International Journal of

Review Article
Dermatology and Venereology
OPEN

Possible Mechanisms and Prospects of Stem

Cell Therapy for Keloids
Min-Min Zhang1 and Xiao-Dong Chen1,2,∗
1
Medical School, Nantong University, Nantong, Jiangsu 226001, China, 2 Department of Dermatology, Affiliated Hospital of
Nantong University, Nantong, Jiangsu 226001, China.

Introduction accordance with their developmental stage. Stem cells

secrete a variety of paracrine factors that are antifibrotic and
Keloids are a benign proliferative disease of the skin caused
inhibit collagen deposition, and stem cell therapy has
by abnormal healing of physiological wounds. Keloids are
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achieved good results in fibrosis-related diseases such as

similar to hypertrophic scars. However, keloids extend
beyond the margin of the original wound and do not
spontaneously regress, while hypertrophic scars are
confined to the original wound and generally maintain
their shape.1 Keloids cause pain, pruritus, restricted joint
activity and cosmetic problems, and negatively affect
quality of life. The bioactivity of keloids is regulated by
various factors, such as transforming growth factor (TGF)-
b, connective tissue growth factor (CTGF), and hypoxia
inducible factor (HIF).2–4 These inflammatory factors are
involved in keloid fibrosis, collagen production, and the
deposition of extracellular matrix. However, the patho-
genesis of keloids remain unclarified, and it is still one of
the most challenging diseases in clinical practice.
The treatment of keloids includes intralesional cortico-
steroid injections, laser therapy, cryotherapy, compression
therapy, surgery, and combination therapy. The first-line
therapy for keloids is intralesional corticosteroid injec-
tions. However, no methodology has yet emerged as the
“gold standard” of clinical care.1 Furthermore, the current
keloid therapies have many shortcomings, such as a long
treatment course, pain, and a high recurrence rate, which
lead to decreases in patient compliance and confidence
during treatment. Therefore, the exploration of novel and
more effective keloid treatment methods is extremely
urgent and important.
Stem cells are self-renewing pluripotent cells that are
classified as embryonic stem cells and adult stem cells in
∗ Corresponding author: Xiao-Dong Chen, Medical School, Nantong University,
Nantong 226001, Jiangsu, China, and Department of Dermatology, Affiliated
Hospital of Nantong University, Nantong 226001, Jiangsu, China.
E-mail: dermatochen@163.com.
Conflict of interest statement: The authors reported no conflicts of interest.
Copyright © 2019 Hospital for Skin Diseases (Institute of Dermatology), Chinese
Academy of Medical Sciences, and Chinese Medical Association, published by
Wolters Kluwer, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
International Journal of Dermatology and Venereology (2019) 2:3
Received: 23 March 2019, Revised: 3 June 2019, Accepted: 28 July 2019
doi: 10.1097/JD9.0000000000000041
renal fibrosis, pulmonary fibrosis, and urethral stricture.4–6
The fate of stem cells is determined by their microenvi-
ronment. Under normal conditions, the proliferation of
stem cells is tightly controlled. Stem cells with clonality,
pluripotency, and self-renewal capacity are present in
keloids, and these stem cells contribute to the pathological
environment required for the growth of benign tumor-like
cells.7 This suggests that there may be some triggering
factors in keloids that potentially enables the upregulation
of embryonic stem cell markers and the induction of cell
mesenchymal differentiation to form keloids.
To investigate this possibility, we reviewed the recent
application of stem cells in keloids and other fibrotic
diseases and summarized the potential therapeutic effects
of stem cells on keloids.
Possible mechanisms of stem cell therapy
Anti-proliferative effects
The production of keloids is closely related to the abnormal
proliferation of keloid fibroblasts (KFs). Studies have shown
that adipose-derived stem cell (ADSC)-conditioned medium
(CM) promotes the presence of G0/G1 phase cells in KFs, and
significantly reduces the proportion of G2/M phase cells,
thereby inhibiting the proliferation of KFs.8 Compared with
normal fibroblasts, KFs significantly reduce apoptosis under
serum-free culture conditions.9 Thus, the hyperproliferation
of KFs in keloids may be related not only to their rate of
division but also to their decreased apoptosis. ADSCs also
significantly increase the apoptosis of KFs.10 All of the
following mentioned mechanisms are summarized in (Fig. 1).
Antifibrosis
Chemotactic cytokine ligand 2/chemotactic cytokine
receptor 2
Monocyte chemoattractant protein-1, also known as
chemotactic cytokine ligand 2 (CCL2), is a profibrotic
factor that promotes fibroblast proliferation and collagen
formation via the TGF-b pathway. Current research
indicates that peripheral CD14+ monocytes from patients
with keloids induce fibroblast proliferation by releasing

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Zhang and Chen, Int J Dermatol Venereol (2019) 2:3
Figure 1. Mechanisms of different stem cells in treating keloids or other fibrotic diseases. Blue line: antiproliferation; red line: antifibrosis; black
line: anti-collagen deposition.
CCL2.11 Furthermore, CCL2 mediates the amplification of
the pro-inflammatory factor interleukin (IL)-17.12 Fibrosis is
reduced by the inhibition of CCL2 or by the antagonism of its
high affinity receptor, chemotactic cytokine receptor 2
(CCR2). In bleomycin-induced pulmonary fibrosis models,
amniotic fluid-derived stem cells (AFSCs) inhibit pulmonary
fibrosis by modulating the level of CCL2 both in vitro and in
vivo. The underlying mechanism by which AFSC reduces
CCL2 is thought to be that AFSC secretes matrix metal-
loproteinase-2 to induce the proteolytic cleavage of CCL2,
which induces the formation of the CCR2 antagonist
cleavage product. The hydrolysate of CCL2 is a receptor
antagonist of CCR2 with a high affinity for CCR2, but does
not induce a response when bound. CCR2 is expressed in
AFSCs, so the increase in CCL2 concentration has
chemotaxis to AFSC.4,6 Therefore, AFSC may inhibit fibrosis
of keloids through the CCL2/CCR2 pathway.
TGF-b1
TGF-b is a multifunctional cytokine that contains three
different isoforms (TGF-b1, TGF-b2, and TGF-b3) in
mammals and activates the membrane receptor serine/
threonine kinase complex composed of type II (TbRII) and
type I (TbRI) receptors. Upon TGF-b binding, TbRII
phosphorylates and activates TbRI, resulting in activation
of the TGF-b/Smad signaling pathway. The TGF-b/Smad
pathway plays an important role in cell growth, differentia-
tion, apoptosis, and proliferation.2 Furthermore, TGF-b1
plays a key role in the progression of fibrosis by inducing
matrix production via a Smad3-dependent mechanism.13
TGF-b1 levels are significantly reduced by bone marrow
mesenchymal stem cells (BM-MSCs) in a lung fibrosis model
and skin fibrosis model, resulting in a concentration-
dependent antifibrotic effect.14–16 TGF-b also significantly
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increases the expression of collagen I in KFs. The level of
collagen I upregulated by TGF-b in KFs is attenuated by
amniotic mesenchymal stem cells (MSCs). However, TGF-b
and amniotic MSC-CM do not affect the levels of collagen
III in keloids, mature scars, or normal skin fibroblasts.2
In addition to the Smad family, TGF-b1 also activates
the mitogen-activated protein kinase pathway, includ-
ing extracellular signal-regulated protein kinase, c-Jun
N-terminal kinase, and p38 kinase. P38 stimulates the
transcription and expression of TGF-b2 in KFs under serum
stimulation.17 Thus, ADSC-CM reduces collagen deposi-
tion and inhibits hypertrophic scar formation via the p38/
mitogen-activated protein kinase signaling pathway,18 and
may play the same role in keloids.
a-Smooth muscle actin
In keloids, the expression of a-smooth muscle actin (a-SMA)
is higher than that in mature scars and normal skin.2 In a
dermal fibrosis model, a-SMA expression is strongly positive,
suggesting that myofibroblasts are active in the formation of
skin fibrosis. MSCs promote myofibroblasts to remain
dormant and reduce the expression of a-SMA, suggesting
potential therapeutic value for keloids.19 The expression of
a-SMA in keloids is significantly upregulated by TGF-b,
while AFSC-CM significantly attenuates a-SMA expression
upregulated by TGFb in KFs.2
Connective tissue growth factor
CTGF is a 36–38-kDa stromal cell protein belonging to
the multifunctional cysteine-rich angiogenic inducer 61,
CTGF, and nephroblastoma-overexpressed family. CTGF
expression is induced by TGF-b, vascular endothelial
growth factor (VEGF), angiotensin II, and human growth
factor. However, TGF-b is the most important promoter
Zhang and Chen, Int J Dermatol Venereol (2019) 2:3
of CTGF expression. Continued overproduction of
CTGF was responsible for the maintenance of keloid
fibrosis, suggesting that inhibition of CTGF activity
may reduce keloid formation.3 In a renal fibrosis
model, human ADSCs significantly reduce the level of
CTGF.20
Anti-inflammatory response
Wound healing in the mammalian fetal period is scar-free,
as the healing process involves less inflammatory cells,
less inflammatory mediators, and a shorter inflammatory
reaction phase than that in the non-fetal period. The
oral mucosa has a similar extracellular matrix to
the fetal phase, and thus also has minimal scar forma-
tion.21 In recent years, inflammation has been recognized
as the leading cause of keloid formation. Therefore,
reducing the concentrations of inflammatory cells and
inflammatory mediators, and shortening the process of
inflammation are very important for the treatment of
keloids.
Inhibition of inflammatory cell infiltration
The development of keloids is closely related to the long-
lasting inflammatory response. Mouse ADSCs (mADSCs)
reduce the infiltration of neutrophils, macrophages, and T
lymphocytes in the inflammatory phase of lung injury,
suggesting that similar effects may be exerted in keloids.16
Inhibition of pro-inflammatory factors
IL-12 is a cytokine with a wide range of biological activities
that is mainly produced by activated inflammatory cells.
The expression of IL-12 is significantly increased in keloid
macrophages.22 The expressions of TNF-a and IL-12
mRNA in macrophages cocultured with mADSCs are
significantly downregulated in a dose-dependent manner,
indicating that mADSCs may control the inflammatory
response in keloids by inhibiting the expression of IL-12.16
IL-6 is a pleiotropic cytokine that is involved in the
inflammatory pathway, hematopoiesis and immune regu-
lation. Keloids are associated with IL-6 gene polymor-
phisms in Japanese and Chinese populations.23-24
Furthermore, BM-MSCs reduce the level of IL-6 in a liver
fibrosis model, suggesting that they may play the same role
in keloids.25–27
Anti-vascular factors
The mechanical biology of the dermis and blood vessels may
play an important role in the pathogenesis of scars. An
increase in wound tension may result in increased inflamma-
tion and vascular permeability as a result of the expansion of
the gap between the endothelial cells of the blood vessel wall.
This increase in vascular permeability allows inflammatory
cells to migrate into the interstitial space.28 Keloids have a
significantly greater degree of angiogenesis than normal skin.
Therefore, inhibition of angiogenesis may inhibit the
development of keloids by slowing down the inflammatory
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International Journal of Dermatology and Venereology
response. CD31+ and CD34+ vasculature in keloid tissue is
significantly inhibited by ADSC-CM.8
Inhibition of collagen production
TGF-b: is described earlier in “Antifibrosis” section.
Plasminogen activator inhibitor-1 (PAI-1) gene: PAI-1
plays an important role in the progression of tissue
fibrosis. ADSC-CM attenuates the accumulation of
collagen in keloids by inhibiting the expression of the
PAI-1 gene.8
Collagen I: The increase in extracellular matrix deposi-
tion is characterized by overexpression of collagen I and
collagen III, and ADSC-CM significantly downregulates
the expression of the collagen I gene, but has no significant
effect on collagen III expression.8 Similarly, BM-MSCs
reduce the level of collagen in a skin fibrosis model.15
Hypoxia inducible factor (HIF)-1a: After hypoxia, HIF-
1a, CTGF and VEGF are significantly upregulated in KFs
and normal fibroblasts, thereby increasing collagen
deposition.13 Human AFSCs inhibit the expression of
HIF-1a and reduce collagen deposition.4
Tissue inhibitor of metalloproteinase (TIMP)-1: TIMP-1 is
a glycoprotein of the TIMP family that may lead to the
deposition of collagen I in keloids.29 The level of expression
of TIMP-1 in keloids is significantly reduced by ADSC-CM.8
Heat shock protein 47 kDa (HSP47): HSP47 is an
endoplasmic reticulum-resident and collagen-specific
chaperone that recognizes the collagen hydrophobic
amino acid sequence (Gly-Pro-Hyp) and aids in the
secretion of correctly folded collagen. Elevated collagen in
keloids is associated with HSP47 expression.30 BM-MSCs
reduce the transcription level of HSP47 in a bleomycin-
induced skin fibrosis model.15
Inhibition of cell invasion
The enhanced invasiveness of dermal fibroblasts is a key
factor in the development of keloids, while ADSC-CM
significantly inhibits the invasion of KFs.8
Antibacterial activity
The formation of keloids is thought to be related to local
bacterial infections. Human MSCs mediate antibacterial
activity against Escherichia coli and Pseudomonas
aeruginosa by secreting the antimicrobial peptide LL-37.31
Stem cell treatment
Abnormally proliferating stem cells in keloids may be a
source of inflammatory factors.7 Thus, the introduction of
normally functioning stem cells or their secreted factors
may have a therapeutic effect on keloids.
Stem cell therapy is currently a hot topic, and stem cell
transplantation has achieved a certain amount of success.
Methods of stem cell transplantation include intravenous
injection and local injection. The injection of stem cell-CM
and topical stem cell-CM also has an effect on some fibrotic
diseases.
Zhang and Chen, Int J Dermatol Venereol (2019) 2:3
Intravenous injection
Intravenous injection is a very simple method of stem cell
transplantation. Many studies have shown that injury has a
chemotactic effect on stem cells, which provides a basis for
the intravenous injection of stem cells.32-33 For example,
BM-MSCs migrate to the site of liver injury.19
MSCs have special immunological properties, and
cord blood stem cells can escape the surveillance of the
immune system, even if they are incompatible with the
major histocompatibility complex. Thus, the intravenous
infusion of cord blood stem cells does not result in
serious adverse events.34 However, despite the chemotax-
is, systemic administration of cord blood stem cells
results in a massive loss of stem cells during transplanta-
tion. Therefore, researches are needed to improve the
effectiveness of stem cell transplantation.
ADSCs are easier to obtain than other types of stem
cells. During the extraction of ADSCs, N-acetylcysteine is
added to the swelling fluid used in liposuction, as N-
acetylcysteine protects ADSCs from oxidative stress and
increases the survival rate of ADSCs. N-acetylcysteine also
reduces the differentiation of ADSCs into mature adipocytes
and improves the survival rate of transplanted ADSCs.35 At
present, liposuction and fat transplantation techniques are
relatively mature and involve few ethical problems.
During the culturing of stem cells, the induction of MSCs
under hypoxic conditions (the creation of hypoxia-
preconditioned MSCs) results in increased inhibition of
extracellular matrix production by fibroblast cells com-
pared with normally cultured MSCs. However, it also
promotes the expression of HIF and VEGF and promotes
cell proliferation. As keloid development is a type of
hyperplastic disease and the expression of HIF and VEGF is
upregulated in keloids, hypoxia-preconditioned MSCs may
not be suitable for keloid treatment.36 The homing potential
of MSCs is improved by melatonin pretreatment, and
adenovirus-mediated overexpression of decorin in BM-
MSCs effectively prevents fibrotic changes in animal models
of cirrhosis.37-38 Other drugs can also synergize with stem
cells to increase the effectiveness of stem cell treatment.39
Local injection
Local injection of stem cells results in poor stem cell
survival rates. In an attempt to overcome this problem,
recent research has focused on stem cell scaffolds; the
effectiveness of stem cell transplantation is greatly
improved by the use of scaffolds, including umbilical
cord blood-derived MSC-seeded fibronectin-immobilized
polycaprolactone nanofibers, decellularized scaffolds, and
three-dimensional hydrogels.40
Stem cell derivatives
Stem cell research has recently focused on exosomes,
which are cell secretions containing proteins and micro-
RNAs that alter cellular activity in target cells.41 The
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therapeutic effect of stem cells is thought to be mainly
achieved through paracrine effects. The exosome con-
tains the paracrine factors of stem cells, and some studies
have even suggested that exosomes have the same
characteristics as their stem cells.42 Thus, exosomes
may replace stem cells as a more accessible and safer
treatment option.
Existing problems and prospects
Although most of the factors secreted by stem cells have a
therapeutic effect on keloids, there are still some
complications. A small number of stem cell types, such
as Wharton’s jelly-derived MSCs, enhance the expression
of the profibrotic marker PAI-1d while downregulating the
expression of the antifibrotic TGFb-3 gene and promoting
the proliferation of KFs.43 Furthermore, the transplanta-
tion of some stem cells, such as human AFSCs, promotes
VEGF expression and may be counterproductive to the
treatment of keloids.4 At present, most studies on keloids
are performed in vitro, and the lack of established animal
models makes it difficult to convert research findings to
clinical applications. In addition, the application of stem
cells is ethically controversial, which makes it difficult to
advance to clinical treatment. Despite these difficulties,
stem cells are becoming increasingly widely used in the
treatment of skin diseases. For example, hypertrophic
scars and acne scars are improved by fat grafting, the
intravenous injection of MSCs is being performed in
various animal model studies of systemic scleroderma, and
various bioscaffolds carrying stem cells are being used in
the study of skin wound healing.44–46 Due to the compact
nature of keloid tissue, stem cell scaffolds and exosome
sustained release devices may have good clinical prospects.
Conclusion
Stem cells can inhibit the proliferation of KFs and have
antifibrosis, anti-inflammatory response and other functions
that can inhibit the development of keloids. Furthermore, the
technology of stem cell transplantation is becoming more and
more mature. It appears that stem cells have invaluable
potential as a potential method for treating keloids.
Acknowledgement
The authors want to thank Dr. Matetei Pachuau for language help.
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