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7 Physiology andPathophysiology ofWound Healing inDiabetes
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The inammatory response is further exacerbated and
prolonged due to polymicrobial infection of the wound, usually with biolm-forming bacteria that together sustain the
inux of proinammatory cells and at the same time impede
host response to infection [314–316]. In addition, it was
found that the accumulation of intracellular S. aureus in the
epidermis of DFUs suppressed the antimicrobial peptide
perforin- 2 and triggered AIM2 inammasome activation
leading to pyroptosis, an inammatory form of cell death,
contributing to inhibition of healing [317]. Previous studies
have considered neutrophils to be elevated in chronic wounds
compared to acute wounds [228, 318, 319]. However, recent
studies have demonstrated neutrophil presence to be location
specic in which neutrophils are abundant in the wound bed
and absent at the wound edge of DFU [101, 103]. At the
wound edge, decreased neutrophil recruitment was found to
be due to the suppression of transcriptional regulators
involved with immune cell function and recruitment that
include FOXM1 and STAT3 [101]. Increased presence of
neutrophils in the wound bed is attributed to attenuation of
neutrophil apoptosis and phagocytosis [103]. T cells have
been shown to play a major role in regulating the wound
healing response through local secretion of growth factors
and exerting antimicrobial effects [320, 321]. T cells isolated
from chronic wound patients are less responsive to
stimulation and are functionally impaired [320]. In normal
wounds, CD4 and CD8 T cells are recruited to the site of
injury and peak around 5–7 days post-wounding [322]. It
was demonstrated that the depletion of either CD4 or CD8 T
cells resulted in impaired immune cell recruitment of macrophages and neutrophils and displayed a deregulated cytokine
prole [322]. However, despite these signicant changes in
immune cell recruitment and cytokine proles, depletion of
either CD4 or CD8 T cells did not signicantly impair wound
healing. Regulatory T cells (Tregs) have also been demonstrated to play an important role in wound healing. Specic
ablation of Tregs in murine models of wound healing resulted
in delayed wound healing with decreased INFγ expression
and macrophage recruitment [323]. In addition, the depletion
of Tregs facilitated the expansion of αβ T-cell populations
with profound changes in the cytokine milieu, further contributing to impaired healing [324]. Gamma-delta (GD) T
cells have also been shown to play a major role in regulating
wound healing and are the predominant T-cell population
present in the epidermis [321]. It was demonstrated that
Staphylococcus epidermidis-activated GD T cells induce
expression of perforin-2 which correlated with an enhanced
ability of skin cells to eliminate intracellular infections [325].
Moreover, GD T cells promote wound healing by secretion
of several growth factors that include KGF1 and IGF1 that
enhances keratinocyte proliferation and migration. Depletion
of GD T cells resulted in defects of keratinocyte proliferation
and epithelization and delayed wound healing [326, 327].
The nuclear factor-like 2 (Nrf2)-mediated oxidative stress
response pathway plays a role in protecting cells against oxidative damage and promoting detoxication [328–330].
Nrf2 contributes to acute wound repair by regulating inammation and promoting survival of keratinocytes under stress
conditions [331]. Decreased levels of Nrf2 is associated with
increased oxidized proteins, and high glucose induces intracellular ROS in diabetic patients [332, 333], indicating an
important role for Nrf2 in diabetic wound healing.
Furthermore, in a streptozotocin-induced diabetic murine
model, Nrf2 knockout mice exhibited a delay in wound healing compared with Nrf2
+/+
mice, partly as a result of higher
oxidative DNA damage, increased MMP9 expression and
apoptosis, and low TGF-β1 expression levels [334, 335].
Infected DFUs are responsible for around 60% of lowerleg amputations [336, 337]. Local infection triggers the activation of neutrophils and causes the release of neutrophil
extracellular traps (NETs). NETs are chromatin structures
associated with antimicrobial molecules that serve to remove
dead cells and infectious microorganisms [71, 72].
Neutrophils die by NETosis once infection is controlled [75].
However, deregulated NETosis can lead to tissue damage
and excessive inammation [338, 339]. High-glucose levels
and hyperglycemia are shown to increase NETs release and
circulating markers of NETosis in diabetic patients [340,
341]. Furthermore, NETosis has been shown to delay dia-
betic wound healing in humans and murine models [242].
Inhibition of the FOXM1 transcription factor was shown to
increase ROS levels leading to increased NET formation and
inhibition of wound healing in DFU [243]. In addition,
TREM1 activation was found to promote FOXM1+ neutrophil recruitment, inhibit NET formation, and reversed effects
of diabetes to promote healing in a diabetic mouse model of
wound healing [243], suggesting the therapeutic potential of
TREM1 modulation for chronic DFU.
Stem andProgenitor Cells inWound Healing
The ability of the skin to replenish itself and contribute to
tissue renewal and the overall wound healing process relies
on resident epidermal stem cells. They are found in three distinct stem cell niches in the skin, including the basal layer of
the epidermis (stratum basale), the base of sebaceous glands,
and the “bulge region” of the hair follicle [342–344]. The
microenvironments of these niches are important for modifying the activity and fate of the stem cells that reside in them
[345, 346]. Stem cells have been shown to mobilize and
migrate to areas of wounded and ischemic skin tissue where
they promote wound healing, reepithelialization, and angiogenesis [342, 347–350].
There are two proposed mechanisms by which stem cells
maintain homeostasis of healthy epithelium. In the classic
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hierarchical model, stem cells in the basal layer give rise to
transit amplifying daughter cells, which undergo a nite
number of cells as they travel upward before becoming terminally differentiated [342, 351, 352]. In this model, the
stem cells and their progeny are organized in epidermal proliferative units. The stochastic model of homeostasis has
emerged to challenge the classic model. In the stochastic
model, epidermal stem cells can divide an unlimited number
of times into two undifferentiated basal cells, two terminally
differentiated cells, or one of each [342, 347, 353–355].
Studies support both models, which is most likely explained
by variations in epidermis at different anatomical sites [342,
354]. Resident stem cells are quiescent in healthy unwounded
skin; however, they lose their quiescence in response to
injury and are recruited to replace the damaged tissue [356–
358]. A recent landmark study has revealed epigenetic mem-
ory of epidermal stem cells, relying on chromatin
modications imprinting the past exposures to inammatory
stimuli and enhancing the potential of a skin stem cell to
respond to future wounding stimuli [359, 360]. In addition to
their role in proliferative renewal of the epidermis, there is
new evidence that epidermal stem cells can modulate and
accelerate diabetic wound healing process indirectly through
paracrine signaling mediated by exosomes loaded by miRNA
with regenerative capability [361]. In addition, extensive
research has conrmed the ability of mesenchymal stem cell
(MSC) exosomes to induce proliferation and migration of
broblasts in both acute and chronic wounds, as well as promote angiogenesis [62, 342, 362–365]. Exosomes are small
membrane-bound vesicles 30–120nm in diameter secreted
by many different cell types that contain nucleic acids, proteins, and lipids and function in intercellular communication
[62, 366]. The use of exosomes provides an advantage over
stem cells due to their greater stability allowing prolonged
shelf life, decreased immunogenicity, and decreased risk of
tumor formation [362, 366–368]. Multiple studies have evaluated the efcacy of exosomes from multiple stem cell
sources, as well as their use with various delivery approaches
such as hydrogel and a microneedle patch [369, 370]. Current
literature reports the success of epidermal stem cell exosomes, adipose-derived stem cell exosomes, MSC exosomes,
and umbilical cord blood-derived exosomes in promoting
wound healing through decreasing inammation, accelerating proliferation, stimulating angiogenesis, inducing M2
polarization of macrophages, and promoting collagen synthesis [361, 371, 372]. Exosomes have been studied in various conditions including hypoxia and diabetes and have been
shown to promote wound healing [373–375]. Exosomes provide the additional advantage of promoting regeneration of
skin appendages and decreased scarring [376]. Recent studies have extensively explored the effects of different exosome-derived noncoding RNAs on angiogenesis. Exosomal
circRNA-itchy E3 ubiquitin protein ligase (circ-ITCH) from
BM-MSCs was shown to inhibit ferroptosis and induce
angiogenesis through activation of nuclear factor erythroid
2-related factor 2 (Nrf2) signaling pathway invitro and in
mouse models [377]. CircHIPK in exosomes protected endothelial cells from hyperglycemia via the miR- 20b- 5p/Nrf2/
VEGFA axis [378]. Exosomes isolated from umbilical cord
MSCs were also shown to promote angiogenesis through the
miR-106a-5p and FGF4/p38MAPK pathway [379].
Improved understanding of the exosome-mediated paracrine
effects of stem cells and enhanced delivery mechanisms will
allow development of novel therapies for diabetic wound
healing.
Because of their diverse functions and major role in the
wound healing process, stem cells have been extensively
explored as potential treatment for chronic wounds, especially DFUs. Stem cells from various tissue sources have
been used successfully to treat both acute and chronic
wounds and have been shown to accelerate wound healing,
facilitate reepithelialization, and promote angiogenesis
[380–382]. To date, many lines have been identied to have
therapeutic potential including MSCs, bone marrow-derived
mesenchymal stem cells (BM-MSCs), umbilical cordderived MSCs, adipose-derived stem cells (ADSCs),
placenta- derived stem cells, bone marrow-derived mononuclear cells (BM-MNCs), and bone marrow-derived endothelial progenitor cells [62, 342, 348, 380, 382–385]. MSCs
have received the most attention and are most commonly
used in animal studies, preclinical, and clinical trials so far
[342, 380, 386, 387].
Autologous application of isolated lines of either
BM-MSCs or BM-MNCs has consistently been shown to
improve wound healing rates and epithelialization [388,
389]. Additionally, bone marrow progenitor cells have been
shown to improve peripheral circulation and boost angiogenesis in humans to support wound healing [386, 387, 389].
However, the regenerative capability of MSCs may be
affected by an aging phenotype characterized by increased
oxidative stress, which was successfully reversed by ectopic
overexpression of catalase that induced estrogen receptor
signaling, reduced oxidative stress, and promoted wound
closure in human exvivo wound model [390]. Recognizing
and overcoming the age-related impairment of the regenerative functions of stem cells should be addressed in the future
studies utilizing both MSCs and their exosomes as a therapeutic modality for wound healing disorders.
Hematopoietic stem cells are another family of progenitor
cells gaining attention for their potential application to
chronic wound healing and DFUs, especially their potential
to improve circulation in diabetic limbs. CD34+ endothelial
progenitor cells are the most abundant and thus are the most
frequently studied. Additionally, there is new evidence that
CD34+ cells are lacking or decreased in nonhealing ulcers
[298], which further supports the exploration of these pro-
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genitor cells in DFUs and their therapeutic potential. These
cells can be isolated from bone marrow or peripheral blood
after administration of cytokines like granulocyte macrophage colony-stimulating factor (GM-CSF) [348]. So far,
animal studies have been promising, but there have been no
major trials yet in humans. A small pilot study with ve
patients in Japan demonstrated the safety and feasibility of
CD34+ endothelial progenitor cells in patients with nonhealing DFUs [391], but larger multicenter studies are needed
before their efcacy in chronic diabetic wounds can be properly assessed [392].
Adipose tissue is emerging as another source of progenitor cells. ADSCs are enticing because they are easily obtained
through liposuction procedures, and adipose tissue is more
abundant than marrow or other sources [348, 390, 393, 394].
There is growing evidence of their efcacy in animal models
[348], but there are limited human trials at this time. One
recent, small randomized controlled trial (RCT) showed the
efcacy of ADSCs in decreasing time to closure in DFUs
[395]. The major limitation for ADSCs is that it is very difcult to degrade the surrounding tissue to isolate the stromal
vascular fraction or the ADSCs contained therein. Additional
RCTs are needed to further investigate the healing capacity
of ADSCs.
Human amnion and chorion membranes have also come
forth with potential to improve healing in chronic lower
extremity wounds. Partly, interest has arisen because fetal
skin wounds repair rapidly and without any scar formation,
although the exact mechanisms are not fully understood.
These membranes have been found to promote tissue regeneration, wound healing, and even recruiting resident stem
cells into wounded areas [396, 397]. Recently, an RCT
showed that a placental membrane with growth factors,
MSCs, broblasts, and epithelial cells showed signicantly
improved healing and less complications than standard of
care therapy in human DFUs [398]. Although this does not
prove efcacy for placental membranes or MSCs individually, it further supports the concept of using combined
approaches when managing these difcult to heal wounds
[399]. In short, placental products and membranes have the
potential to improve treatment of chronic wounds by improving wound healing themselves and by supporting stem cells.
Lastly, recent developments allow for the reprogramming
of differentiated somatic cells into induced pluripotent stem
cells (iPSCs) [1, 223–225, 342]. Many different cell lines
can be serve as a source of iPSCs in humans including keratinocytes, broblasts, lymphocytes, and liver cells [342],
which can be reprogrammed via retroviral transduction [223,
400]. iPSCs have been shown to differentiate into many cell
types including broblasts and keratinocytes, which have
been used to create human skin equivalents [1, 224]. One
potential remedy to bypass DFU broblasts healing impaired
epigenetic memory is to reprogram these broblasts into
“normal,” pro-healing, broblasts. In a series of recent studies, broblasts from chronic DFUs and reprogrammed into
iPSC to regain normal cellular functions. These iPSCs were
then transformed back into normal broblasts [222–225]. In
an array of functional assays, these reprogrammed broblasts displayed enhanced healing capabilities that was, in
part, attributed to miRNA-induced epigenetic reprogramming [224, 225]. The advantages of iPSC include that they
can be derived from autologous cells to circumvent rejection,
can produce a multitude of differentiated cells necessary for
wound healing, and can be reprogrammed into specically
desired cell types. Disadvantages include cancer risk due to
the use of retroviral vectors, inefcient reprogramming
resulting in low iPSC yield, genetic instability, and potential
immunogenicity [401]. However, newer techniques for safer
reprogramming are in development. Thus, iPSCs are an
intriguing source of progenitor cells with the potential to
improve DFU wound healing in the future.
Stem cells and progenitor cells can be delivered to wounds
locally (e.g., sprays or injections) or systemically [342, 348,
402]. Systemic administration carries the added risk of cell
trafcking and malignancy as well as difculty targeting the
cells to the wound [348]. Direct application of stem cells has
been hindered by low cell proliferation and survival rates with
a lack of persistence in the wounds [403]. Thus, there is a
strong need for alternative strategies to optimize cellular therapy. So far, skin scaffolds and dermal matrices have been
developed to enhance cell survival. They can be classied as
natural, synthetic, or hybrid, and they promote cell proliferation and regeneration by providing a spatiotemporal environment [342, 404, 405]. Examples of these include the successful
direct application of autologous MSCs with a brin spray system in both acute and chronic wounds in humans and mice
[406], application of autologous BM-MSCs embedded in collagen matrices [407], and delivery of ADSCs within natural
and synthetic scaffolds [385, 408, 409].
In summary, there is tremendous interest and profound
therapeutic potential for stem cells and their exosomes in the
eld of chronic wounds and DFUs. They have shown promise in promoting reepithelialization, angiogenesis, and
improving the overall wounding healing process. Although
showing great promise, it is important to remember that no
stem cell therapy to date has accumulated enough evidence
to earn FDA approval for treatment of chronic wounds.
Because the pathogenesis of DFUs is so complex, it is
likely that future treatments for these hard to treat wounds
will involve a multimodal approach utilizing stem cells along
with other local and systemic therapies. However, each DFU
has some unique characteristics and a more personalized
approach incorporating better diagnostic tools, standard of
care, plus newer adjunctive and advanced treatments will
likely prove to be the most effective at promoting successful
wound healing. Despite the recent advances, the most effec-
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tive treatment regimen has yet to be determined, and further
research in this area is needed to optimally manage this devastating complication of diabetes.
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