Hindawi

Mediators of Inflammation
Volume 2017, Article ID 5217967, 14 pages
https://doi.org/10.1155/2017/5217967

Review Article
Advances of Stem Cell Therapeutics in Cutaneous Wound
Healing and Regeneration

Suman Kanji1 and Hiranmoy Das2

1
Cardiovascular Stem Cell Research Laboratory, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
2
Vascular Biology and Stem Cell Research Laboratory, Department of Biomedical Sciences, School of Pharmacy, Texas Tech
University Health Sciences Center, Amarillo, TX 79106, USA

Correspondence should be addressed to Hiranmoy Das; [email protected]

Received 13 May 2017; Revised 14 August 2017; Accepted 13 September 2017; Published 29 October 2017

Academic Editor: Juarez A. S. Quaresma

Copyright © 2017 Suman Kanji and Hiranmoy Das. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.

Cutaneous wound healing is a complex multiple phase process, which overlaps each other, where several growth factors, cytokines,
chemokines, and various cells interact in a well-orchestrated manner. However, an imbalance in any of these phases and factors
may lead to disruption in harmony of normal wound healing process, resulting in transformation towards chronic nonhealing
wounds and abnormal scar formation. Although various therapeutic interventions are available to treat chronic wounds, current
wound-care has met with limited success. Progenitor stem cells possess potential therapeutic ability to overcome limitations of
the present treatments as it offers accelerated wound repair with tissue regeneration. A substantial number of stem cell therapies
for cutaneous wounds are currently under development as a result of encouraging preliminary findings in both preclinical and
clinical studies. However, the mechanisms by which these stem cells contribute to the healing process have yet to be elucidated.
In this review, we emphasize on the major treatment modalities currently available for the treatment of the wound, role of
various interstitial stem cells and exogenous adult stem cells in cutaneous wound healing, and possible mechanisms involved in
the healing process.

1. Introduction venous ulcers. In current medical practice, chronic cutaneous

wound healing often demands a major, long-term medical
Skin, the largest organ of the body, has multiple important attention and consumes a substantial amount of expenses
functions, such as acts as a barrier to foreign pathogens, [4]. The cost of treatment related to wounds and associated
regulates body temperature, supplies sensation, and prevents complications exceed $20 billion annually in the US [5]. For
dehydration of the body [1]. An open wound could be example, a diabetic foot ulcer typically costs around $50,000
defined as a type of injury in which the skin is torn, cut, or to treat due to its refractory nature and continuous care [6].
punctured resulting in disruption of normal anatomic struc- Thus, enormous effort has been invested in developing
ture and function [2]. Normal wound healing process is innovative and efficient therapies to improve wound healing.
composed of a well-orchestrated process of cell migration, Current wound care has limited success and is very
proliferation, and extracellular matrix deposition undergoing expensive. Thus, the approach of regenerative medicine has
three overlapping but distinct phases of inflammation, prolif- emerged as an alternative to improve the outcome of healing
eration, and maturation [3] and is a critical survival factor for and has potential in reducing continuous economic burden.
an individual. Disruption of the cellular and molecular sig- Regenerative therapy mainly focuses on stem cells that have
nals in conditions such as diabetes, infection, or radiation the ability to self-renew and differentiate into multiple cell
exposure may result in an inefficient healing. The skin wound types and is crucial for physiologic tissue renewal and for
might be of different nature and varies from surgical to acci- regeneration after injury. As the understanding of stem cell
dental lacerations, burns, pressure ulcers, diabetic ulcers, and biology grows through basic research, including preclinical
2 Mediators of Inflammation

models, stem cell-based therapies are increasingly evident cascades of inflammatory reactions and prevent infection
in translational medicine. Current review emphasizes the (Figure 1(b)). PMNs are removed by macrophages through
understanding of the role of different endogenous and apoptosis, called PMN debridement via slough eschar
adult stem cells in cutaneous wound repair. [9, 12]. Monocytes come to the wound bed after PMN and
transform into macrophages, which are abundant during
2. Events in Normal Wound Healing Process day 2 and 3 but remain there for weeks. Different factors,
such as macrophage chemoattractant protein- (MCP-) 1,
The skin consists of three layers such as epidermis, der- macrophage inflammatory protein- (MIP-) 1α, vascular
mis, and hypodermis. The epidermis, most outer layer, endothelial growth factor (VEGF), PDGF, and transforming
consists of multilayered epithelium extending from the growth factor- (TGF-) β, attract monocytes to the wound
basement membrane, which separates the dermis to the bed, and activated macrophages secrete IL-1α, IL-1β, IL-6,
air. It is devoid of extracellular matrix (ECM) except the and TNF-α to perpetuate inflammatory reactions [9]. This
basement membrane. The basement membrane contains inflammatory phase lasts for the first 4 days in normal
progenitor cells, which undergo continuous self-renewal wound healing process [13]. Besides eliminating microbes
and differentiate into keratinocytes. The keratinocytes and debris, these inflammatory cells also initiate repair
migrate towards the surface of the skin where they even- and mediate angiogenesis as the wound exits its inflam-
tually undergo terminal differentiation and maturation [3]. matory phase.
These keratinocytes form a keratinized layer of dead cells
at the skin surface, which provides the main barrier [7]. 2.2. Tissue Remodeling. Inflammatory cells promote the
The dermis is the thickest of the three layers of skin, recruitment and proliferation of fibroblasts, vascular endo-
which is present just below the epidermis. The dermis is thelial cells, and keratinocytes during the proliferative phase
a connective tissue comprised of fibroblasts, ECM, vascu- [14]. Approximately 4 days after injury, the provisional
lar endothelial cells, and skin appendages (hair follicles, ECM begins to be replaced by the granulation tissue (GT).
sweat glands) [7]. Fibroblasts secrete molecules like colla- GT is composed of fibroblasts, collagen, blood vessels, and
gen and elastin, which provide mechanical strength and macrophages. Fibroblasts are one of the most important cell
elasticity to the skin. The hypodermis underneath the der- types in the wound healing process. Several matrix metallo-
mis is composed of adipose tissue, which provides insula- proteinases (MMPs), such as MMP-1, -2, and -3, play
tion and cushioning between the skin and other skeletal important roles in migration of fibroblasts into the provi-
structures, like bone and muscle [7]. Cutaneous wound sional wound matrix. Fibroblasts secrete collagen, increased
healing process is imperative to restore a skin defect and the amount of deposited collagens, especially collagen-I,
to regain lost integrity, tensile strength, and barrier func- and enhance cross-linking, which resulted in an increase
tion of the skin [8]. Cutaneous wound repair is a multi- in mechanical strength of the wound. Collagen production
faceted process involving inflammation, proliferation, and begins approximately 3 to 5 days after tissue injury and is
tissue remodeling [9]. stimulated by a number of growth factors, including PDGF,
TGF-β, epidermal growth factor (EGF), insulin-like growth
2.1. Inflammation. The wound healing process starts with factor (IGF)-1, and fibroblast growth factor- (FGF-) 2 [9].
coagulation and fibrin clot formation called hemostasis. Fibroblasts differentiate into myofibroblasts, which pro-
Platelets from damaged cutaneous blood vessels are motes wound contraction and results in reduction of the
exposed to ECM upon injury and damage. Fibrin binds wound area.
to monocytes and neutrophils through integrin CD11b/
CD18 receptor and participates in the inflammatory phase. 2.3. Proliferation. Neovascularization also occurs in concert
Fibrin also binds to endothelial and fibroblast cells via with the help of invaded capillaries, recruited vascular endo-
αvβ3 integrin [10] and stimulates angiogenesis. Platelets thelial cells, and endothelial progenitor cells to support the
and mast cells release diffusible factors, such as tumor newly formed tissue and to transport circulatory cells to the
necrosis factor- (TNF-) α and platelet-derived growth fac- wound [4]. Endothelial cell migration is initiated on day 2
tor (PDGF), and exert inflammatory response [11]. Local of postwounding and stimulated by VEGF, FGF, angiopoie-
inflammatory agents, such as activated complement and tin, and TGF-β. Several MMPs including MMP-1, MMP-2,
histamine, cause redness and swelling. This matrix is rap- MMP-9, MMP-19, and membrane associated MT-MMPs
idly invaded by neutrophils, followed by monocytes, and play crucial a role in various aspects of angiogenesis. Deposi-
other immunocompetent cells to remove dead tissues and tion of GT mediates reepithelialization to the provisional
control infection. Polymorphonuclear cells (PMNs) are wound bed. Keratinocytes migrate from the wound edges
the first inflammatory cells to arrive at the site of a cuta- and proliferate on the surface of the GT [13]. For the progres-
neous wound in large numbers between 24–48 hours sion of wound healing, bidirectional interactions between
[12]. Several growth factors and cytokines, such as inter- keratinocytes and fibroblasts are necessary by creating a
leukin (IL)-8, PDGF, and growth-related oncogene paracrine loop [9, 15]. Occurrence of GT usually observed
(GRO)-α/CXCL1 chemokine (C-X-C motif) ligand, are between 5 to 20 days of postwounding [7]. In the maturation
involved in drawing PMNs to a wound bed [9]. These phase, the wound becomes reepithelialized and the dermis
PMNs are the major source of proinflammatory cyto- regains most of its tensile strength. After complete wound
kines, such as IL-1α, IL-1β, IL-6, and TNF-α, and exert closure, tissue remodeling takes place below the epidermis
Mediators of Inflammation 3

and may take up to a year or longer to complete [3]. In adults, was successfully engineered in the laboratory for clinical
a mature, nonerythematous flat linear scar formation is the application. There were two approaches to develop bioengi-
hallmark of an ideal wound healing [16]. neered skin, matrix-based product, where biodegradable
matrix was used and the cell-based products, where cells were
3. Acute and Chronic Wounds used for the application. There are bioengineered skin con-
structs, which are currently available and approved for clini-
Acute cutaneous wounds resulted from a trauma, which cal practice for the treatment of diabetic neuropathic ulcers.
undergo a repair process and lead to a benign scar when A bilayer living skin construct is also approved for venous
the repair process is orderly and timely [2]. Failure of this and diabetic ulcers. Integra® is the first commercially avail-
process may lead to an undesirable scar or a nonhealing able engineered skin substitute used for deep burn wound.
wound due to the extended wound area or the depth Cross-linked collagen and chondroitin-6-sulfate copolymer
exceeds the patient’s ability to heal (Figure 1). The ability are mixed together to form the dermal matrix. A silicon sheet
to heal diminishes in different pathological conditions. is used which acts as a temporary epidermal layer [26]. Allo-
Patients with chronic wounds (most notably diabetic foot derm® is another skin substitute, specifically a dermal substi-
ulcers) have underlying conditions, such as high blood tute, used for both wound repair and reconstructive surgery.
sugar level and obesity, that impair wound healing. Pressure This dermal substitute is made up of human cadaver dermis
ulcers and venous ulcers are also some of the most com- and used successfully for a full-thickness burn. Alloderm has
mon forms of chronic wounds. Chronic wounds are fre- reduced angiogenic components due to the risk of graft rejec-
quently linked to old age [17] and correlates with a poor tion [27]. Epicel™ is an example of a cultured autologous epi-
reservoir of fully functional stem cells [18–20]. It is also dermis made up of human keratinocytes and used as an
linked with the age-related decreased strength and elasticity epidermal substitute for burned wounds, acute wounds, and
of skin and decreased blood flow to the extremities due to chronic wounds [27]. Although Epicel has a little risk of
sedentary lifestyle and smoking [7]. Several studies suggest rejection for large area wound coverage, this graft has limita-
that psychological stress have a negative impact on wound tion due to its short half-life and fragile nature. Instead of
healing [21, 22]. having novelty, artificially engineered skin is having certain
disadvantages. In order to apply onto a patient, a skin biopsy
4. Current Treatments for Wound Healing not only takes several weeks to be expanded into sufficient
cultured epidermis but also the product is very costly [26].
To achieve a complete healing of the wound, an appropriate
wound care is critical, and standard treatment modalities are 4.3. Hyperbaric Oxygen Therapy. Oxygen therapy under
used to improve the wound bed. Therapy for chronic wounds pressure also called as hyperbaric oxygen (HBO2) has been
mainly focuses on the identification and correction of the tried to improve wound healing for the last forty years with
precipitating and perpetuating factors. This approach limited clinical benefits. HBO2 uses in wound healing on
includes the use of antibiotics for accompanying cellulitis, the basis of the fact that oxygen under certain pressure
revascularization of ischemic limbs, and compression devices when applied to wounds can stimulate angiogenesis, pro-
for venous ulcers and rigorous off-loading for decubitus mote fibroblast proliferation, and enhance immune func-
(pressure) ulcers [23, 24]. Despite the advancement in cur- tion. There are very few evidences from clinical studies
rent wound care, chronic wounds do not heal or heal very that demonstrate the efficacy of HBO2 therapy in any kind
slowly in the majority of the cases. Therefore, in recent years, of foot ulcers or refractory wounds [28]. However, the
efforts have been made to develop more and more advanced application of HBO2 is currently not in clinical practice
treatment strategies such as application of growth factors and because this therapy could lead to significant side effects
cytokines [25], skin grafting [26, 27], and hyperbaric oxygen including myopia, oxygen toxicity in the brain leading to
(HBO2) therapy [28]. seizures, and pneumothorax [31].
4.1. Growth Factors and Cytokines. Therapeutic effects of var- Hence, approximately 50% of the patients with chronic
ious growth factors and cytokines were tested in the clinical ulcers do not heal when their ulcers were previously resistant
management of nonhealing wounds. Among these growth to conventional therapy [32]. It is more and more evident
factors, PDGF, VEGF, bFGF, and granulocyte-macrophage from the wound healing experience of the last decade that
colony stimulating factor (GM-CSF) were tested extensively more radical steps, such as stem cell therapy, need to be taken
[29]. PDGF-BB was the most popular and approved by the to propel the treatment of chronic wounds in a direction that
Food and Drug Administration (FDA) for the treatment of will not only take care the external complexities of the wound
diabetic neuropathic ulcers of the foot in the United States but also will act on multiple modalities of wound healing
of America. However, later, the FDA announced the malig- systemically. For example, adult stem cells, which are multi-
nancy risk associated with this product [29, 30]. Hence, the potent and angiogenic, might be a suitable candidate for
journey of finding appropriate therapeutic growth factor for this purpose. Additionally, these stem cells can also be used
chronic wounds still continues. as a vehicle for gene therapy, such as VEGF, and PDGF-BB
[33, 34], which will add an extra dimension in treating
4.2. Skin Graft. Efforts have also been devoted into tissue chronic wounds such as diabetic ulcer. However, selection
engineering in making appropriate skin grafts to heal refrac- of a suitable cell type as a clinical candidate for wound heal-
tory wounds successfully. The skin is the first tissue, which ing therapy would be a great challenge.
4 Mediators of Inflammation

5. Role of Stem Cells in Wound Repair wound fails to heal, especially with the increasing age. Hence,
(Endogenous and Exogenous) appropriate exogenous stem cell transplantation might be an
alternative strategy to cure chronic wounds. It is also believed
The epithelium of the skin has a remarkable ability of self- that resident endothelial progenitor cells in the skin also con-
renewal over the lifetime and also produces daughter cells tribute to wound neovascularization through angiogenesis
that differentiate into one or multiple lineages. Cutaneous [45]. Isolated tissue resident endothelial progenitor cells con-
wound healing is the natural response but in case of severe tribute to angiogenesis by differentiating into blood vessels
conditions such as burn or diabetes, the repair process is upon transplantation [46].
insufficient to achieve an effective cure. In these chronic con-
ditions, the result is neither aesthetically nor functionally 7. Cell-Based Therapy for Wounds
perfect with the loss of epidermal appendages and the gener-
ation of connective tissue scar. Although epidermal stem cells Human stem cells may offer considerable opportunities pro-
in the basal layer, as an endogenous source of stem cells, can viding both undifferentiated and differentiated cells for gene
regenerate skin, but these cells are not sufficient to provide therapy, drug discovery, and regenerative medicine [47]. In
perfect repair after deep and extensive skin damage. Thus, addition, stem cells could be transduced ex vivo and manipu-
exogenous supply of stem cells in traumatic conditions may lated cells reintroduced into the host. Manipulated stem cells
be one of the novel therapeutic strategies to achieve perfect could also offer new therapeutic approaches for specific dis-
skin repair. eases conditions. Wound repair is a complex process and is
influenced by numerous secreted factors, including cytokines,
6. Endogenous Stem Cells chemokines, and growth factors. In theory, application of
stem cells to wounds is advantageous over administration
6.1. Hair Follicle and Interfollicular Epidermal Stem Cells. of a single agent because stem cells have a unique feature
Three major compartments of the epidermis, such as inter- of interacting with wound environment and modulate
follicular epidermis, sebaceous gland, and hair follicle, are their activity to release multiple factors, which may facili-
capable of self-renewal (Figure 1). Among these compart- tate wound healing process (Figure 1). Stem cells can also
ments, interfollicular epidermis and sebaceous glands potentially serve as a source of cells for providing skin
undergo constant self-renewal, whereas hair follicles undergo substitutes in applications for tissue engineering. Thus,
cycles of phases such as resting, growth, and involution [35]. the selection of a suitable stem cell is a challenge in order
In physiological condition, these compartments of the epi- to achieve a desirable efficacy in wound healing. Embry-
dermis are rejuvenated by the differentiation of their own onic stem cells could be the most favorable over adult
stem cells. However, during injury, these epidermal compart- stem cells for the repair and regeneration of skin tissues
ments are capable of repopulating one another [36, 37]. In due to their capacity of self-renewal and unlimited supply
case of full-thickness wounds, where the hair follicle is of differentiated keratinocytes or keratinocyte progenitors
obliterated, wound healing occurs slowly from the wound for treating cutaneous injuries. However, embryonic stem
edge; whereas, in case of partial thickness, wound healing cell-related research has raised difficult ethical issues and
is accelerated and relies on reepithelialization with the has evoked a great public interest and controversy.
migration of cells from the hair follicle and sebaceous Moreover, embryonic stem cells have a potential to
gland [38, 39]. The hair follicle bulge to epidermal stem generate tumors. The development of therapies using stem
cells in partial thickness wound regeneration, which is cells in the context of injury and wound healing has pri-
transient and bulge-derived cells are replaced eventually marily relied on adult stem cells. Adult stem cells derived
by interfollicular epidermal stem cell progeny as the injury from the bone marrow, peripheral blood, umbilical cord
is recovered or stress is relieved [37, 40]. Although bulge blood, or adipose tissue with their limited capacity of self-
epidermal stem cells are not essential for wound closure renewal and proliferation would be more acceptable for ther-
[39], these cells significantly expedite closure in the early apeutic application in human skin tissues. Thus, an immense
stages of wound healing [41]. Thus, hair follicle and its con- amount of research is going on to prove the efficacy and
nective tissue sheath are attractive targets for the develop- mechanisms of action of these stem cells for skin regenera-
ment of regenerative therapies due to its accessibility and tion. There are already some encouraging results from
richness of stem cells. human studies using multipotent adult stem cells as thera-
peutic agents for tissue repair [44, 48–50]. Endogenous stem
6.2. Endothelial Progenitor Cells. Endothelial progenitor cells cell populations are thought to play an important role in dif-
play an important role in wound healing process via angio- ferent aspects of skin wound healing including inflammation,
genesis and facilitate wound closure. These progenitor cells reepithelialization, neovascularization, and tissue remodeling
might be tissue resident or originate from the bone [51]. However, in pathological conditions, it has been observed
marrow. Bone marrow-derived endothelial progenitor cells that administration of exogenous adult stem cell accelerated
home to the site of cutaneous injury in response to wound healing through various mechanisms such as accel-
hypoxia-inducible factor (HIF)-1-induced stromal cell- eration of reepithelialization, stimulation of neovasculariza-
derived factor (SDF)-1 in hypoxic milieu [42, 43]. However, tion in a paracrine manner, or directly differentiating into
these phenomena are impaired in pathophysiological condi- various cell types such as keratinocyte, fibrocytes, endothelial
tions such as diabetes and with the age [44]. Thus, diabetic cells, and pericytes (Table 1).
Mediators of Inflammation 5

Refractory wound Refractory wound

Exogenous A B Exogenous A B
stem cells (+) Treatment (‒) Treatment stem cells (+) Treatment (‒) Treatment

Eschar Eschar
Epidermis Epidermis
v v vv vv vv vv
vv v v
vv vv vv
vv vv vv
vv vv IL-10, VEGF, PDGF, and TGF-
훽
vv vv IL-10, VEGF, PDGF, and TGF-
훽vv IL-1, and 6, TNF
훼, and MMP-1, 2, 3, and 13

Dermis Dermis

Adipose tissue Adipose tissue IL-1, and 6, TNF
훼, and MMP-1, 2, 3, and 13

Phase I Phase II
Fibroblast Platelet plug Exogenous stem cells Fibroblast Platelet plug Exogenous stem cells
vv Neutrophil Hair follicle and interfollicular Myofibroblast vv Neutrophil Hair follicle and interfollicular Myofibroblast
epidermal stem cells epidermal stem cells
Fibrin clot regulated Fibrin clot regulated
Late macrophage Late macrophage
Resident and circulatory Resident and circulatory
endothelial progenitor cell Collagen endothelial progenitor cell Collagen
Early macrophage Adipose cell Early macrophage Adipose cell

(a) (b)
Refractory wound
Exogenous A B
stem cells (+) Treatment (‒) Treatment

Eschar
Epidermis
vv vv
vv vv
vv IL-10, VEGF, PDGF, TGF-
훽
IL-10, VEGF, PDGF, TGF-
훽 vv IL-1, and 6, TNF
훼, and MMP-1, 2, 3, and 13

Dermis

Adipose tissue IL-1, and 6, TNF
훼, and MMP-1, 2, 3, and 13

Phase III
Fibroblast Platelet plug Exogenous stem cells
vv Neutrophil Hair follicle and interfollicular Myofibroblast
epidermal stem cells
Fibrin clot regulated
Late macrophage
Resident and circulatory
endothelial progenitor cell Collagen
Early macrophage Adipose cell

(c)

Figure 1: Graphical presentation of stem cell-mediated effect on refractory wound healing process. (a) Phase I: in inflammatory phase,
the wound bed contains a large number of neutrophils, early phase macrophages, platelet plugs, and fibrin clots. Initiation of healing
process occurs at this phase. (b) Phase II, A: systemic or local administration of stem cell homed to the wound bed. Exogenous stem
cells mobilize host resident stem cells to take part in the healing process in GT formation by facilitating angiogenesis. Exogenous stem
cells also directly take part in this healing process. The surrounding mobilized fibroblasts also differentiate into myofibroblasts and with
collagen deposition facilitate reepithelialization process. B: in the absence of stem cell therapy, inflammatory cells such as neutrophils
and macrophages still remain within the wound bed and impaired recruitment of endogenous stem cells occurs, which mediate an
imbalance in the orchestrated harmony. GT formation is hindered due to the lack of angiogenesis, myofibroblast differentiation, collagen
deposition, and reepithelialization. (c) Phase III: stem cell therapy generates scar tissue within the wound by replacing the provisional
matrix. However, without stem cell therapy, refractory condition remains. The wound bed remains enriched with inflammatory cells and
their proinflammatory secretory products. IL: interleukin; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor;
TGF-β: transforming growth factor beta; MMP: matrix metalloproteinase.

7.1. Embryonic Stem Cells. Embryonic stem cells (ESCs) are as ethical concerns exist regarding the harvest of cells from
pluripotent in nature which reside within the blastocyst. live embryos. Moreover, the potential for immune rejec-
These cells have a potential to differentiate into any of the tion and teratoma formation remains as other concerns.
three primary germ layers namely endoderm, mesoderm, Hence, focus has been redirected towards adult stem cells
or ectoderm [52]. Embryonic stem cells can be differentiated as an alternative source with potential to apply in various
into keratinocytes in presence of selected medium contain- disease conditions.
ing specific growth factors. These keratinocytes are capable
of forming multilayered epidermis in culture, making them 7.2. Induced Pluripotent Stem Cells. Induced pluripotent stem
a key cell type for bioengineered skin [53]. However, cells (iPSCs) are the multipotent cells with self-renewal prop-
the use of embryonic stem cells remains controversial, erties, which are engineered from differentiated adult somatic
6 Mediators of Inflammation

Table 1: Overview of stem cell-based therapies for cutaneous wound management in vivo and their mechanism of action.

Wound model Type of cell therapy Regenerative mechanisms Reference

Excisional wound splinting Recruitment of macrophages and endothelial
BM-MSC [124]
model/Balb/C mice lineages by paracrine factors
Excisional wound splinting
BM-MSC Differentiation and angiogenesis [129]
model/diabetic mice
Excisional wound splinting Immunomodulation, M2 macrophage
GMSC [118]
model/C57BL/6 J mice polarization
Full-thickness excisional
ASC Differentiation and vasculogenesis [130]
wound/STZ-induced diabetic rat
Full-thickness excisional Human blood-derived
Vasculogenesis [103]
wound/STZ-induced diabetic mice CD34+ cells
Limb ischemia and Human fetal aorta-derived Paracrine stimulation of angiogenesis and
[105]
wounding/STZ-induced diabetic mice CD133+ cells activation of Wnt signaling
Fibroblast proliferation and enhancement
Full-thickness excisional Nanofiber-expanded cord
of collagen deposition and decreased [101]
wound in NOD/SCID mice blood-derived CD34+ cells
MMP expression
Full-thickness excisional wound Nanofiber-expanded cord
Immunomodulation, angiogenesis [102]
in NOD/SCID mice blood-derived CD34+ cells
BM-MSC: bone marrow-derived mesenchymal stem cells; GMSC: human gingiva-derived MSC; STZ: streptozotocin; ASC: adipose-derived stem cells.

cells, such as fibroblasts and keratinocytes, using transcrip- marrow and other tissues such as adipose tissue, nerve tissue,
tion factors (e.g., Oct-3/4, Sox2, c-Myc, and KLF4) [54–56]. umbilical cord blood, and dermis with phenotypic heteroge-
Unlike ESCs, iPSCs not only eliminate ethical issues but also neity [74–79]. In regenerative medicine, unlike embryonic
reduce the chances of immune rejection while using it thera- stem cells, the use of mesenchymal stem cells could avoid
peutically [57]. A negligible immune response was also ethical issues. Also, allogeneic MSC transplantation may
observed in iPSCs derived from human skin fibroblasts induce little immunoreactivity to the host [80, 81]. Thus,
[58]. The unique reprogramming of iPSC technology made MSCs have received considerable attention for modulating
it possible to generate genetically diverse patient-specific cell wound repair [82]. MSCs have been tested for skin repair
lines from genetic skin disorders or chronic wounds which and regeneration in various acute and chronic skin injuries
have tremendous potential for disease modeling and drug like acute incisional and excisional wounds, diabetic skin
screening [59, 60]. During the last decade, significant prog- ulcers, radiation, and thermal burns [76, 83, 84]. Inflamma-
ress has been made in the differentiation of the mouse, tion and oxidative stress generated during wound healing
human iPSCs in to dermal stem cells and hair follicle lineages not only attract bone marrow-derived mesenchymal stem
[58, 61], mesenchymal cells with the potential of forming cells at the wound area and conducive to self-renewal and
dermal papilla [62], fibroblasts [63], melanocytes [64], kera- proliferation [85] but also support wound healing through
tinocytes [65, 66], among others. The multipotent capacity differentiation and the promotion of blood vessel formation.
with limited immunoreactivity of iPSCs makes them a pro- MSC therapy has shown enhanced wound healing through
spective agent for treating chronic skin disorders and unre- increased angiogenesis, reepithelialization, and tissue granu-
solved wounds [67]. iPSCs generated from patients also lation. In clinical settings, MSC also showed a great promise
could be modified and have the potential for cell therapy that in treating refractory wounds. In clinical studies, after MSC
have been shown in several studies as a proof of concept treatment, patients showed improvement of their wounds
[66, 68]. However, application of iPSCs in human patients within days following administration, characterized by a
need further extensive analyses for safety and reliability of decrease in wound size, an increase in the vascularity of the
the reprogramming technology due to the risk of teratoge- dermis, and increased dermal thickness of the wound bed
nicity, mutagenesis, among others [69]. iPSCs can also pro- [48, 86]. Additionally, coadministration of MSC at the
vide a foundation for modeling a complex human organ wound site along with an autologous graft composed of
like skin tissue due to their ability to be differentiated into autologous skin fibroblasts on biodegradable collagen mem-
multiple cell types in the body, and their unlimited growth branes also decreased wound size and increased vascularity
potential was also demonstrated in various in vivo models and dermal thickness in chronic diabetic foot ulcers [84].
[70, 71]. iPSCs therefore hold a great promise in the field of All these findings from preclinical and clinical studies dem-
wound repair and regenerative medicine. onstrated that MSCs can contribute to wound repair and
may be a resource for regenerative therapy.
7.3. Mesenchymal Stem Cells. Mesenchymal stromal cells,
also known as mesenchymal stem cells (MSCs), are adult 7.4. Adipose-Derived Stem Cells. Adipose-derived stem cells
stem cells capable of self-renewal and multipotential differ- (ASCs) are the precursor cells that are present within the
entiation [72, 73]. MSCs can be obtained from the bone stromal-vascular fraction of an enzymatically digested fat
Mediators of Inflammation 7

tissue. Minimal invasive nature of tissue harvest has made after systemic administration, these stem cells reached to the
these stem cells more attractive for regenerative medicine. wound bed and facilitated wound healing. Our study revealed
ASCs are multipotent in nature and can be differentiated into that nanofiber-expanded cord blood-derived CD34+ cell ther-
different lineages such as bone, fat, cartilage, and muscle [75, apy accelerates wound healing by inhibiting several matrix
87]. ASCs can be characterized while in culture dish as metalloproteinases at the wound bed which prevents collagen
CD73+/CD90+/CD105+/CD44+/CD45−/CD31− cells, which degradation and increased the abundance of collagen
can be distinguished from the bone marrow-derived MSCs components, procollagen1A1 at the wound bed [101]. Unlike
by their expressions of CD36 and negative for CD106 mole- previous experiments, we demonstrated for the first time that
cules on their cell surface [88]. Although both of these cell nanofiber-expanded cord blood-derived CD34+ stem cells
types share surface markers, biologically they are different accelerated wound closure by secreting collagen and thereby
in terms of proliferation rate and differentiation, cytokine positively contributed to extracellular matrix [101], indicat-
secretion, and chemokine expressions [89–91]. Thus, ASCs ing that CD34+ stem cell treatment is having a potential to
and MSCs may contribute to the wound healing differently. treat the refractory wounds resulting from diabetes or trau-
The capability of ASCs to secrete growth factors, to differen- matic skin injuries. We further extended this work to explore
tiate into multiple cell types, and to promote angiogenesis the regulation of inflammatory response by CD34+ cell
renders them a viable skin substitute [92, 93]. The ability of therapy using the same mouse wound model. Overall, our
ASCs for soft tissue reconstruction makes them attractive study demonstrated that CD34+ cell therapy mediated sup-
for wound healing [94]. pression of prolonged inflammation, positively contributed
to increased angiogenesis, and accelerated wound closure
7.5. Hematopoietic Stem Cells. The possible role of hemato- compared to nontreated wounds [102]. These data provided
poietic stem cells (HSC) in skin regeneration is evident in a valuable information regarding the benefits of CD34+ stem
many occasions. HSC can be isolated from the bone marrow cell-mediated wound healing and cell therapetic mechanism
(BM), umbilical cord blood, and peripheral blood by using its behind accelerated wound closure. In another study, treat-
surface markers. In several occasions, skin “chimerism” ment with human CD34+ peripheral blood mononuclear
(identification of epithelial cells of donor genotype) has been cells also accelerates healing of full-thickness skin wounds
observed after clinical HSC transplantations such as BM or in diabetic mice by accelerated revascularization and epider-
peripheral blood mononuclear cells (PBMC) [95–97]. The mal healing [103]. A similar observation was also found in a
findings of donor-derived contribution of HSC to epithelial report where cord blood-derived CD34+ cell treatment accel-
lineages in the host offer the broad-spectrum plasticity of erated diabetic wound closure by stimulating keratinocytes,
HSC and indicate the possibility of skin regeneration by fibroblast proliferation, and neovascularization in a paracrine
transplantation of HSC in chronic wound disorders. In a manner [104]. In another study, human fetal aorta-derived
murine excisional wound model, a significant number of dif- CD133+ progenitor cells and their conditioned medium
ferentiated green fluorescent protein (GFP) positive cells treatment accelerated healing in ischemic diabetic ulcer by
were found in the hair follicles, sebaceous glands, and epider- stimulating angiogenesis with activation of the Wnt signaling
mis in host skin 21 days after transplantation of syngeneic pathway in the host [105]. These findings indicate that blood-
GFP + bone marrow cells [48]. Additionally, a study has also derived progenitors may have a therapeutic potential in the
shown that the differentiation potential of human umbilical treatment of skin lesions in complex pathological condi-
cord blood stem cells into keratinocytes in vitro [98]. Apart tions such as diabetes.
from plasticity, the role of HSC in angiogenesis is also evident
in myocardial infarction model, which is important and may 8. Mechanisms of Stem Cell-Mediated Wound
be ascribable for the perfect and functional repair of skin tis- Healing
sue [99]. An emerging concept, epithelial and mesenchymal
cell interaction is supposed to be a vital phenomenon in ker- 8.1. Immunomodulation, Resolution of Inflammation, and
atinocyte proliferation and differentiation, might play a cru- Fibrosis. An imbalance in regulation of inflammation at the
cial role in cutaneous wound healing and reepithelialization wound bed leads to defective healing. Sustained unresolved
[4, 92]. The expression of CD34 and CD133 cells in dermal inflammation leads to chronic wound. Prolonged inflam-
fibroblast and follicular matrix during embryogenesis pro- mation even leads to fibrotic scar formation. In chronic
vides an indication for the role of HSC in the molecular con- wounds, unresolved inflammation leads to increased prote-
trol of epithelial-mesenchymal cell interactions [100]. ase activity and deregulated fibroblast activity, which resulted
Peripheral blood, fetal aorta, and umbilical cord blood in decreased collagen deposition and ECM formation. Hence,
are also enriched with stem and progenitor cells, which resolution of inflammation is a big challenge in diabetic
express CD34 and CD133 markers. These cells are also multi- wound healing. In recent years, several studies have demon-
potent and have shown a neovascularization potential in pre- strated the immunomodulatory function of cultured adult
clinical ischemic models [33, 34]. In preclinical wound stem cells in laboratory conditions obtained from various
healing models, we and others reported that CD34+ or sources like the umbilical cord blood, amniotic fluid, and
CD133+ cells accelerate wound closure. We have demon- bone marrow. Thus, allogeneic stem cell therapy induces
strated the wound healing ability of nanofiber-expanded cord immunomodulation in the wound bed and facilitates wound
blood-derived CD34+ cells in a mouse excisional wound healing by resolving inflammation, as well as helping in
model and an in vitro cellular model. We have shown that reducing scar formation [106].
8 Mediators of Inflammation

A substantial number of studies have demonstrated that Tissue resident and peripheral macrophages play a signif-
treatment of MSCs has significant immunomodulatory icant role in initiation of inflammation after injury and
effects during wound healing and in other inflammatory con- resolving inflammation in a timely manner during the heal-
ditions [107]. This immunomodulatory effect on the host not ing process. Macrophages shift gears between proinflamma-
only makes them a suitable candidate for allogeneic trans- tory M1 and anti-inflammatory alternatively activated M2
plantation [108] but also makes them an attractive cell ther- states. Studies have shown in various models that MSCs
apeutic agent to treat chronic wounds [106]. Studies have may influence macrophage M1/M2 polarization after contact
demonstrated that MSCs obtained from various sources such with macrophage [115–117]. M2 polarized macrophages play
as the umbilical cord and bone marrow showed an anti- an important role in the resolution of inflammation and
inflammatory effect in rat cutaneous wound and in vitro clearance of dead cells from the wound environment for
fibroblast model. MSC treatment demonstrated a signifi- accelerated healing. In a mouse wound healing model, it
cantly lower number of inflammatory cells and proinflamma- was shown that the human gingiva-derived MSC treatment
tory cytokines such as IL-1 and TNF-α with an increased level in vivo promoted an M2 macrophage polarization, which
of IL-10 at the cutaneous wound bed in a rat model [109]. In was correlated well with anti-inflammatory wound environ-
addition, when murine BM-MSC were cocultured with ment and accelerated cutaneous wound healing [118]. The
human fibroblasts, the mRNA levels of intercellular adhesion ability of MSCs to resolve inflammation might be useful in
molecule 1 (ICAM1) has decreased [110]. These studies sug- treating chronic unresolved wounds.
gest the potential of MSC in attenuating wound inflamma- Moreover, dysregulated fibrosis or scarring is caused by
tion and inducing healing in chronic inflammatory stage. excessive deposition of ECM. Inflammation largely regulates
Allogeneic transplantation of cord blood and cord blood- fibrosis process. The immunomodulatory activity of MSCs
derived stem cells is also regarded as less immunogenic [111]. might regulate fibrosis and therefore anti-inflammatory
Our results demonstrated that nanofiber-expanded cord activity of MSCs reduces the scar formation. In an in vivo
blood-derived CD34+ cells might have an immunomodula- murine wounding model, it showed that BM-MSCs atten-
tory effect in vitro and in vivo wound healing models [102]. uated development in skin fibrosis [119].
Systemically transplanted CD34+ cells accelerated wound
closure, which was correlated with decreased inflammatory 8.2. Differentiation. In several studies, it has shown that adult
activity at the wound bed characterized by reduced inflam- stem cells are multipotential and able to contribute to wound
matory gene expression such as, IL-1β, TNF-α, IL-6, and healing by differentiating into several tissue lineages starting
NOS2A. At the same time, expression of anti-inflammatory from the inflammatory cells to myofibroblasts. During the
molecule IL-10 was significantly increased indicating that inflammatory phase, HSCs from the bone marrow undergoes
CD34+ cell therapy has the potential to control the inflam- myelopoiesis with the help of MSC and supply the leukocytes
mation during wound healing process. To further elucidate to the wound region [92]. Also, tissue resident stem cells
the mechanism, we showed that CD34+ cells secrete IL-10, undergo differentiation in response to various stimuli during
an anti-inflammatory molecule, and suppress NF-κB acti- the wound healing process [120, 121]. From the regenerative
vation in a human primary fibroblast cell model. In the perspective, differentiation is one of the key phenomenon by
similar in vitro model, when human primary fibroblasts which exogenously applied adult stem cells exert therapeutic
were cocultured with CD34+ cells in presence of inflam- efficacy in cutaneous wound models. MSC is one of the most
matory stimulus with TNF-α, NF-κB activation was signif- widely studied in this regard. Several studies have demon-
icantly decreased by upregulation of IL-10 [102]. Sustained strated that transplanted MSCs can differentiate into epider-
or unresolved inflammation prevents wound healing by mal keratinocytes, endothelial cells, and pericytes directly
inhibiting angiogenesis and catabolizes extracellular matrix participating in the structural repair of a wound. MSC trans-
in the wound bed. Our results suggest that nanofiber- plantation led to accelerated cutaneous wound closure in
expanded cord blood-derived CD34+ cell therapy might both normal and diabetic mice, where MSCs express
be a potential candidate to treat chronic wounds to resolve keratinocyte-specific markers suggesting their role to pro-
inflammation in a timely manner that will facilitate further mote wound healing by differentiation [76]. Similarly,
angiogenesis and ECM formation for accelerated healing. another study demonstrated that MSCs also transdifferenti-
Other studies have also suggested that ASCs also modulate ate into keratinocytes, endothelial cells, and pericytes in cuta-
the immune system and downregulate the inflammation neous wounds after intravenous injection in mice [122].
by releasing growth factors critical for healing which are Adipose-derived stromal cells are also capable of differentiat-
described in the reviews [112]. ing into epithelial, endothelial, and fibroblast lineages in vivo
Antimicrobial activity is critical for wound clearance when applied to wounds by means of a seeded scaffold [92].
from infection. Studies have shown that MSCs have anti- A similar kind of low-level transdifferentiation phenomenon
microbial activities, which may also be helpful for chronic was also observed in human skin after HSC transplantation
wound resolution. Antimicrobial activities of MSCs were where the mesodermal origin of HSC contributes to epithelial
shown directly by the secretion of antimicrobial factors lineage in the host [95, 96].
such as LL-37 [113]. In another study, it was shown that
MSCs could secrete immune-modulating factors, which 8.3. Angiogenesis. Optimal repair and restoration of
will upregulate bacterial killing and phagocytosis by immune functional vasculature is crucial to achieve ideal healing of
cells [114]. wounds. The process of neovascularization primarily
Mediators of Inflammation 9

accomplishes revascularization of the wound bed. Neovascu- addressed. Further studies are necessary to characterize the
larization is achieved through two independent processes niche of MSC, which helps MSCs to be effective in the wound
called angiogenesis and vasculogenesis, which lead to the healing process. Further investigation on experimental and
development of functional microvascular networks. Tradi- clinical application of stem cells in wound healing is neces-
tionally, vasculogenesis is the de novo synthesis of new ves- sary to identify the ideal source of stem cells and the most
sels by endothelial progenitor cells whereas angiogenesis is efficacious mode of cell delivery.
the development of new vessels from existing capillaries Human umbilical cord blood is rich in stem and progen-
[123]. In a refractory wound-like diabetic wound, wound itor cells and is easily accessible for blood collection. The
revascularization is affected due to an imbalance in the regenerative potential of CD34+ and CD133+ cell therapy
release of soluble mediators and improper function of endog- in cutaneous tissue repair obtained from peripheral or umbil-
enous progenitor and stem cells which is essential for ideal ical cord blood opens up a possibility of providing cheap and
wound healing, leading to a hindered and orchestrated heal- affordable care for refractory wounds. Thus, a suitable tech-
ing process. Several other and our own published studies nology like ex vivo expansion technique would be useful to
[101, 102] have demonstrated that transplantation of adult get a large number of stem cells for the clinical application.
stem or progenitor cells contribute to angiogenesis or vascu- Our group and others have shown promising results in
logenesis through directly differentiating into cell types expansion of umbilical cord blood-derived stem cells. The
essential for blood vessel formation or by stimulating endog- expanded stem cells were characterized (CD34+) and have
enous mediators or cells in a paracrine manner. Studies have shown their multipotential and angiogenic capabilities in
found that MSC expresses high levels of vascular endothelial preclinical ischemic models as well as in murine cutaneous
growth factor (VEGF) and angiopoeitin-1, which indicate wound models [33, 34, 101, 102] where CD34+ stem cell
that the MSC-mediated accelerated wound healing is due to therapy accelerated wound closure by resolving inflamma-
the release of proangiogenic factors and induction of angio- tion with concurrent inhibition of MMP expressions. Addi-
genesis [76]. Additionally, paracrine signaling and the release tionally, these cells also can be manipulated in vitro with
of soluble factors (e.g., VEGF) by MSC are found to promote proangiogenic factors like VEGF and PDGF, which are effica-
angiogenesis at the wound bed after cutaneous injury in nor- cious in improving ischemia-related complications in pre-
mal and diabetic mice [124, 125]. Another interesting clinical peripheral and cardiac ischemic models. Thus,
hypothesis about MSC is that these cells may also act as peri- looking at their angiogenic and anti-inflammatory potential,
cytes, which stabilizes the blood vessel formation [126]. this pool of stem cells may have a very promising future in
Future studies will further bolster this claim. However, the treating refractory wounds. Moreover, nanofiber-expanded
role of MSC in promoting angiogenesis is firmly evident by stem cells coupled with the innovative biotechnologies
several instances in normal and refractory wound healing may open a new direction for plastic and reconstructive
models [127, 128]. surgeons. Finally, the use of stem cells to induce cutaneous
In other stem cells like ASC, it was noticed that ASC tissue regeneration holds a great promise for modern
treatment also promotes angiogenesis and accelerates wound regenerative medicine.
healing by producing VEGF [93]. Thus, induction of angio-
genesis to accelerate wound healing by stem cell therapy is Conflicts of Interest
not only evident in MSC and ASC but is also found in several
other types of stem and progenitor cells [103, 105]. Thus, No competing financial interests exist.
increased angiogenesis by stem cell therapy not only
supports GT formation but also supplies nutrients and Acknowledgments
clear the apoptotic cells from the wound bed and helps
in wound resolution. This work was supported in part by the National Institute
of Health (NIH) Grant nos. R01AR068279 (NIAMS), STTR
R41EY024217 (NEI), and R41EY024217-01A1S1 (NEI)
9. Conclusions and Future Directions and the Texas Tech University Health Sciences Center
It is evident that stem cells have a tremendous potential for start-up fund.
cutaneous tissue regeneration, as these cells not only can
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