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Contents lists available at ScienceDirect

Prostaglandins and Other Lipid Mediators

eview

icosanoids: Emerging contributors in stem cell-mediated woundealing

lizabeth Berry a, Yanzhou Liu a,b, Li Chen c, Austin M. Guo a,b,∗

Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, NY 10595 United StatesDepartment of Pharmacology, School of Medicine, Wuhan University, Wuhan, 430071, People’s Republic of ChinaState Key Lab of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou,10060, People’s Republic of China

r t i c l e i n f o

rticle history:eceived 19 July 2016eceived in revised form9 September 2016ccepted 3 November 2016vailable online xxx

a b s t r a c t

Eicosanoids are bioactive lipid products primarily derived from the oxidation of arachidonic acid (AA). Theindividual contributions of eicosanoids and stem cells to wound healing have been of great interest. Thisreview focuses on how stem cells work in concert with eicosanoids to create a beneficial environment inthe wound bed and in the promotion of wound healing. Stem cells contribute to wound healing throughmodulating inflammation, differentiating into skin cells or endothelial cells, and exerting paracrine effectsby releasing various potent growth factors. Eicosanoids have been shown to stimulate proliferation,

eywords:icosanoidstem cellsngiogenesisound healing

migration, homing, and differentiation of stem cells, all of which contribute to the process of woundhealing. Increasing evidence has shown that eicosanoids improve wound healing through increasingstem cell densities, stimulating differentiation, and enhancing the angiogenic properties of stem cells.Chronic wounds have become a major problem in health care. Therefore, research regarding the effectsof stem cells and eicosanoids in the promotion wound healing is of great importance.

© 2016 Elsevier Inc. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Synthesis of eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Eicosanoids in regulation of stem cell functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Contribution of stem cells in wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.1. MSCs in wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. EPCs in wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Emerging role of eicosanoids in stem cell-mediated wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.1. COX-derived eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .005.2. LOX-derived eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.3. CYP-derived eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

6. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Introductioninclude inflammation, proliferation, and remodeling [1,2]. In patho-logical conditions such as diabetes and peripheral vascular diseases,

Please cite this article in press as: E. Berry, et al., Eicosanoids: Emerging cOther Lipid Mediat (2016), http://dx.doi.org/10.1016/j.prostaglandins

Wound healing in response to tissue injury occurs in a highlyoordinated sequence of overlapping but distinct phases, which

∗ Corresponding author at: New York Medical College, 15 Dana Road, BSB 546A,alhalla, NY 10595 United States.

E-mail address: austin guo@nymc.edu (A.M. Guo).

ttp://dx.doi.org/10.1016/j.prostaglandins.2016.11.001098-8823/© 2016 Elsevier Inc. All rights reserved.

wounds fail to follow the coordinated sequence of healing and con-sequently become chronic wounds [3]. For example, a wound maybecome chronic due to overwhelming factors such as ischemia [4].In developed countries such as the United States, it is expected that

ontributors in stem cell-mediated wound healing, Prostaglandins.2016.11.001

1–2% of the population will experience a chronic wound. This beingsaid, with the current population in the United States of 320 million,approximately 6.5 million people will be affected [5]. Additionally,obesity is a rising health issue across the world and Wagner et al.

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emonstrated that vasculogenic progenitor cells of obese individ-als have lower capabilities to migrate and proliferate effectively,

eading to delayed wound closure [6]. Multiple new therapies areeing assessed in preclinical and clinical studies to supplementound dressings and improve the rate of healing in these prob-

ematic situations. Among these new treatment modalities, stemell-based therapies have gained increasing interest [7,8].

Stem cells are classically defined as undifferentiated cells thatave the capacity to differentiate into diverse specialized cell typesnd to self-renew in order to produce more stem cells [9]. Both dif-erentiation and incorporation as mature endothelial cells (ECs),nd paracrine signaling have been identified as mechanisms byhich stem cells improve wound healing [10].

Eicosanoids are a wide variety of 20-carbon bioactive lipidroducts primarily derived from the oxidation of arachi-onic acid (AA), including prostaglandins (PG), thromboxanesTX), leukotrienes(LT), lipoxins (LX) epoxides, hydroxyeicosate-raenoic acids (HETEs) and epoxyeicosatrienoicacids (EETs) [11,12].icosanoids are highly potent, short-lived molecules that act locallynd have been strongly associated with a variety of physiologicalnd pathological processes including cancer, inflammatory dis-ases, wound healing, etc. [13]. In this review, we will focus on themerging role of eicosanoids in stem cell-mediated wound healing.

. Synthesis of eicosanoids

Eicosanoid biosynthesis occurs in three steps: (1) the conversionf polyunsaturated fatty acids (PUFAs) into arachidonic acid (AA),ocosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), all ofhich are primarily stored in an esterified form [14]; (2) the phos-

holipase A2 (PLA2)-catalyzed release of free fatty acids from AA,HA, EPA; and (3) the metabolism of free fatty acids into biolog-

cally active eicosanoids via cyclooxygenase (COX), lipoxygenaseLOX), and cytochrome P450 (CYP) enzymes [15,16].

As summarized in Fig. 1, AA metabolized by the COX pathwayorms PGs and TXs. This process yields the unstable intermediateGG2 which is reduced to form PGH2 and is isomerized to matureGs, PGD2, PGE2, PGF2, and PGI2; TXA2 is synthesized from PGG2hich is reduced to PGH2 and then converted to TXA2 [11,17,18].

he LOX pathway leads to the formation of LXB4 from LXA4, andTB4, LTC4, LTD4 and LTE4 all by 5-LOX. LTs are first convertedo LTA4 from 5-hydroperoxyeicosatetraenoic acid (5-HPETE) andhen to the subsequent LTs. Additionally, the LOX pathway forms2-HETE and 15-HETE through 12-LOX and 15-LOX, respectively19]. The CYP pathway comprises a large number of enzymes

ainly divided into two branches: �-hydroxylases and epoxyge-ases. �-Hydroxylases CYP4A and 4F convert AA into HETEs, whilepoxygenases CYP2C and 2J generate various EETs [18,20]. 20-HETEs the major metabolite of the CYP �-hydroxylases [21]. EETs cane further metabolized by soluble epoxide hydrolase (sEH) to the

ess active dihydroxyeicosatrienoic acids (DHETs) [22].Many different types of cells can synthesize and produce

icosanoids. For example, ECs can produce PGs, LTs, LXs, 20-HETEnd EETs [23–26]; leukocytes can synthesize LTs, LXs [27–29];nd macrophages can form PGs, LTs [30]. More importantly, stemells can also synthesize eicosanoids. Mesenchymal stem cellsMSCs) constitutively express COX, PGE [31,32], 5-LOX, and 12-LOXynthases [33], producing PGs and LXs respectively. In addition,hese cells can also express the major 20-HETE-producing enzymesYP4A11, CYP4F2 [34] and EET-producing enzyme CYP2J2 [35,36],

Please cite this article in press as: E. Berry, et al., Eicosanoids: Emerging cOther Lipid Mediat (2016), http://dx.doi.org/10.1016/j.prostaglandins

ynthesizing significant levels of 20-HETE and EETs. In additiono MSCs, embryonic stem (ES) cells can produce PGs [37], andndothelial progenitor cells (EPCs) can form PGs [38,39] as wells 20-HETE [36]. Notably, EPCs are a rich source of PGE2 [39].

PRESSpid Mediators xxx (2016) xxx–xxx

3. Eicosanoids in regulation of stem cell functions

Eicosanoids are known to play important roles in the modula-tion of stem cell functions. They can stimulate the proliferation ofstem cells in the bone marrow, and when adequate numbers arereached, stem cells are mobilized and homed towards the wound,where they differentiate to replace damaged cells and tissues. Ithas been shown that various types of eicosanoids promote eachphase of stem cell progression in wound healing, starting in thebone marrow niche to the site of injury.

In response to injury, stem cells first increase their numbersthrough cell proliferation. Administration of PGE2 in mice resultsin a significant increase in the number of EPCs in the bone marrowand peripheral circulation [39]. Jang et al. demonstrated that PGE2stimulates human umbilical cord blood MSC (hUCB-MSC) prolifer-ation through �-catenin-mediated c-Myc and vascular endothelialgrowth factor (VEGF) expression [31]. Consistently, ex vivo treat-ment of isolated EPCs with the clinically approved PGE1 analoguealprostadil, enhanced EPCs numbers, while COX-2 inhibitor, pare-coxib, significantly reduced EPCs numbers [39]. Additionally, LTD4has been shown to stimulate mouse ES cell proliferation via STAT3,phosphoinositide 3-kinases PI3 K/Akt and the GSK-3�/�-cateninpathway [40]. Recently, our lab has shown that 20-HETE can stim-ulate EPCs proliferation, while HET0016, a selective inhibitor of20-HETE synthesis, reduces proliferation [41]. These findings col-lectively support a crucial role of eicosanoids in the regulation ofstem cell proliferation.

Upon reaching sufficient cell numbers, stem cells gain theability to migrate towards a chemotactic gradient. Yun et al.reported that PGE2 partially stimulates hMSC migration throughthe interaction between Pfn-1 and F-actin via EP2 receptor-dependent-b-arrestin-1/JNK signaling pathways [42] .EPCs arePGI2 receptor IP expressing cells and PGI2 can promote migra-tion and proliferation of EPCs which is tightly regulated bythe PGI2/IP pathway [38]. Additionally, pro-resolving lipid medi-ator LXA4 can significantly enhance the migration capacityof human periodontal ligament stem cells (hPDLSCs) throughthe activation of its cognate receptor ALX/FPR2 [43]. Recently,LTB4 has been found to significantly increase migration ofCD34−/CD133+/VEGFR2+EPCs with more potent homing and vas-cular repair ability than classic CD34+/CD133+/VEGFR2+EPCs. LTB4can also trigger adhesion of both CD34−/CD133+/VEGFR2+EPCs andCD34+/CD133+/VEGFR2+EPCs [44]. Lastly, we have recently demon-strated that the CYP4A/F-20-HETE system can also stimulate EPCsmigration in an autocrine and paracrine manner [41].

The next phase of injury response requires stem cells to mobilizefrom the bone marrow into the peripheral circulation and subse-quently home toward target tissues to initiate repair processes;thus, making stem cell mobilization and homing two crucial eventsin the cascade of injury response. Accumulating evidence suggeststhat eicosanoids can regulate these two processes. It was found thatin vivo blockade of PGE2 production by selective cyclooxygenase-2inhibition virtually abrogated ischemia-induced EPCs mobilization[39]. Also, short-term ex vivo exposure of adult hematopoietic stemcells (HSCs) to PGE2 enhances homing of HSCs to SDF-1� throughan increase in the expression of CXCR4 on HSCs [45]. Additionally,AMD3100, a selective inhibitor of CXC4R, reduces the migrationof HSCs. This indicates the importance of this receptor for inter-action with PGE2 [46]. In addition, pharmacologic stabilization ofHIF-1� can increase CXCR4 expression and enhance HSC hom-ing [47]. HIF-1� is found to be responsible for PGE2-enhancedCXCR4 upregulation and homing of stem cells [47]. Recent data

ontributors in stem cell-mediated wound healing, Prostaglandins.2016.11.001

from our group demonstrated that 20-HETE enhances EPCs secre-tion of pro-angiogenic molecules such as HIF-1�, VEGF and SDF-1�[41]. Growth factors such as VEGF and SDF-1� have been reportedto stimulate the mobilization and homing of stem cells toward

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Fig. 1. Major Enzymatic Pathways of Eicosanoids Biosynthesis. Free AA is converted to eicosanoids via three major pathways: the COX, LOX, and CYP450 pathways. In theCOX pathway, AA is converted to PGG2 which is then reduced to PGH2 and subsequently metabolized to PGs and TXs by specific PG and TX synthases. For PG synthases,PGH2 is converted to PGD2, PGE2, PGF2 and PGI2. For the TX synthases, PGH2 is converted to TXA2. In the 5-LOX pathways, AA is converted to 5-HpETE, which is furtherm , LTC4, LTD4, and LTE4. 5-LOX can also convert AA to LXA4 and then to LXB4. 12-LOX and1 y metabolizes AA into 20-HETEs and EETs via metabolism through CYP4A/F and CYP2C/Jf

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Fig. 2. Contribution of Stem Cells in Wound Healing. MSCs enhance wound healingthrough the modulation of inflammation, differentiation into epidermal and dermal

etabolized to form the unstable LTA4, and is then subsequently converted to LTB45-LOX convert AA to 12-HETE and 15-HETE respectively. The P450 pathway mainlamilies respectively.

argeted tissues [48]. Thus, it is possible that 20-HETE may also pro-ote mobilization and homing of EPCs. Lastly, 11,12-EET can also

romote hematopoietic stem and progenitor cell homing via mech-nisms involving an upregulation of AP-1 and several cytokinesuch as CXCL8 and CCL2 [49].

As stem cells arrive at their targeted tissues, cell differentia-ion takes place to replenish the injured cell population, allowingissue repair to take place. One study found that LTB4 can induceifferentiation of CD34 + HSCs which can be abolished by BLT, anntagonist of LTB4 receptors [50]. Another study found that atten-ation of the cysteinyl leukotriene pathway with specific cysteinyl

eukotriene type 1 receptor antagonists contributes to hMSCs dif-erentiation [51]. Additionally, 15-HETE promotes differentiation ofuman bone marrow MSCs to adipocytes [52]. Furthermore, Kimt al. found that the expression levels of CYP4A11 and CYP4F2n MSCs were decreased during adipocyte differentiation, whilexogenous treatment with 20-HETE increased adipogenesis in aose-dependent manner [34]. Lastly, hMSCs are found to expressigher levels of EETs compared to MSC-derived adipocytes and EETsecrease MSCs-derived adipocyte stem cell differentiation by thepregulation of HO-1-adiponectin-AKT signaling [35].

. Contribution of stem cells in wound healing

Wound healing is a dynamic and complex process, comprisingf overlapping phases of homeostasis, inflammation, and prolif-ration. During healing, inflammation and neovascularization arehe two most critical components. A continuous state of inflam-

ation in the wound perpetuates a non-healing state and leadso defects in new blood vessel formation, which strongly impairsound healing [10,53–55]. Consequently, angiogenesis is essential

o wound healing since it provides nutrient delivery to cells [56,57].

Please cite this article in press as: E. Berry, et al., Eicosanoids: Emerging cOther Lipid Mediat (2016), http://dx.doi.org/10.1016/j.prostaglandins

t is increasingly evident that wound healing occurs because ofvents in two compartments. Within the wound, neovascular-zation occurs, and within the bone marrow, various signalingathways lead to the mobilization of stem cells involved in the heal-

cells, and paracrine effects. EPCs accelerate wound healing mainly due to their keyrole in post-natal vasculogenesis. EPCs can differentiate into ECs and secrete VEGF,SDF-1�, and IGF-1, directly contributing to neovasculogenesis.

ing cascade [58]. Mounting studies have reported that various stemcells can promote both acute and chronic wound healing [59–61].Tateishi-Yuyama et al. demonstrated that injection of bone mar-row mononuclear cells into the gastrocnemius muscle of chronicischemic patients improved ankle-brachial index, pain and walk-ing ability of all 32 patients in the study [62]. Among stem cells, themost promising populations for wound healing are MSCs and EPCs,as shown in Fig. 2.

4.1. MSCs in wound healing

ontributors in stem cell-mediated wound healing, Prostaglandins.2016.11.001

Given their immunomodulatory and angiogenic properties,MSCs involvement in wound healing has been studied extensively[63]. MSCs enhance wound healing through the modulation of

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nflammation, promotion of angiogenesis, and differentiation intopidermal and dermal cells. MSCs can differentiate into multiplekin cell types, including keratinocytes and pericytes, which con-ribute to the repopulation of the wound bed, as well as ECs, toield new vessels [64]. In addition, MSCs can secrete importantytokines necessary for wound healing including epidermal growthactor (EGF), insulin-like growth factor-1 (IGF-1), keratinocyterowth factor (KGF), transforming growth factor-� (TGF-�), fibro-last growth factor (FGF), SDF-1�, VEGF and angiopoietin [65,66].tudies have shown that bone marrow (BM)-MSCs-treated woundsxhibited significantly accelerated wound closure, with increasedngiogenesis through differentiation and release of proangiogenicactors, VEGF and angiopoietin-1 [67]. Mucosally transplantedolonic MSCs also stimulate intestinal healing by promoting angio-enesis [68].

Another significant mechanism of MSCs is that they directlyttenuate the inflammatory response [65]. Studies have shown thatSCs can be activated by proinflammatory signals to introduce two

egative feedback loops. In one loop, MSCs are activated to upregu-ate expression of COX2 and other components of the AA pathway,esulting in the secretion of PGE2 that drives resident macrophagesoward an M2 anti-inflammatory phenotype. In another loop,he activated MSCs increase the expression of anti-inflammatoryrotein TNF� stimulated gene/protein 6 (TSG-6), resulting in aecrease in secretion of TNF� and other pro-inflammatory media-ors, such as IL-1�, IL-6 and PGE2 [69,70]. A chronic inflammatory

icroenvironment can also impair the activity of MSCs. It iseported that hydrogel which can prohibit chronic inflammation,romotes growth factor FGF and TGF-�1 secretion by MSCs, and theombination of hydrogel with MSCs exhibits significantly greateround contraction in diabetic mice [71]. The result implies that

ubstances which have anti-inflammatory effects in combinationith MSCs may be able to promote wound healing.

.2. EPCs in wound healing

EPCs play an important role in postnatal vasculogenesis [72,73].everal publications reported that EPC transplantation acceleratesound healing by enhancing neovascularization [74–76]. In normal

omeostatic conditions, EPCs reside within a stem cell niche in theM, but when wound injury occurs, EPCs responding to mobilizing

actors, such as VEGF, SDF-1, and CXCR4, are then mobilized intoeripheral circulation [77,78]. Once in circulation, EPCs respond tohemokine signaling in the tissues and home to the injury site. EPCshen invade and migrate through the endothelial monolayer andlood vessel basement membrane [79]. After they reach the sitef the wound bed, EPCs can directly incorporate into neovessels,ifferentiate into ECs and produce paracrine signals, such as VEGF,DF-1�, and IGF-1, contributing to neovasculogenesis [80]. VEGFnd SDF-1� are two of the most important regulators which canecruit BM-derived stem cells to the sites of injury and promotengiogenesis [81]. Thus, the improvement of EPCs mobilization,oming, migration, invasion, proliferation and differentiation mayave beneficial effects on wound healing.

Moreover, others have shown that enhanced growth of EPCsn wounds can accelerate wound healing [82]. For example, sub-tance P, which enhances EPC mobilization, can accelerate woundealing [83]. Additionally, DBcAMP, which has been shown to accel-rate wound healing, promotes recruitment of EPCs into wounds84]. Furthermore, inactivation of CXCL12, the major chemokineor EPCs recruitment and homing, via matrix metalloproteinasesMMPs), impedes the wound healing process, while local inhibi-

Please cite this article in press as: E. Berry, et al., Eicosanoids: Emerging cOther Lipid Mediat (2016), http://dx.doi.org/10.1016/j.prostaglandins

ion of MMPs increases the wound healing rate [85]. In patientsith diabetic foot ulceration, complete wound healing is associatedith a parallel reduction in circulating CD34 + KDR+ cells, markers

f EPCs, suggesting an enhanced homing of EPCs during the heal-

PRESSpid Mediators xxx (2016) xxx–xxx

ing process [54]. However, reduced levels and impaired function ofEPCs have been found in diabetes [86,87]. Clinical management ofchronic wounds, such as diabetic wounds, relies mainly on dress-ings and pharmacological therapies that can improve endothelialrepair and regeneration [80]. Thus, EPCs in combination with chem-icals which can augment EPC function may provide a therapeuticbenefit for chronic wounds.

5. Emerging role of eicosanoids in stem cell-mediatedwound healing

Eicosanoids are abundant in the wound bed [88] and can con-tribute directly to wound healing. Endogenous PGE2 stimulatesthe healing of small intestinal lesions by inducing angiogenesis[89]. Also, the use of PGE1 in a rat’s ear skin wound was foundto significantly increase the wound bed blood flow [90]. It is longbelieved that EETs can stimulate organ and tissue regeneration,and treatment with 11,12- or 14,15-EETs in a mouse ear woundmodel accelerates wound closure as compared with controls [91].In another study, genetically modified mice with either high EET(Tie2-CYP2C8-Tr, Tie2-CYP2J2-Tr, and sEH-null) or low EET (Tie2-sEH-Tr) were used. Wound healing was accelerated with increasedvascularization in high EET mice, while suppressed in low EETmice when compared with wild-type (WT) mice [92]. Addition-ally, the binding of AA to GPR40 on hUCB-MSC increases motility ofthese stem cells to the wound site and accelerates wound heal-ing [93]. Taken together, the ability of eicosanoids to promotewound healing and modulate stem cell functions give rise to a par-ticular interest in understanding the role of eicosanoids in stemcell-mediated wound healing.

5.1. COX-derived eicosanoids

Apoptotic cells release growth signals that can stimulatethe proliferation of stem cells, which ultimately contributes towound healing. A key player in this process is PGE2, which actsdownstream of caspases 3, and 7 [94]. Also, PGE2 helps newbone formation by stimulating stem cell differentiation into anosteoblastic cell line [95]. In a rat segmental bone defect model,results show that with PGE2 treatment, there is a significantbone healing response due to stimulation of bone marrow osteo-progenitor cells [96]. To demonstrate clinical applicability, Herrleret al. [39] found that administration of hEPCs following ex vivoPGE1 pretreatment in a hind limb ischemia murine model resultedin a significantly greater enhancement of limb perfusion recoveryas compared to vehicle-treated hEPCs.

It is known that NSAID administration inhibits COX-1 andCOX-2, which decreases TX and PG production. Administrationof aspirin has been showed to delaye re-epithelialization duringwound healing after skin puncture due to reduced contact of 12-hydroxyheptadeca-trienoic acid (12-HHT), a downstream productof COX, with Leukotriene B4 receptor type 2 (BLT2) [97]. Addi-tionally, Goren et al. demonstrated that treatment with ibuprofen,a COX inhibitor, reduced PGE2 levels and was associated withimpaired wound healing [98]. Furthermore, Yun et al. demon-strated that through the binding of TXA2 to its receptor on humanadipose derived MCSs (hADSCs), hADSCs were activated to prolif-erate, migrate and differentiate to promote wound healing [99].

It has also been reported that PGI2 contributes to angiogenesis incooperation with BM-derived cells, such as EPCs [100]. Inactivationof COX-1 and PGI2 synthase (PGIS) by siRNA significantly impaired

ontributors in stem cell-mediated wound healing, Prostaglandins.2016.11.001

angiogenesis in vitro and in vivo [101]. In addition, engineered EPCsthat constitutively secrete high levels of PGI2 (PGI2-EPCs) showsignificantly less caspase-3/7 activity and enhanced angiogeniccapability in vitro than native EPCs. This is demonstrated through

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Fig. 3. Eicosanoids in Regulation of Stem Cell-mediated Wound Healing. Uponwound injury (step 1), cytokines released from the wound lead to the activationand mobilization of bone marrow-derived stem cells. As stem cells home to thewound site (step 2), they produce eicosanoids which can potentially influence thewound bed in a paracrine manner. Eicosanoids may also influence the stem cellsthemselves in an autocrine manner, positively contributing to stem cell prolifer-ation in the wound bed (step 3). Additionally, the wound bed itself can produceeicosanoids due to injury stimuli. Once established in the wound bed, stem cells can

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he promotion of better tube formation by conditioned PGI2-EPCedium compared with a native EPC conditioned medium [102].

y deletion of the BM-specific PGI2-specific receptor IP, Aburakawat al. [103] demonstrated that WT mice transplanted with IP-eleted BM showed impaired blood flow recovery after hind limb

schemia, while blood flow could be completely recovered by intra-uscular injection of WT EPCs. Blood flow recovery may have

een impaired because the expression of integrins in EPCs wasecreased. Furthermore, it is conceivable that the ability of EPCso augment the biosynthesis of vasoactive substances such as PGI2n the vessel wall may also contribute to the regenerative functionf EPCs [104]. This is consistent with the finding which showedhat patients with critical limb ischemia have low levels of EPCs,nd that use of the prostacyclin analogue, Iloprost, increased cir-ulating EPCs in patients with critical limb ischemia [105]. Theseesults suggest that COX-derived eicosanoids may be developed as

novel and safe strategy to facilitate wound healing.

.2. LOX-derived eicosanoids

12/15-LOX is one of the other key enzymes catalyzing unsatu-ated essential fatty acids to lipid mediators in the skin. Hong et al.106] found there were more MSCs in the wounded dermis of WT

ice, along with higher levels of 12/15-LOX protein and its prod-cts, 12S-HETE and 15S-HETE, compared to 12/15-LOX−/− mice.ince densities of MSCs are critical for wound healing, skin woundealing impaired by 12/15-LOX−/− may involve suppressed densi-ies of pro-healing MSCs. Although undifferentiated ES cells wereevoid of components of the 5-LOX pathway, differentiating ES cellsithin embryoid bodies express all the necessary enzymes of the

-LOX pathway and acquire the ability to synthesize all types ofTs. Pharmacological inhibition of LT signaling significantly inhibitsasculogenesis of ES cells [107]. Although no research has studiedhe contribution of eicosanoids in the regulation of inflammationn stem cell-mediated wound healing, other models may give us

hint. LXA4 was the first identified anti-inflammatory and prore-olving eicosanoid [108]. In a LPS-induced acute lung injury mouseodel which pathophysiologic mechanisms include inflammation,

t was found that both MSCs and LXA4 can improve survival andecrease the production of the proinflammatory mediator TNF-�,hile exposure to WRW4, a LXA4 receptor antagonist, attenuates

heir beneficial effects. This implies that MSCs contribute to healingf lung injury through their receptor for LXA4 [33].

.3. CYP-derived eicosanoids

Previous studies in our laboratory identified the CYP4A11–20-ETE system as a novel regulator of several EPCs functionsssociated with the neovascularization response [41], a hallmarkf wound healing. Recently, we found that EPCs increase angio-enesis in vivo using a Matrigel plug angiogenesis assay, and thathese increases are markedly reduced by the local inhibition ofhe 20-HETE system. These results strengthen the notion that0-HETE regulates the angiogenic functions of EPCs in vitro andPC-mediated angiogenesis in vivo [109] and, in turn, may facilitatehe wound healing process. Furthermore, EETs are natural angio-enic mediators. Treatment with EETs and the sEH inhibitor t-AUCBignificantly accelerates neovascularization in healing wounds andound closure as compared to controls in the hairless mouse

ar wound model [110]. EPCs treated with the sEH inhibitor-AUCB can increase EET levels [111]. Recently, t-AUCB are demon-

Please cite this article in press as: E. Berry, et al., Eicosanoids: Emerging cOther Lipid Mediat (2016), http://dx.doi.org/10.1016/j.prostaglandins

trated to augment migratory activity of EPCs from patients withcute myocardial infarction, increase VEGF expression in EPCs, andmprove the activity of EPCs capillary tube formation in a dose-ependent manner in vitro [111]. These findings may imply that

either differentiate into mature tissue specific cells or secret growth factors that arerequired for wound repair (step 4). Thus, eicosanoids may regulate the mobilization,homing, proliferation, and differentiation of stem cells involved in wound healing.

EETs can also modulate the function of EPCs to contribute to woundhealing.

6. Conclusion and future directions

Due to the high prevalence of wound injury, especially non-healing chronic wounds and the high monetary cost of treatments[5], the significance of studying wound repair has become essen-tial. Regenerative medicine has taken great interest in the role stemcells play in wound repair [112] and more recently the effects ofeicosanoids, in conjunction with stem cells, on repair.

In this review, we describe the association of stem cells andeicosanoids in the promotion of wound healing [113]. As illus-trated in Fig. 3, when a wound occurs, stem cells are activated[114] and eicosanoids are produced [88]. Eicosanoids can functionin autocrine and paracrine manners [115]. Other than the woundsite, eicosanoids can also be formed by stem cells [31,33]. In turn,eicosanoids regulate proliferation, migration, homing and differen-tiation of stem cells [40,42,45]. MSCs and EPCs have been shown tobe the most potent stem cells in the stimulation of healing. MSCscontribute to wound healing through the attenuation of the inflam-matory environment of the wound [112], differentiation into skincells [64] and the production of paracrine effects [65]; while EPCsaccelerate wound healing mainly due to their key role in post-natal vasculogenesis, which attributes to the mobilization, homing,migration and differentiation of EPCs [74,82,83]. All together, thesefindings indicate the importance of stem cells in conjugation witheicosanoids to promote wound healing.

In summary, increased eicosanoids in ischemic tissues can regu-late ischemic-mediated neovascularization that is essential for thesupport of wound healing processes via stem cell proliferation,mobilization, homing and differentiation [40,42,45]. Conversely,the inhibition of either ischemic-tissue derived or stem cell-derivedeicosanoids synthesis or the antagonization of their actions reduces

ontributors in stem cell-mediated wound healing, Prostaglandins.2016.11.001

the ischemia-induced compensatory neovascularization and thus,impeds wound healing. Therefore, eicosanoids may be a noveltherapeutic target in manipulating stem cell-mediated neovas-cularization underlying the ischemic diseases, but the detailed

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echanisms by which eicosanoids affect stem cell functions remaino be largely unknown. Due to the unique application of stem cellsnd eicosanoids in the promotion of wound healing, this area ofnterest warrants further investigation.

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