was
coined for the peripheral blood circulating fibroblast
progenitor that produces collagen and also expresses the
hematopoietic marker CD34 [
]. Since there are various
studies that have focused on fibrocytes involved in
diverse pathogeneses, including fibrosis and
inflammation, different views of the origin of fibrocytes have
arisen. In 1994, Bucala and his colleagues first described
a subpopulation of spindle-shaped adherent cells that
expressed collagen, CD34, and CD45. They named these
cells “fibrocytes”, which represented about 10% of the
whole cell population in the wound chamber [
Fibrocytes constitute 0.1–0.5% of circulating
nonerythrocytes and were isolated from the peripheral blood
]. Thus, historically, it was believed that
fibrocytes were one type of monocyte in the peripheral
blood. However, emerging evidence indicates that
fibrocytes are more likely to be originally derived from
]. Their presumed monocyte origin is proved
by the expression of CD11b and CD11c. Interestingly,
monocytes consisting of a mixed population of
progenitors likely replenish the tissue-resident macrophage and
dendritic cell populations in the absence of inflammation
after an initial differentiation into different subtypes of
monocytes before they enter the tissues. During
inflammatory processes, however, a population of monocytes
directly migrates to inflamed sites, predominantly through
a CCR2-mediated signaling pathway, and differentiate into
fibrocytes as a player in inflammation and tissue repair
]. There are several distinct regulators involved in
the process of fibrocytes differentiation. An animal study
revealed that differentiation of fibrocytes is critically
dependent on CD4+ T cells and T-cell activation, which
determines whether the development of fibrocytes is
supported or blocked [
]. Cytokines produced by Th1 and
Th2 cells, respectively (such as interleukin (IL)-4, IL-13,
IL-2, and tumor necrosis factor (TNF)), inhibit or
promote fibrocyte fate [
]. In serum-free media, some
peripheral blood monocytes differentiated into fibrocytes
within 5 days, and such differentiation was inhibited by
the blood plasma protein serum amyloid P (SAP) 
likely through its interaction with FcγRI [
factors affecting fibrocyte differentiation include hyaluronic
acids and CD44. High molecular weight hyaluronic acid
(HWMHA) potentiates the differentiation of human
monocytes to fibrocytes and, in contrast, low molecular
weight hyaluronic acid (LWMHA) inhibits fibrocyte
differentiation. CD44 may be involved in the regulation of
the process of fibrocyte differentiation, with a dominance
hierarchy of SAP > LMWHA > HMWHA > IL-4 or IL-13
]. The number of circulating fibrocytes was not
decreased when a monoclonal antibody against CCR2 was
used to deplete monocytes in a mouse model, suggesting
that fibrocytes develop outside the kidney independent of
infiltrating monocytes and rely on CCR2 for migration
into target organs.
Circulating fibrocytes, a slender spindle-shaped cell type
(Fig. 1), exhibit several phenotypic characteristics attributed
to the variety of their properties. Consistent with
their bone marrow or hematopoietic origin, fibrocytes
express CD45, leukocyte-specific protein-1 (LSP-1), and
CD34 (a hematopoietic progenitor marker) [
fibrocytes produce collagen or ECM they were not
discovered until the early 1990s. This is likely due to an
underestimation of fibrocyte counts as they progressively lose
CD34 and CD45 [
]. Moreover, collagen could be a noisy
marker to discriminate between other lineages because of
its overlap expression by fibroblasts or macrophages [
To address this confusion, Pilling et al. screened
fibrocytes, monocytes, and macrophages with commercially
available reagents to identify markers that could accurately
discriminate between these populations, together with
their different morphology [
]. One of their principal
findings was that only fibrocytes (50–200 μm long
spindle-shaped cells with an oval nucleus) expressed
CD45RO, 25F9, and S100A8/A9, but not PM-2 K, which
could distinguish fibrocytes from other populations [
Some additional characteristics and markers of fibrocytes
are summarized in Table 1. As mentioned above, there is
currently no unified or specific standard for identifying
fibrocytes. Fibrocytes have the characteristics of both
macrophages and fibroblasts. To differentiate fibrocytes
from macrophages and fibroblasts, positive staining of
intracellular collagen, fibronectin and vimentin, the
coexpression of specific markers (such as CD34, CD45,
CXCR4), and the presence of at least several unique
features indicated in Table 1 would be an appropriate criterion
for defining fibrocytes. In addition, fibroblasts constitute
the main resident cells of connective tissue and are
considered in a state of activation. In fact, active
fibroblast morphology is different from fibrocytes. Fibroblasts
have a branched cytoplasm surrounding an elliptical,
speckled nucleus (Fig. 2), and, in contrast, inactive
fibrocytes are small and spindle-shaped.
Proliferating and transforming cytokines of fibrocytes
Several studies have identified a profibrotic lung phenotype
in aging mice characterized by an increase in the number
of fibroblasts lacking the expression of thymocyte
differentiation antigen 1 (Thy-1) and an increase in transforming
growth factor (TGF)-β1 expression [
23, 25, 26
findings suggest that TGF-β1 epigenetically regulates the
lung fibroblast phenotype through methylation of the
Thy-1 promoter [
24, 27, 28
]. Targeted inhibition of DNMT
in the right clinical context might prevent fibroblasts from
myofibroblast transdifferentiation and collagen deposition,
which in turn could prevent fibrogenesis in the lung and
other organs [
]. However, the proliferation ability of
fibrocytes in vitro is limited; they cannot proliferate
indefinitely because of the Hayflick limit.
Homing chemokines of fibrocytes (CXCL12/CXCR4)
Fibrocytes can migrate to the site of injury and
inflammation, mediated by various chemokine receptors (Table 1),
and are able to produce numerous cytokines which take
part in the process of inflammation or tissue remodeling.
Once there, they differentiate into myofibrocytes and
begin the process of tissue remodeling which ultimately
culminates in fibrosis [
]. The pivotal CXCL12/CXCR4
axis in fibrocyte chemotaxis, which is implicated in the
recruitment process of fibrocytes, has recently attracted
]. Both anti-CXCL12 antibody and direct
CXCR4 antagonism have shown protective effects against
the development of fibrosis by blocking the fibrocyte
Inhibition of the mammalian target of rapamycin
(mTOR) pathway, a possible upstream factor of CXCL12/
CXCR4, with rapamycin has been shown to effectively
reduce the recruitment of fibrocytes into tracheal allografts
and mitigates the development of tracheal luminal fibrosis.
Some other signaling pathways such as CCL2/CCR2 and
soluble factors including TNF, IL-10, monocyte
chemotactic protein 1 (MCP-1), IL-1, and IL-33 were shown, at least
in part, to relate to the migration of fibrocytes in distinct
fibrotic diseases [
]. Following the recruitment to the
tissues, fibrocytes were thought to differentiate into
myofibroblasts, driven by TGF-β1, IL-4, and IL-13, and exhibit
upregulation of α-smooth muscle actin (α-SMA) and the
progressive loss of CD34 and CD45 expression [
It is complicated to elucidate all the functions of
fibrocytes involved in various pathologic processes; however,
we might conclude that fibrocytes play different roles to
some extent, mainly in inflammation and fibrosis. In
other words, there are a number of distinct cytokines
produced by fibrocytes that play their corresponding
roles during the different stages of disorders. Early studies
have shown that fibrocytes express α-SMA and are able to
contract collagen gels in vitro, revealing their potential to
differentiate into myofibroblasts and contribute to wound
]. Fibrocytes also produce soluble mediators
that induce myofibroblast transformation in culture such
as platelet-derived growth factor (PDGF) and TGF-β1
], and have been shown to control angiogenesis via
secretion of soluble mediators including growth factors
(TGF-β, PDGF-A, and fibroblast growth factor (FGF)-7),
chemokines (MCP-1 and macrophage inflammatory
protein (MIP)-1α), and ECM (collagen I and α-SMA) [
one of the most potent fibrogenic factors, TGF-β1 may
facilitate fibroblast transformation both in vivo and in
vitro in various fibrotic diseases [
]. Wang et al.
showed that fibrocytes from humans with chronic airway
obstruction could transform to myofibroblasts induced by
TGF-β1 in vitro . Neveu et al. considered that TGF-β1
epigenetically regulated the lung fibroblast phenotype in
vivo, and inhibition of TGF-β1 DNA methyltransferase
could prevent fibrogenesis in the lung and other organs
]. In the injured liver, a sharp release of TGF-β1 was
observed to accompany liver fibrosis, and helped in
triggering fibrocyte recruitment to the liver injury site and
promoting their differentiation [
]. In fibrotic kidney
diseases, several clinical trials and experimental models
used pharmacological blockade of TGF-β1 as an
antifibrotic therapy to improve or slow the decline in kidney
]. Moreover, in response to IL-1β, fibrocytes
were induced by the secretion of IL-6, IL-8, CCL2, CCL3,
and intercellular adhesion molecule-1 (ICAM-1) which
would be expected to recruit inflammatory cells .
Fibrocyte involvement in ocular disorders
Given the conjunction of ongoing inflammation and
fibrosis present in many ocular complications, fibrocytes
have been proposed to be a critical player in ocular
disease. To date, accumulated evidence has demonstrated
the involvement of fibrocytes in a wide variety of ocular
disorders, including thyroid-associated orbitopathy (TAO)
, age-related degeneration (AMD), degenerative retinal
diseases, intraretinal revascularization, subfoveal choroidal
neovascularization (CNV), postoperation scar formation
following trabeculectomy, corneal endothelial dystrophy,
pterygial fibrous tissues, and vitreomacular traction
syndrome and macular hole. A better understanding of
cellular mechanisms underlying the regulation of fibrocytes in
the initiation and progression of ocular disorders will shed
light on the identification of novel therapeutic strategies
to treat ocular disease.
TAO is an immune-mediated inflammatory disorder
usually associated with Grave’s disease (GD) that causes
enlargement of the orbital muscles and fat. The
molecular mechanisms of TAO are poorly understood. In the
past, orbital fibroblasts were thought to be the principal
cell type that could give rise to the exophthalmos of
patients with TAO, whether or not they were
predominantly of the fat or muscle type. Fibrocytes have been
shown to be related to inflammation and fibrosis in
diverse pathogenesis of tissue remodeling-related disease
]. Douglas and colleagues found that peripheral
blood mononuclear cells (PBMCs) isolated from GD
patients yielded approximately fivefold more fibrocytes
compared with the control healthy population; however,
fibrocyte yields were not statistically different in active
TAO patients compared with those with stable disease,
and the severity of exophthalmos of the more affected
orbit failed to correlate with fibrocyte yields .
Thyroidstimulating hormone receptor (TSHR) is an essential
antigen of GD expressed at high levels on fibrocytes isolated
from patients, consistent with the study by Gillespie et al.
] that circulating fibrocytes expressed markedly
increased TSHR and proinflammatory chemokines in
response to TSH. What was more surprising was that the
expression of TSHR on fibrocytes was comparable with
that found on cultured thyrocytes. In contrast,
undifferentiated orbital fibroblasts, even those from patients with
GD, failed to express detectable TSHR. These findings
revealed that fibrocytes might be involved in the
inflammatory response by activating TSHR and producing various
]. In healthy humans fibroblasts are
uniformly CD34−, and of great potential importance was
the finding that those expressing TSHR fibroblasts were
uniformly CD34+, strongly suggesting that they derive
from circulating fibrocytes [
]. In addition, fibrocytes
defined as CD34+ and LSP-1+ infiltrated to orbital tissues
in large amounts, suggesting that they may migrate to the
orbit and mediate tissue reactivity and remodeling
through local production of cytokines such as IL-6 and
]. The same group then carried out an in-depth
study where they suggested that fibrocytes displayed
particularly high levels of functional CD40. CD40/CD40
ligand binding raised the production of several
proinflammatory cytokines, amongst which IL-6 expression was
mediated through the Akt and NF-κB pathways [
expression and function of CD40 on fibrocytes also
suggested that they might provide the antigen-specific
Tcell reaction [
]. Douglas’ team also showed that CD40
expression in fibrocytes is induced by TSH and mediates
IL-8 expression [
]. Fernando et al. reported that
fibrocytes from GD patients not only express TSHR, but
also express thyroglobulin (Tg); moreover, GD orbital
fibroblasts, which contain CD34+ and CD34− cells,
express much lower levels of Tg and TSHR . All these
findings indicated that fibrocytes from GD patients are
characteristic of multiple thyroid-specific markers by
which it potentially shares the derivation with the
fibroblast in GD patients. Reducing signaling from TSHR on
fibrocytes could be a useful strategy in treating TAO. A
theoretical schematic of the roles of fibrocytes in TAO is
shown in Fig. 3.
Despite many risk factors associated with
vitreoretinopathy, inflammation and fibrosis are thought to be the
predominant cause in the pathologic process of different
ocular fibroproliferative diseases. Proliferative diabetic
retinopathy (PDR), one of the proliferative vitreoretinopathies
and sequelae of diabetes mellitus, is caused by the
inflammation and metabolic changes resulting from diabetes
mellitus, which results in vascular leakage with alteration
of the phenotype of fibrocytes [
]. Fibrocytes were
detected in the vitreous and fibrovascular membrane in PDR
patients. Cultured cells from the vitreous of PDR patients
exhibited a spindle shape and expressed fibrocyte markers,
and these cells could differentiate into myofibroblasts via
TGF-β1. These findings indicate that fibrocytes might be
involved in the development of PDR [
]. An earlier study
revealed that circulating fibrocytes migrated to the
epiretinal membranes of proliferative vitreoretinopathy
(PVR), differentiated into myofibroblasts, and contributed
to wound healing predominantly via the chemotactic
CXCL12/CXCR4 pathway [
Moreover, an ultrastructural study of patients with
vitreomacular traction syndrome revealed that
myofibroblasts are the predominant cell type in the epiretinal
tissue and the inner limiting membrane of 12 out of 14
]. Other ocular fibrotic processes, such as
macular hole, also showed that fibrocytes were in the
tissue removed at the time of surgery [
]. Taken together,
these finding suggested that circulating fibrocytes are a
precursor of myofibroblasts in pathologic epiretinal
membranes, consistent with the effects of fibrocytes in
the process of inflammation and fibrosis of other
Corneal wound healing
The stromal opacity during corneal wound healing is a
process associated with precipitation of ECM and
myofibroblast generation and persistence. Animal studies
revealed that PRM-151, a recombinant form of human
pentraxin-2 (also referred to as serum amyloid P),
modulated the generation of myofibroblasts after
opacity-producing corneal injury in rabbits by inhibiting
differentiation of circulating monocytes into fibrocytes
and profibrotic macrophages [
]. This finding indicates
that PRM-151 inhibited myofibroblast generation after
opacity induction, and also suggests that fibrocytes
contribute to corneal myofibroblast generation.
Furthermore, other investigators have found that bone
marrowderived cells could differentiate into myofibroblasts, with
increased expression of α-SMA in the corneal stroma
after irregular phototherapeutic keratectomy, and that
the presence of these cells within the cornea is
associated with corneal stromal haze.
Pterygium is commonly observed in ocular pathological
fibrosis and consists of elastotic degeneration of collagen
and fibrovascular degeneration [
immunoreactivities against progenitor cell markers such as CD34,
ckit, vascular endothelial growth factor (VEGF) receptor 1
and 2 were detected in surgically removed pterygium
]. CXCR4-positive cells aggregated in the
pterygium stroma in response to stromal cell-derived factor
(SDF)-1 and might represent the process of differentiation
for monocyte precursors into myofibroblasts [
probable cellular mechanism of pterygium formation is that
dysregulated healing signaling exceeds the requirement
for the recovery of tissue damage, and thereby limbal basal
cells will be changed to abnormally altered pterygial cells,
and the excessive wound healing process and remnant,
altered cells resulted in recurrence using the same
mechanism. Clinically, patients with pterygium treated by
temporary amniotic membrane patch after pterygium
removal were found to have circulating CD34+ cells, which
represent the active subset of fibrocytes, increased slightly
compared with a marked increase in the bare sclera
group; this might represent an effective therapeutic
approach for controlling pain—lower collagen expression,
and excessive infiltration of bone marrow-derived stem
Other ocular disorders
Given that they might be a pivotal player in
inflammation and fibrosis, circulating fibrocytes have drawn
increased attention for the study of ocular disease. Two
representative examples of such ocular disorders are
postoperation scar formation following trabeculectomy
and choroidal neovascularization.
Conclusions and future directions
A growing body of literature over the last decade has
shown that circulating fibrocytes may serve as an
important source of fibroblasts and myofibroblasts during
normal or aberrant reparative processes in diverse
fibrotic disorders associated with inflammation.
Fibrocytes have been implicated in many inflammatory and
fibrotic ocular diseases, and their presence at high levels
is one of the biomarkers for TAO. Previous studies have
demonstrated that both growth factor-induced and
hypoxia-driven CXCR4 expression is mediated through
the PI3K/mTOR pathway and can be inhibited by
rapamycin, which substantially diminished the accumulation
of fibrocytes in target tissues. Therefore, the PI3K/AKT/
mTOR/CXCR4 signaling pathway may serve as a
promising pharmaceutical target to treat ocular disorders. The
molecular mechanisms underlying the transformation
and differentiation process of fibrocytes into fibroblasts
and myofibroblasts remains largely unclear, which also
reminds us that fibrosis is not exclusively caused by
fibroblasts. How these relative cells correlate with each
other phenotypically, how they lose expression of some
critical markers (e.g., CD34, CD90), and the inhibition of
the pathway should be the concern for the future for a
possible therapeutic strategy.
In summary, fibrocytes and the fibrotic process may
serve as novel targets for intervention in chronic
inflammatory eye diseases. A better understanding of the
identity and characteristics of fibrocyte subsets as well as
their regulatory mechanisms in ocular disorders will
provide valuable insights into the identification of new
target of rapamycin; PBMC: Peripheral blood mononuclear cell; PDGF:
Plateletderived growth factor; PDR: Proliferative diabetic retinopathy; PVR: Proliferative
vitreoretinopathy; SAP: Serum amyloid P; SMA: Smooth muscle actin;
TAO: Thyroid-associated orbitopathy; Tg: Thyroglobulin; TGF: Transforming
growth factor; Thy-1: Thymocyte differentiation antigen 1; TNF: Tumor necrosis
factor; TSHR: Thyroid-stimulating hormone receptor
YH was supported by the National Natural Science Foundation of China
(grant no. 81600714) and the Natural Science Foundation of Hunan province,
China (grant no. 2017JJ3451). KL was supported by the National Natural
Science Foundation of China (grant no. 81402247). This work was supported
by the Department of Science and Technology, Hunan (no. 2015TP2007).
Availability of data and materials
All data are fully available without restriction.
FZ and YH conceived and wrote the paper. FZ, KL, and HZ collected
information and designed the figures and tables. KL and YH reviewed and
edited the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
All authors have given consent for publication.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
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