Received: 28 February 2021 Revised: 4 June 2021 Accepted: 7 June 2021

DOI: 10.1111/wrr.12954

PERSPECTIVE ARTICLE

Diabetic wound healing: The impact of diabetes on

myofibroblast activity and its potential therapeutic treatments

Rou Wan MD1 | Joshua P. Weissman BBA2 | Kendra Grundman DO3 |

Lin Lang MD4 | Damian J. Grybowski MD1 | Robert D. Galiano MD FACS1

1
Department of Surgery, Division of Plastic
and Reconstructive Surgery, Northwestern Abstract
University Feinberg School of Medicine, Diabetes is a systemic disease in which the body cannot regulate the amount of
Chicago, Illinois, USA
2 sugar, namely glucose, in the blood. High glucose toxicity has been implicated in the
Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA dysfunction of diabetic wound healing, following insufficient production (Type 1) or
3
Department of Surgery, Franciscan Health, inadequate usage (Type 2) of insulin. Chronic non-healing diabetic wounds are one of
Chicago, Illinois, USA
4
the major complications of both types of diabetes, which are serious concerns for
Department of Surgery, Shanghai New
Hongqiao Medical Center, Shanghai, China public health and can impact the life quality of patients significantly. In general, dia-
betic wounds are characterized by deficient chemokine production, an unusual
Correspondence
Robert D. Galiano, Department of Surgery, inflammatory response, lack of angiogenesis and epithelialization, and dysfunction of
Division of Plastic and Reconstructive Surgery,
fibroblasts. Increasing scientific evidence from available experimental studies on ani-
Northwestern University Feinberg School of
Medicine, 675 North Saint Clair Street, Suite mal and cell models strongly associates impaired wound healing in diabetes with dys-
19-250, Chicago, IL 60611, USA.
regulated fibroblast differentiation to myofibroblasts, interrupted myofibroblast
Email: rgaliano@nm.org
activity, and inadequate extracellular matrix production. Myofibroblasts play an
This article is part of a Special Issue on
important role in tissue repair by producing and organizing extracellular matrix and
Myofibroblasts.
subsequently promoting wound contraction. Based on these studies, hyperglycaemic
conditions can interfere with cytokine signalling pathways (such as growth factor-β
pathway) affecting fibroblast differentiation, alter fibroblast apoptosis, dysregulate
dermal lipolysis, and enhance hypoxia damage, thus leading to damaged microenvi-
ronment for myofibroblast formation, inappropriate extracellular matrix modulation,
and weakened wound contraction. In this review, we will focus on the current avail-
able studies on the impact of diabetes on fibroblast differentiation and myofibroblast
function, as well as potential treatments related to the affected pathways.

KEYWORDS
chronic wounds, extracellular matrix, fibroblast-to-myofibroblast differentiation, M2
phenotype macrophage, myofibroblast

Abbreviations: α-SMA, alpha smooth muscle actin; DAMP, damage-associated modifying

1 | INTRODUCTION
proteins; DFU, diabetic foot ulcers; ECM, extracellular matrix; FOXO1, forkhead box protein
O1; HIF-1, hypoxia inducible factor-alpha 1; HRE, hypoxia response element; IGF-1, insulin-
like growth factor 1; KGF-1, keratinocyte growth factor 1; M1, macrophage Type Diabetes is a systemic disease that results in hyperglycaemia either
1 phenotype; M2, macrophage Type 2 phenotype; MMP, matrix metalloproteinase; PAMP,
pathogen-associated modifying protein; PEMF, pulsed electromagnetic field; ROS, reactive
from an insufficient level of circulating insulin hormone or from insulin
oxygen species; SDF-1, stromal cell derived factor 1; Smad, mothers-against- resistant cells and organs.1 According to the International Diabetes
decapentaplegic-homolog; TGF-β, transforming growth factor beta 1; Thy-1, Thy-1 cell
Federation, approximately 463 million adults (age 20–79 years) were
surface antigen; TIMP, tissue inhibitors of metalloproteinases; TNF-α, tumour necrosis factor
alpha; VEGF, vascular endothelial growth factor. living with diabetes in 2019, and this number is predicted to rise to

Wound Rep Reg. 2021;29:573–581. wileyonlinelibrary.com/journal/wrr © 2021 The Wound Healing Society. 573
574
700 million by 2045. Diabetic chronic wounds are a serious concern
for public health in both the United States and worldwide. Compared
to the general population, those with diabetes are 10 to 20 times
2,3
more likely to undergo an amputation due to chronic ulcers. Wound
healing in diabetes is a complex response of biological and molecular
events and the influence of diabetes can be seen in all stages of
wound healing (Figure 1).
Normally, wound healing progresses through phases of inflamma-
tion, proliferation, and tissue remodelling. It is a complex process, and
any failure can cause different tissue repair scenarios. Myofibroblasts,
which play an essential role in the proliferation and remodelling phases
of wound healing, are defined as a heterogeneous group of cells that
produce and regulate collagen extracellular matrix (ECM) and promote
physical tissue integrity following injury.4 This transition of fibroblasts
into myofibroblasts is apparent by the expression of α-smooth muscle
actin (α-SMA) found in the stress fibres of myofibroblasts, which give
them their contractile properties5 Myofibroblasts rise from different
precursor cells. In skin and adjacent tissue layers, the precursor cells are
identified as fibroblasts, adipose tissue cells, smooth muscle cells, mes-
enchymal stem cells, and smooth muscle cells.6,7 In diabetes, experi-
mental and clinical evidence suggests that the progression of wound
healing can dysregulate myofibroblast differentiation from precursor
cells and subsequently lead to a lack of cellular proliferation, insufficient
deposition of the ECM, an increase in proteolytic activity, and a
decrease in wound contraction.
This review will describe and evaluate the impact of diabetes on
wound healing, myofibroblast biology, relevant signalling cascades,
and potential therapeutic treatments based on published experimental
and clinical studies. This article serves as a framework for the impact
of diabetes on the wound healing pathway and specifically
myofibroblast functionality (Figure 2). We will review five important
signalling pathways in diabetic wound healing, as well as other factors
that can interrupt normal wound healing process in diabetes.
2 | C HR O N I C H E A LI N G A F F E C T S A LL
P H A S E S O F W O U N D RE P A I R
During the inflammatory phase, neutrophils are replaced by macro-
phages after initiating healing and apoptotic cells are also phagocy-
tosed by macrophages. These newly arrived macrophages have a
continuum of phenotypes. The classical M1 phenotype induced by T-
helper 1 and the alternative M2 phenotype induced by T-helper
2 cytokines.8 M2 phenotype macrophages aid in shifting the wound
healing process towards the proliferative phase.9 They produce
WAN ET AL.
F I G U R E 1 The impacts of diabetes
on myofibroblasts can be seen in all
stages of wound healing
growth factors, such as insulin growth factor-1 (IGF-1), vascular endo-
thelial growth factor (VEGF), and transforming growth factor-β1 (TGF-
β1) that stimulate fibroblast differentiation into myofibroblasts.10
Contrary to the M2 phenotypes, the M1 macrophages are involved
with bactericidal, phagocytic, and pro-inflammatory roles.9 Diabetes
has been shown to deter the shift in M1 to M2 phenotype.10 Analysis
of diabetic wounds reveals elevated levels of oxidative stress, an apo-
ptotic cell burden, and a shift to M1 expression of macrophages.10
This chronic inflammatory state severely impairs the granulation tissue
formation, angiogenesis, and the epithelialization process of wound
healing.11
During the proliferative phase, dysregulated fibroblast to
myofibroblast differentiation results in impaired angiogenesis,
decreased secretion of ECM, and weakened wound contraction.10,12
Fibroblasts are mesenchymal cells with many important functions such
as aiding the dermal architecture and orchestrating the complex wound
repair and healing pathway.13–15 When injured, these fibroblasts differ-
entiate to a more active state namely terms myofibroblasts.16–18 In
addition, M2 phenotype macrophages facilitate re-vascularization and
wound re-epithelialization9,19 in the proliferative phase.20,21 Angiogene-
sis is necessary to support wound regeneration through oxygenation
and nutrient delivery to the hypermetabolic tissues.21 Thus, the lack of
M1 to M2 phenotype shifting can cause impaired angiogenesis that fur-
ther complicates chronic wounds in the proliferative phase.10,20 Signifi-
cantly delayed epithelialization in diabetes is also seen in non-healing
wounds.22 Typically, basal cells proliferate from the wound edges and
interact with the framework of the ECM created by myofibroblasts.
Without proper signalling intermediates and myofibroblast functional-
ity, keratinocytes are unable to migrate and formally epithelialize the
wounds.23,24 This is because keratinocytes need a basal lamina con-
taining basement membrane Type IV collagen on which to migrate.
They will not migrate on a fibrin clot ECM. This leads to delays in tissue
maturation, which eventually contributes to chronic non-healing
wounds and the impaired skin barrier.12
During the remodelling and maturation phase, myofibroblasts syn-
thesize and build up matrix metalloproteinase (MMP) to reconstitute
the ECM, and collagen III is replaced by a stronger collagen I to ensure
complete remodelling.25 Myofibroblasts also produce tissue inhibitors
of MMPs (TIMPs) which act to block MMPs and balance the degrada-
tion of the ECM.26 Hyperglycaemic conditions found in diabetes are
reported to induce higher levels of MMPs and reduced TIMPs, resulting
in abnormal ECM modification and chronic wound healing.26,27
There are many other factors, including decreased oxygenation,
non-enzyme glycosylation of tissues, hyperinflammation, malnutrition,
and insensitivity to heat and pain, that contribute to pathologic
WAN ET AL.
F I G U R E 2 The impacts of diabetes
on different wound healing signalling
pathways and specifically myofibroblast
functionality
wound healing in diabetes.28 However, based on experimental studies
on cell and animal models, the impairment in fibroblast differentiation,
delayed myofibroblast function and subsequent reduced amounts of
collagen fibres29 may be some of the major contributing factors to
chronic non-healing diabetic wounds. This remains a subject of ongo-
ing debate as a very limited number of human studies have been con-
ducted on the topic. Understanding the influence of diabetes on the
myofibroblast biological activity can help scientists and clinicians com-
prehend and manage diabetic wound healing more efficiently.
3 | E X P E R I M E N T A L S T U D I E S ON A N I M A L
A N D CE L L M O D EL S O N T H E I M P A CT S OF
DIABETES ON MYOFIBROBLASTS ACTIVITY
3.1 | Impact of diabetes on TGF-β/Smad signalling
pathway and macrophage phenotypes
A number of cytokines are essential in the wound closure process, in
particular TGF-β. One of the most notable activities of TGF-β is to
promote fibroblast proliferation and its differentiation
575
to myofibroblast, thus modulating collagen ECM deposition.30 The
impact of diabetes on TGF-β signalling happens in the canonical path-
way. The canonical pathway relies on the interplay between TGF-β
isoforms and specific transcription factors, including mothers-against-
decapentaplegic-homolog (Smad) proteins. Compound Smad 2/3 leads
to transcription and expression of α-SMA.31 Although there is no sin-
gle marker for complete myofibroblast differentiation, α-SMA has
been regarded as one of the most stable cytoskeletal components that
allows for its identification.32,33
In non-obese Goto-Kakizaki diabetic rats, which were produced
by repeating of selective breeding of Wistar rats with glucose
intolerance,34 the levels of TGF-β1 mRNA and protein were found to
be lower in platelets, macrophages, and fibroblasts nearby excisional
wounds, compared with non-diabetic rats.35 Thus, downstream Smad
signalling is affected. While Smad 2/3 is an indicator of TGF-β1 activ-
ity, Smad 7 negatively regulates TGF-β1/Smad signalling. In diabetic
wounds on Goto-Kakizaki rats, the impairment of TGF-β1/Smad sig-
nalling is further proven by decreased expression of Smad2 but aug-
mented expression of Smad 7.35 This resulted in downregulation of
the marker of myofibroblast differentiation and disturbed
myofibroblast proliferation.35 Wetzler's study tested cells at the
576
wound margins on genetically diabetic db/db mice and noticed
reduced levels of TGF-β.28,36 The homozygous db/db mice is a good
model to explore diabetes-associated disorders because the leptin
receptor activity is halted by the mutation of the diabetes gene (db),
leading to severe insulin resistance with significant hyper-
glycaemia.37,38 In order to study the effects of diabetes on wound
contraction and re-epithelization, Wang et al. utilized a db/db versus
db/m mice model to illustrate the db/db wounds presented with del-
ayed closure and impaired wound contraction.39 The diabetic dermal
fibroblasts also had significantly lower contractile ability. Additionally,
α-SMA levels were constantly lower in the db/db mice which repre-
sented lowered fibroblast to myofibroblast differentiation.39 Perhaps,
the biggest conclusion was that the TGF-β signalling pathway was
reduced which also may impair fibroblast to myofibroblast
differentiation.
Reduced levels of TGF-β1 can additionally lead to fewer M2 phe-
notype macrophages. As introduced above, M2 macrophages promote
myofibroblast formation by secreting certain growth factors, most
importantly TGF-β1. TGF-β1 in turn facilitates macrophage differenti-
ation towards M2 phenotype.40 The interfered interaction between
M2 phenotype macrophages and TGF-β1 in diabetic wounds contrib-
utes to halted fibroblast differentiation.34 Independent from TGF-β1
levels, diabetic mouse models have shown low M2 macrophage num-
bers and high M1-derived cytokines.41–43 This is because, as seen in
wounds of diabetic mice models, hyperglycaemia impairs macro-
phages' ability to efferocytose spent neutrophils,43,44 which causes an
10
increased number of neutrophils and apoptotic cells. Increased apo-
ptosis created by neutrophils enhances levels of pro-inflammatory
45
cytokines and this change in diabetic wounds impedes the process
of pushing M1 towards M2 phenotype.10 In conclusion, wound
healing cells found in hyperglycaemic conditions have reduced levels
of TGF-β and reduced number of M2 macrophages.
3.2 | Impact of diabetes on IGF-1 signalling
pathway
Another specific cytokine that also actively participates in the wound
healing pathway is IGF-1. It is responsible for the mitogenic action of
46
myofibroblast proliferation and fibroblast differentiation and plays a
key role in ECM collagen synthesis and stimulation of fibroblasts and
keratinocytes.46 IGF-1 is primarily found in the epithelium and the
47
later stages of granulation tissue development. During granulation,
tissue fibroblasts change structural and chemical characteristics to
resemble ultra-smooth muscle cells, focusing on α-SMA and microfila-
ment cells.47,48
IGF-1 levels normally increase during wound healing, but research
shows that this growth factor is decreased in the diabetic wound envi-
ronment on streptozotocin diabetic rats.49 Diabetes in these rats is
induced by a compound from Streptomyces achromogenes, which
is used for treating pancreatic β cell carcinoma and can therefore dam-
age β cells, causing hyperglycaemia. 50
Another study comparing the
expression of α-SMA between circular incision wounds in diabetic and
WAN ET AL.
non-diabetic rats also demonstrated that the diabetic group had sig-
nificantly less α-SMA expression 14 and 21 days after incision.46
Hehenberger and Hansson studied the effect of a hyperglycaemic
environment on fibroblast proliferation and growth factor-induced
cellular proliferation. After obtaining fibroblast cultures and altering
glucose concentrations, the group concluded that D-glucose levels at
15.5 mM and above, which are representative of hyperglycaemic con-
ditions in patients with diabetes, were shown to impair fibroblast pro-
liferation and cause cells to be resistant to growth factors such as
IGF-I and EGF.51 Besides animal and cell models, Blakytny et al.
highlighted the absence of IGF-1 proteins in the basal layer of
keratinocytes at the edge of the diabetic foot.52 The inadequate
amount of IGF-1 found in diabetic patients contributes, at least in
part, to lower levels of myofibroblasts and overall wound healing and
repair.52 In all, reduced expression of IGF-1 and the resistance to it in
diabetic wounds relates to retarded myofibroblast function.
3.3 | Impact of diabetes on hypoxia inducible
factor-1 signalling pathway
Hypoxia inducible factor-alpha (HIF-1) is an important factor in the
induction of myofibroblast differentiation, especially in hypoxia
wounds. Normally, in a hypoxia microenvironment, decreasing intra-
cellular pH triggers fibroblasts differentiation to myofibroblasts due to
the pH-dependent activity of TGF-β.53 Importantly, the increase of
lactic acid in damaged hypoxic areas results from HIF-1-mediated gly-
colytic metabolism.54 TGF-β can induce the transcription factor HIF-1
in an acidic environment and the overexpression of HIF-1 induces
hypoxia-induced myofibroblast differentiation.54 In addition, inhibition
of HIF-1 expression is found to inactivate the TGF-β-induced
myofibroblast differentiation.53 There is considerable evidence that
HIF-1 signalling is impaired in diabetes.55 Gao et al. reported
that hyperglycaemia inhibited HIF-1 mRNA expression directly by
lowering the hypoxia response element promoter transactivation.56
Catrina et al. showed that hyperglycaemia interfered with the stabili-
zation of HIF-1 by impairing its protective ability against proteasomal
degradation.57 Tissues from diabetic ulcer biopsy also displayed
reduced HIF-1 expression than in non-diabetic ulcers.58 Thangarajah
et al. stated that in pre-clinical models of diabetes cells, the HIF-1
defect is attributed to a methylglyoxalation event on an arginine resi-
due in cofactor p300 that prevents formation of the transcription and
activation of HIF-1 response gene, such as VEGF, and stromal cell
derived factor 1 (SDF-1).59 A failure to respond to hypoxic stimulus
due to a downregulation of HIF-1 has been shown to propagate
chronic hypoxia, impair myofibroblast differentiation and halt ECM
production.60
VEGF released by fibroblasts, macrophages, and epithelial cells
helps activate and phosphorylate endothelial nitric oxide synthase in
the bone marrow, which stimulates the mobilization of circulating
endothelial progenitor cells to the peripheral circulation.60 SDF-1α
helps the process of neovasculogenesis. In diabetic mice that were
treated with Streptozocin, Gallagher et al. showed impaired
WAN ET AL.
phosphorylation of endothelial nitric oxide synthase, which limits
mobilization from the bone marrow to the circulation.61 They also
highlight that SDF-1α was lowered in both epithelial cells and myo-
fibroblasts, which may be responsible for lack of endothelial progeni-
tor cells' inability to travel to wounds, as well as diminished wound
healing ability.61 Stimulation of angiogenesis is paramount in normal
wound healing, but hyperglycaemic conditions disrupt both the activa-
tion of HIF-1 and the angiogenesis process. These factors contribute
to the continual formation of chronic wounds.62
3.4 | Impact of diabetes on Notch1 signalling
pathway
To expand on the molecular mechanism of fibroblast dysfunction in dia-
betes, Shao et al. have recently identified the Notch1 signalling path-
63
way as a key regulator of the plasticity and function of fibroblasts in
wound healing and angiogenesis.64 The experimental study using db/db
mice found that the Notch1 signalling pathway was only activated in
the diabetic mouse but not in normal skin or non-diabetic wounds.63
Wound healing, in which Notch1 was activated in diabetic mice, was
also significantly delayed. Additionally, there were significantly fewer
myofibroblasts in the granulation tissues of the diabetic mice suggesting
that high levels of Notch1 present in diabetic wounds can inhibit fibro-
blast differentiation.63 Diabetic-induced Notch1 levels in fibroblasts
diminished their ability to modulate angiogenesis.63 This has several
implications for diabetic wound healing as the Notch1 pathway may be
a potential therapeutic agent for treatment of chronic diabetic wounds.
4 | IMPACT OF DIABETES ON
MYOFIBROBLAST APOPTOSIS
When functioning normally, myofibroblasts are highly specialized cells
that are differentiated early in healing and are removed after the gran-
4
ulation tissue phase. Retamal et al. concluded that diabetes leads to
delayed myofibroblast differentiation in the early healing phase, but
also noted that myofibroblasts were present in higher amounts at
later 15-day time points in diabetic rats induced by using
streptozotocin.29 The delay in recruitment at the beginning of the
repair process and a long-term persistence many days after the granu-
lation phase was only seen in the diabetic wounds. Many in vitro
models have shown that hyperglycaemia alters fibroblast physiology
leading to granulation refractoriness, senescence, and apoptosis.65
The apoptotic behaviour plays a significant role in chronic diabetic
wound healing. Using db/db mice, Siqueira et al. found that
diabetic wounds to have significantly higher levels of tumour necrosis
factor alpha (TNF-α), fibroblast apoptosis, caspase-3/7 activity, and
enhancement of the pro-apoptotic transcription factor, forkhead box
protein O1 (FOXO1).66 It has been recently noted that manipulating
TNF-α helps to reduce apoptosis and increase fibroblast proliferation
and myofibroblast density in diabetic mice.66 Similarly, Desta et al.
attributed the delay in epithelial and connective tissue repair to
577
increased apoptosis and reduced cell proliferation.67 The group partic-
ularly observed oral wound healing in both db/db mice and mice
treated with injection of streptozotocin and noticed enhanced cleaved
caspase-3 and increased FOXO1 nuclear translocation in fibroblasts in
diabetic wounds.67 Both pathways facilitate cell apoptosis and thus
result in decreased number of fibroblasts, which is the major precursor
cells for myofibroblasts. Molecularly, wounds in diabetic mice had sig-
nificantly larger numbers of TUNEL labelling apoptotic cells than the
wounds in control mice, and the differences were statistically signifi-
cant at both 7 and 14 days after the wounds were created. Further
investigation revealed that the identity of some of these apoptotic
cells were fibroblasts.68 While the exact mechanism is still not fully
defined, the interplay between diabetes and the apoptotic nature of
fibroblasts should be studied by means of additional experimental
models. Structurally, gap junctions between cells are essential for sig-
nalling of cell apoptosis including the removal of fibroblasts.69 Con-
nexins, which are the main gap junction proteins, have increased
expression in diabetic wounds.69 The upregulation of gap junction
synthesis can produce improper apoptotic signalling.
5 | EC M D E FE C T S I N D I A B E T I C W O U N D S —
A C O R E F UNC T I O N OF M Y OFI B R O B LASTS
GOES WRONG
5.1 | Impact of diabetes on MMPs and TIMPs
Many studies have indicated that the ratio of MMPs/TIMPs is elevated
in both diabetic wound cells and serum of diabetic patients or animal
models.70–72 Reduced TIMP levels lead to overactive MMPs function
and elevated MMPs proteins result in failure of ECM deposition in dia-
betic wounds.73–75 A study on urethral scars suggested that the expres-
sion of TIMP-1 and α-SMA in fibroblasts were positively correlated. The
group found TIMP-1 significantly raised levels of α-SMA, TGF-β and
subsequently induced transformation of fibroblasts to myofibroblasts.76
Moreover, in db/db mice, research has shown severe impairment in
VEGF production in combination with the pro-degradative activity of
fibroblasts due to the increased amount of MMP-9.77
5.2 | Impact of diabetes on the quality of ECM
ECM is not only diminished in diabetic wounds, but it is also secreted
with altered texture. Maione et al. developed 3D biomimetic in vitro
models that exhibit key features of impaired healing in diabetic foot
ulcers (DFUs).78 The group compared isolated primary fibroblasts from
DFUs to site matched diabetic and non-diabetic skin and found differ-
ences consistent with impaired angiogenesis, enhanced proliferation
of keratinocytes, diminished re-epithelialization and ECM deposition
associated with DFUs in vivo.79–81 Maione et al. further expanded on
their previous 3D models of DFUs and showed that fibroblast cell
strains from diabetic patients have overlapping patterns of gene
expression that exhibit different features and characteristics from
578 WAN ET AL.

TABLE 1 Potential therapeutic techniques or agents for diabetic wounds

Product/technique Author Year Title Type of study Conclusion

Photobiomodulation Mokoena 2020 Photobiomodulation at 660 nm Irradiated cell model comparing Increased α-SMA
et al. stimulates fibroblast diabetic to control wound (myofibroblast marker),
differentiation cells Thy-1 (fibroblast cell marker)
decreased in diabetic
wounds.
IGF-1 Achar RAN 2014 Use of insulin-like growth Rat model (diabetic vs. control) Increase in myofibroblast
et al. factor in the healing of open activity (per α-SMA activity),
wounds in diabetic and non- more rapid re-epithelization
diabetic rats. in diabetic wounds with IGF.
KGF-1 Peng et al. 2019 KGF-1 accelerates wound Rat model (treated with KGF-1 Secretion of functioning TGF-
contraction through the vs. control) β1 was induced by KGF-1
TGF-β1/Smad signalling and wound contraction was
pathway in a double- accelerated in a double-
paracrine manner. paracrine manner.
Jamun Honey Chaudhary 2020 Wound healing efficacy of Rat model (diabetic vs. control) Diabetic mice treated with
et al. Jamun honey in diabetic Jamun honey showed
mice model through re- enhanced wound closure,
epithelialization, collagen collagen deposition, and re-
deposition and angiogenesis. epithelization.
PEMF Choi et al. 2016 PEMF promotes collagen fibre Rat model (treated with PEMF A positive correlation was
deposition associated with vs. control) found between collagen
increased myofibroblast fibre deposition and
population in the early myofibroblast population on
healing phase of diabetic Day 7 in the PEMF-treated
wound. rats, indicating the potential
benefit on diabetic wound
healing.

Abbreviations: α-SMA, α-smooth muscle actin; IGF-1, insulin growth factor-1; KGF-1, keratinocyte growth factor 1; PEMF, pulsed electromagnetic field;
TGF-β1, transforming growth factor-β1.

those fibroblasts from healthy, control patients. The group demon-
strated that DFU-derived fibroblasts produced significantly thinner
ECM, which may be suggestive that the production of ECM may fur-
ther contribute to impaired wound repair.82 These ECMs were cov-
ered in fibronectin for an increased duration of time and responded
82
abnormally with the incorporation of TGF-β. Fibronectin has been
shown to provide a scaffold for collagen deposition and ECM
remodelling, but ultimately it must be replaced by a more mature and
lasting ECM during the healing process.83 The increased expression of
fibronectin has been well studied in the case of diabetic nephropathy,
but its role in diabetic wound healing remains a topic of debate.84
In humans, Black et al. analysed the effects of Types 1 and 2 dia-
betes mellitus and glycaemic control on the wound healing process in
85
diabetic patients. The group concluded that the deposition of
hydroxyproline, a major form of protein collagen, was significantly
impaired in Type 1 diabetic patients.85 Without proper hydroxyproline
formation, collagen cannot be properly twisted and stabilized.86
6 | P O T E N T I A L TH E R A P E U T I C A G E N T S
F O R D I A B E T I C WO U N D H E A L I N G
The lack of fibroblast to myofibroblast differentiation, excess inflam-
mation, diminished angiogenesis, and dysfunctional cytokines have
posed severe challenges to the complete repair of diabetic wounds.
Fortunately, there have been efforts to improve the complications of
diabetic wound healing (Table 1). Mokoena et al. were successful in
using photobiomodulation to stimulate the differentiation of fibro-
blasts into myofibroblasts in diabetic wounded cells.31 The technology
uses red or near infrared light to stimulate, rejuvenate, and revive
injured or damaged cells.76 The group noted this improvement in dif-
ferentiation was independent of the TGF-β/Smad pathway.31 The dia-
betic cell models all displayed a pattern of decreasing Thy-1
(a fibroblast cell marker) and increasing α-SMA. Photobiomodulation
has great potential for the healing of diabetic wounds. Given the defi-
ciency of IGF-1 in diabetic wounds, Achar and coworkers explored
the use of topical IGF-1 cream in a diabetic rat model as compared to
a control group.46 Macroscopic observations of wounds exemplified a
more rapid re-epithelialization and improvement of scarring in diabetic
wounds treated with IGF-1. Pertinent to myofibroblasts, the group
found on immunohistochemical analysis that revealed α-SMA
increased in the diabetic mice. A significant increase was observed in
the expression of myofibroblasts in the mice treated with IGF-1 com-
pared to those who had no application of IGF-1.46While promising
and in line with the current data supporting IGF-1 deficiency in dia-
betics, the results were only tested on animal models and need to be
applied to human patients before any significant conclusions can
be made.46
WAN ET AL.
Another promising treatment that involves myofibroblast markers
involves keratinocyte growth factor 1 (KGF-1). Loss of the KGF-1
gene in diabetic mice has been implicated in the failure of wound con-
traction.87 The authors further explored the role of KGF-1 in diabetic
wound contraction through the TGF-β1/Smad pathway and con-
cluded that diabetic wounds treated with KGF-1 had significantly
higher levels of myofibroblast markers TGF-β1, Smad3, and α-SMA
expression.87 It was found that Smad2 and p-Smad3 were significantly
higher expressed in those wounds treated with KGF-1 relative to con-
trols. Importantly, fibroblasts do not have KGF-1 receptors. Therefore,
KGF-1 accelerated the diabetic wound healing process through the
TGF-β1/Smad pathway in a paracrine manner.87 The exact mechanism
in KGF-1's role in wound contraction is still not clearly understood
but remains a continued point of research.
Another topic cream, namely Jamun honey, was tested against
the control FDA approved Manuka honey for diabetic wound healing
in an in vitro wound (primary fibroblasts) model and in an in vivo of
diabetic mice. Primary outcome variables included for wound re-epi-
thelialization, subepithelial connective tissue modification, and angio-
genesis in diabetic mice. It was found that diabetic mice treated with
Jamun honey showed significant (p < .05) wound closure, collagen
deposition, re-epithelization, and myofibroblast formation. The honey
also significantly modulated many of the previously discussed angio-
genic markers (VEGF, HIF-1α). The study concluded that Jamun had
similar efficacy to the already approved Manuka honey.88 With addi-
tional testing, this has the potential to rapidly accelerate the wound
repair process.
Finally, Choi et al. utilized pulsed electromagnetic field (PEMF) to
promote collagen fibre deposition and myofibroblast differentiation in
diabetic wounds.89 The rat study tested PEMF-treated diabetic rats
versus diabetic rats without PEMF administration. Among the PEMF-
treated rats, the researchers found significantly increased collagen
Type I on Day 7, but not on Day 10 or 14. A positive correlation was
reported between collagen fibre deposition and myofibroblast popula-
tion on Day 7 indicating the potential efficacy of this treatment for
diabetic wound healing.89
7 | C O N CL U S I O N
Myofibroblasts play an essential role in wound healing, particularly in
production of the ECM and wound contraction. Diabetes alters the
activities of myofibroblasts, thus impairing the process of wound
healing in all phases. Hyperglycaemic conditions interfere with cyto-
kine expression, dysregulate lipolysis, and amplify hypoxia-induced
damage. This leads to impairment in myofibroblast differentiation and
inappropriate ECM modulation, which can create a damaged wound
environment necessary for regeneration. Understanding the role of
myofibroblasts in diabetic wound healing can further benefit manage-
ment for non-healing diabetic wounds. Research on myofibroblast
activity in human diabetic wounds is limited and further exploration
on the impact of diabetes on human myofibroblasts should be
conducted.
579
CONFLIC T OF INT ER E ST
The authors report no conflict of interest.
SOURC E OF FUND ING
None.
OR CID
Rou Wan https://orcid.org/0000-0002-9029-4721
Joshua P. Weissman https://orcid.org/0000-0002-5344-5236
Kendra Grundman https://orcid.org/0000-0001-8921-1266
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How to cite this article: Wan R, Weissman JP, Grundman K,
Lang L, Grybowski DJ, Galiano RD. Diabetic wound healing:
The impact of diabetes on myofibroblast activity and its
potential therapeutic treatments. Wound Rep Reg. 2021;29:
573–581. https://doi.org/10.1111/wrr.12954