Role of Stromal Cell-Derived Factor-1 in Endothelial Progenitor Cell-Mediated Vascular Repair and Regeneration

Abstract

Endothelial progenitor cells (EPCs) are immature endothelial cells that participate in vascular repair and postnatal neovascularization and provide a novel and promising therapy for the treatment of vascular disease. Studies in different animal models have shown that EPC mobilization through pharmacological agents and autologous EPC transplantation contribute to restoring blood supply and tissue regeneration after ischemic injury. However, these effects of the progenitor cells in clinical studies exhibit mixed results. The therapeutic efficacy of EPCs is closely associated with the number of the progenitor cells recruited into ischemic regions and their functional abilities and survival in injury tissues. In this review, we discussed the regulating role of stromal cell-derived factor-1 (also known CXCL12, SDF-1) in EPC mobilization, recruitment, homing, vascular repair and neovascularization, and analyzed the underlying machemisms of these functions. Application of SDF-1 to improve the regenerative function of EPCs following vascular injury was also discussed. SDF-1 plays a crucial role in mobilizing EPC from bone marrow into peripheral circulation, recruiting the progenitor cells to target tissue and protecting against cell death under pathological conditions; thus improve EPC regenerative capacity. SDF-1 are crucial for regulating EPC regenerative function, and provide a potential target for improve therapeutic efficacy of the progenitor cells in treatment of vascular disease.

Introduction

Vascular disorders including myocardial infarction and ischemic stroke are leading cause of death and adult disability worldwide [1, 2]. Endothelial dysfunction is considered to be an early event in the occurrence of vascular disease [3] Vascular endothelium is a dynamic structure usually exposed to various stimuli originating from circulating blood, and damage initiates the proliferation of neighbor endothelial cells (ECs) to replace the dysfunctional for maintaining endothelial integrity [4]. Recent studies have demonstrated that endothelial progenitor cells (EPCs) have the potency of differentiating into mature EC and secreting a series of protective cytokines and angiogenic factors [5]. EPCs are bone marrow (BM)-derived immature endothelial cells with robust proliferation, differentiation and regenerative capacity. After recruited to ischemic tissues, they facilitate endothelial repair, promote new blood vessel formation, and increase local blood supply and tissue recovery. Emerging evidence indicates that and the number and function of the progenitor cells are related closely to the outcome of vascular disease including cerebral ischemia and myocardial infarction [6–11]. Endothelial dysfunction or subsequent the occurrence of ischemic vascular disease triggers the mobilization of EPCs from BM into the peripheral circulation. Circulating EPCs then migrate into the ischemic regions where they participate in repair of injured endothelium, formation of new blood vessel and recovery of damaged tissues [12–14]. These multiple steps are tightly controlled by a series of secretive cytokines and growth factors, such as stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6), estrogen, matrix metalloproteinase-9 (MMP-9) and E-selectin [15–22]. SDF-1 signal plays a critical role in trafficking EPCs to neovascularization sites and promoting the cell survival; thus provide a potential target for improving the functional capacity of EPCs in vascular repair and regeneration.

Characterization of EPCs

EPCs are an endothelial precursor cell population lodged in stem cell niches within BM [23]. The cells were initially described as expression of specific markers on their surface, including CD34⁺ and vascular endothelial growth factor receptor-2 (VEGFR -2) or kinase insert domain receptor (KDR) [23]. Since these surface markers have been used for identification of BM-derived hemangioblast and hematopoietic progenitor cells, EPCs are considered to arise from hemangioblast, a precursor of hematopoietic stem cells (HSC) [24, 25]. EPCs are a heterogeneous population presented in different stages of endothelial differentiation with different phenotype and function. Recently, an array of biomarkers including CD34, CD133, CD31, VEGFR-2, von Willebrand factor (vWF), CD144, Tie2, CD117, CD62E and CD45 are used as the most commonly surface markers for defining an EPC population [26–31]. Glycosylated form of CD133⁺ protein is a specific marker of immature progenitor cells, while VEGFR-2 is accepted as a surface marker of endothelial lineage [32, 33]. CD133⁺/ CD34⁺/VEGFR-2⁺ cells more likely reflect immature EPCs [27]. In the differentiation of EPCs toward mature ECs, few surface markers are lost. The marker CD133⁺, for example, is negative expression on ECs [34]. Recent studies have identified a surface marker CXCR7 expressed on EPC, and the marker is associated with the survival and homing of the progenitor cells [35]. There are mainly two different subpopulations of EPCs: early-outgrowth EPCs and late-outgrowth EPCs isolated by different culture methods [36, 37] (Table 1). Early-outgrowth EPCs are obtained from blood sample cultures after 4 ~ 7 days. These cells exhibit spindle-shaped morphology and express CD31, CD133, CD34, VEGFR-2, vWF, hematopoietic-specific cell surface antigen CD45, and the monocyte/macrophage markers CD14 as well as CD115 [27, 38, 39]. These cells possess abilities to uptake acetylated low-density lipoprotein (AcLDL) and to bind of the lectin Ulex europeus agglutinin-1 (UEA-1), the functions commonly ascribed to mature ECs [40]. Early-outgrowth EPCs have a limiting proliferation potential, and their angiogenic capacity mainly depends on secretory function [41]. They produce a number of growth factors and cytokines such as VEGF, fibroblast growth factor (FGF), granulocyte colony stimulating factor (G-CSF) and insulin-like growth factor-1 (IGF-1), which alone or synergetically contribute to endothelial repair and regeneration [41]. Late-outgrowth EPCs are referred to endothelial colony forming cells (ECFCs) with cobblestone morphology displaying in culture [40]. Different from early-outgrowth EPCs, these EPCs are negative expression in monocyte/ macrophage cell surface antigens, CD14, or CD115 [40]. Late-outgrowth EPCs represent more immature cells with powerful capacity in proliferation and forming secondary endothelial cell colonies, and robust ability of forming capillary-like in vitro and perfused blood vessels in vivo [40–42]. Recently studies confirm the role of EPCs in endothelial repair and neovascularization, and SDF-1 signal are crucial for regulating their function.

Table 1.

Characterization of EPCs

EPC Population	Early-outgrowth EPCs	Late-out growth EPCs	References
Appearance in culture	4~7 days	14~28 days	[37]
Cell morphology	Spindle shape	Cobblestone-like shape	[37]
Proliferation capacity	Limiting	Powerful	[37, 52]
Cell surface marker
CD34	+	+	[39]
CD45	+	dim	[49]
VEGFR-2	+	+	[39]
CD31	+	+	[39, 40]
CD133	+	+	[43]
vWF	+	+	37
CD14	+	–	[41, 50]
CD115	+	–	37
Neovascularization function	Secreting angiogenic factors	Incorporating into vessels	[41, 42]

Properties of stromal cell-derived factor -1

SDF-1 is a multifunctional protein widely expressed in an array of different cells and tissues. It is a small 8 kDa secreted cytokine encoded by gene 10q11.1 [43]. This cytokine was initially discovered as an efficacious chemoattractant in directing movement of lymphocytes and monocytes to target tissues during host defense and pathological immune responses [44]. Chemotactic SDF-1 contributes to maintaining retention and function of stem and progenitor cells in BM under physiological conditions, and mobilizing the cells movement into the circulation after injury [45, 46]. The transduction of SDF-1 signal depends on its receptor CXCR-4. CXCR-4 is a G protein-coupled receptor (GPCR) containing seven transmenbrane domains [47, 48]. Binding to the extracellular domains of CXCR-4 modifies the tertiary structure of the receptor, leading to activation of heterotrimeric G proteins. The activated G protein then releases the subunits from its protein complex into the cytosol, and subsequently triggers a series of intracellular downstream pathways [44, 49–51]. The SDF-1/ CXCR-4 axis serves multiple roles in a wide range of molecular and cellular processes [52, 53]. Deficiency of SDF-1 leads to defects of stem and progenitor cells in BM colonization and impaired cardiovascular and cerebrovascular development in animal models [54, 55]. SDF-1 signal plays a critical role in EPC-mediated endothelial repair and regeneration. The mobilization and recruitment of EPCs to neovascularization sites are through SDF-1/CXCR4 mechanism [52, 56]. CXCR-4 is a chemokine receptor for SDF-1 expressed by hematopoietic progenitor and endothelial progenitor cells implicating in the cell bioactivities [57, 58]. Recently studies discovered CXCR7, another receptor of SDF-1, expressed on the surface of EPCs, and SDF-1/CXCR7signal is involved in the homing and survival of the progenitor cells [59]. SDF-1 also expands its signal by crosstalking with other regulatory factors, leading to synergistic effect on EPC functional activities [57, 59–67] (Fig. 1).

Fig. 1.

Role of SDF-1 in EPC-mediated vascular repair and neovascularization. Injury Tissues produce and release SDF-1 followed by the formation of SDF-1 gradient between peripheral circulation and ischemic regions. SDF-1 interacts with its receptor CXCR-4 expressed on EPC surface, resulting in MMP-9 activation and release of sKitL from the stromal cell membrane into surrounding space. The bonding of sKitL and c-kit leads to the movement of c-Kit⁺ EPCs from the cell niche into peripheral circulation. SDF-1can also expands its mobilizing signal by crossing-talk with other mobilizing inducers such as G-CSF, VEGF, and other signal pathway such as eNOS-dependent signal transduction pathway, resulting in further mobilization of EPCs. The circulating EPCs migrate toward the SDF-1 gradient into injury vessel. SDF-1 activates EPCs to express adhesion molecule PSGL-1, a ligant of P-selectin expressed on the activated platelets adhering on exposed subendothelium of damaged vessels. The bonding induces the adhesion of EPCs to the sites of injury. SDF-1 interact with other pro-angiogenic factors such E-selectin and ICAM-1, resulting in synergic effects on EPC adhesion. EPCs then proliferate and differentiate into mature ECs to repair damaged vessels and form new blood vessels, and secrete a series of angiogenic cytokines to facilitate tissue regeneration. EPCs, endothelial progenitor cells; MMP-9, matrix metalloproteinase-9; EC, endothelial cell; BM, bone marrow; SDF-1, stromal cell-derived factor-1; PSGL-1; P selectin glycoprotein ligand-1; ICAM-1, intercellular adhesion molecule-1; VEGF, vascular endothelial growth factor; G-CSF, granulocyte colony stimulating factor

SDF-1 in EPC mobilization

The levels of EPCs in the peripheral circulation are low under physiological conditions. The majority of the progenitor cells reside normally in the BM niche, a specialized microenvironment for the cells to maintain their integrity and functions including self-renew and repopulation [68–70]. The retention of EPCs in the microenvironment depends on integrins that tether the progenitor cells to stromal cells within BM [68]. Recent evidence indicates that EPCs can also be isolated and identified in human cord blood as well as vascular wall [71–73]. BM is considered to be a major source of circulating EPCs implicated in endothelial repair and neovascularization [23]. In response to ischemic stress and injury, EPCs migrate from BM into peripheral circulation and subsequently home to the ischemic sites to repair injured ECs and form new blood vessels [74, 75]. Clinical studies have shown that the number of EPCs are elevated in the peripheral circulation of the patients with cerebral ischemia or myocardial infarction, and the increased levels are closely associated with the better outcome of the disorders [76–80]. Increasing levels of SDF-1 were also detected in the peripheral circulation of the patients with cerebral ischemia, which are closely associated with the circulating number of EPCs and infarct volume in stroke patients [77]. SDF-1 is a key inducer for EPC mobilization. [62]. Injured tissue induces the generation and release of hypoxia inducible factor-1 (HIF-1), followed by its downstream factor SDF-1 production [62, 81]. SDF-1 upregulates its receptor CXCR-4 expressed on EPC surface, and interaction activates the BM progenitor cells [58, 82]. MMP-9 then becomes activated, followed by the release of sKitL from the stromal cell membrane into surrounding space [83]. sKitL is a ligand of c-kit expressed on the surface of EPCs, the bonding resulting in the movement of c-Kit⁺ EPCs from the cell niche into peripheral circulation [83, 84]. Other mobilizing factors, VEGF, G-CSF, Parathyroid hormone (PTH), hepatocyte growth factor, nitric oxide synthase (eNOS), interleukin-6 (IL-6) and estrogen contribute to mobilizing EPCs from BM into peripheral circulation [15–18, 64, 66, 84–86]. SDF-1 also interact with other mobilizing inducers including G-CSF, VEGF and E-selectin, and other signal pathway such as eNOS-dependent signal transduction pathway, resulting in further movement of CXCR4⁺stem and progenitor cell into circulation [87]. Delivery of SDF-1, for example, enhances the production of VEGF in the ischemic area, resulting in elevated number of EPCs in the peripheral circulation [88].

SDF-1 in EPC recruitment

The recruitment of circulating EPCs into ischemic regions is necessary for these progenitor cells to repair damaged endothelium and recovery of injured tissue. The cytokine SDF-1 is a homing signal for trafficking EPCs from circulation into the sites of injury via interaction with its receptor CXCR-4, which is expressed on EPC surface [62, 89]. This is supported by the findings that the levels of SDF-1 are in direct proportion to the number of CXCR-4⁺ progenitor cells in the circulation as well as in the ischemic area [90]. Blockade of SDF-1 signal in ischemic tissue or CXCR-4 on the circulating EPCs reduces the number of the progenitor cells recruited to the neovascularization sites [62]. Gene delivery of SDF-1 significantly increases the levels of EPCs in the ischemic myocardium after acute myocardial infarction, and SDF-1 also attracts CXCR-4⁺ progenitor cells to the sites of ischemia and promotes vessel growth in ischemic mouse brain [56, 91]. A number of risk factors for vascular disease reduce EPC number in circulation, decrease homing of the cells into ischemic regions, impair their capacity in repair damaged vessels, and these effects can be significantly reversed by the administration of cytokine SDF-1 [92–95]. Local application of the cytokine in wounds reverses the nitric oxide-mediated impaired homing of EPCs, and improves the cell recruitment and wound healing under diabetic conditions [96]. Similarly, gene transfer of SDF-1 promotes ischemic neovascularization through increasing the mobilization and homing of EPCs via endothelial nitric oxide synthase pathway in diabetic animal models [97]. These findings demonstrate that SDF-1 signal is critical for recruiting the progenitor cells into target tissues. After released by injury tissue and aggregated platelet into peripheral circulation, SDF-1 forms a concentration gradient between the circulation and the wound, which directs CXCR-4⁺ EPCs to migrate to the  denuded endothelium [98, 99]. Further evidence demonstrates that SDF-1-induced EPC migration is mediated through the PI3K/Akt/eNOS signal transduction pathway [63].

SDF-1 in EPCs adhesion

Incorporation of circulating EPCs into damaged vessels is crucial for the cells to implement their regenerative function. [27, 31, 100]. This depends on the adhesion of EPCs to damaged endothelium via the interaction of their surface molecules with the receptors or ligands on activated ECs or subendothelial matrix proteins [101–103]. The injured tissue and aggregated platelet produce and release cytokine SDF-1, which stimulates the progenitor cells expressing P-selectin glycoprotein ligand-1 (PSGL-1) on their surface [98, 104]. Studies have shown that the expressing levels of PSGL-1 following injury are dose-dependent in the production of SDF-1 [98, 105]. PSGL-1 is a ligand of P-selectin that is expressed on the aggregated platelet in injured vessels [3]. Endothelial injury initiates the adhesion of platelets to the exposed subendothelium, leading to the platelet activation followed by the P-selectin expressed on their surface [104, 106, 107]. The bonding of PSGL-1 expressed on the surface of EPCs and P-selectin expressed on the surface of activated platelets induces the incorporation of the progenitor cells into the sites of injury (104). E-selectin is another intercellular adhesion molecule expressed on activated ECs implicated in the adhesion of circulating stem and progenitor cells to ischemic endothelium [22, 108, 109]. Studies in muscle ischemic models show that the number of EPCs incorporated into the injured vessels is in proportion to the production levels of E-selectin [108]. Increasing E-selection levels facilitate EPCs located in ischemic sites and promote new vessel formation and the recovery of lesions in animal models [110]. CD34 is a ligand of E-selection expressed on the surface of EPCs, and the bonding provides a mediator for cell-to-cell contact [25, 111]. SDF-1 signal increases the production of E-selection and consequently promotes the migration and adhesion of EPCs to injured vessels [22, 65, 110]. Different studies have shown that administration of SDF-1 increases the levels of E-selectin expressed on injured ECs and facilitates the incorporation of EPCs into fibronnectin in vitro, and promotes endothelial repair and diabetic wound healing by upregulating the expression of E-selection in animal models [22, 110]. SDF-1 interacts with other intercellular adhesion molecules, such as α4-integrin, β1- and β2-integrins, resulting in further incorporation and retention of the progenitor cells in damaged tissue [112–114]. α4-integrin is a surface marker of EPCs implicated in attachment of the cells to endothelium [115]. SDF-1 up-regulates α4-integrin levels, and promotes the integrin-mediated cell bindings [114]. EPCs selectively express β1- and β2-integrins that contribute to strengthening the bonding of the progenitor cells to the damaged endothelial monolayer [112]. Activation of β1- and β2-integrins relays on the secreted cytokine high mobility group box 1 (HMGB1). After released by injured tissue, HMGB1 interacts with its receptor expressed on EPC surface, leading to the activation of β1- and β2-integrins and subsequent the adhesion of the progenitor cells to the damaged endothelium [116]. Injury vessels produce intercellular adhesion molecule-1(ICAM-1), the receptor of β1- and β2-integrins [112]. The bonding drives the progenitor cells incorporating into the subendothelium [3]. SDF-1 signal stimulates EPCs expressing β1- and β2-integrins, and enhances the adhesion of EPCs to the neovascularization sites [112]. Additionally, SDF-1 also facilitates further adhesion of EPCs through ICAM-1-dependent pathway via upregulation of E-selectin, since the production of ICAM-1 depends mainly on the presence of E-selectin [108]. Taken together, these results strongly suggest that SDF-1 plays a crucial role in EPC homing and adhesion, and this contribute to the cell-mediated endothelial repair and tissue regeneration.

SDF-1 in EPC-mediated endothelial repair and vessel formation

Vascular endothelium is a layer of endothelial cells that is a dynamic structure and natural barrier between the blood and surrounding tissue [117]. The luminal ECs are usually exposed to various stimuli originating from circulating blood including physical injury, drug-related cytotoxicity and immune response [4]. The integrity of endothelium is dependent on the balance between endothelial damage and repair. Irreversibly structural and functional injury is considered to be an early step in the initiation of atherosclerosis and subsequent occurrence of vascular wall disease [3]. Endothelial damage initiates the proliferation and migration of existing vessel ECs to replace the dysfunctional [118]. Recently, accumulating evidence confirms the contributing role of EPCs in endothelial repair and postnatal neovascularization [23, 41, 119–121]. EPCs are immature endothelial cells lodged in BM with robust proliferation and highly regenerative capacity [40]. Injury signal mobilizes EPCs from BM into peripheral circulation, and subsequently attracts the progenitor cells to sites of endothelial denudation. The cells then proliferate and differentiate into mature ECs and secrete a series of protective factors [41, 122, 123]. These secretory cytokines and growth factors such as SDF-1, VEGF and IGF-1 provide a local microenviroment for further mobilizing the progenitor cells and promoting resided cells survival and endothelial regeneration [5]. Different studies have shown that increasing levels of EPCs in the peripheral circulation and ischemic areas are closely associated with blood supply restoration and tissue recovery after injury [10, 124, 125]. Infusion of EPCs was found to significantly augment the blood vessel density within the lesions in ischemic animal models, and EPCs also contribute to alleviate myocardial ischemia injury and reduce infarct size by restoring blood supply in damaged tissues after myocardial infarction [11, 120, 126, 127]. Clinical studies reveal that the high levels of EPCs not only decrease the occurrence of vascular events, but promote ischemic neovascularization and functional recovery after ischemic injury [56, 128, 129]. Therefore, EPCs may represent a novel approach for repair of endothelial injury and for treatment of ischemic vascular disease. However, the functional capacity of EPCs should be underlined, since they are closely associated with the efficacy of stem cell therapy. Cytokine SDF-1 is crucial for mobilizing EPCs into the circulation and trafficking the cells to target tissue, these contribute to improving the therapeutic efficacy of EPCs [130]. This is supported by the findings that increased levels of SDF-1 after stroke are detected in the cortical peri-infarct regions, accompanied by the increased EPC number and restoration of blood supply in injury tissues, and the functional recovery of ischemic brain [56, 131]. SDF-1 gene therapy promotes EPC number and vessel density in ischemic areas, resulting in a better outcome after cerebral infarction [56]. The high levels of SDF-1 following myocardial infarction increase the number of EPCs recruited in ischemic regions and subsequently contribute to restoring blood supply and alleviating myocardial ischemia [132]. Moreover, local application of SDF-1 significantly increases diabetic wound healing by reversing the defect of diabetic EPCs in mobilization and recruitment [96]. These effects can be blocked by AMD3100, a special blockage agent to SDF-1/CXCR-4signal [133, 134]. These results suggest that SDF-1 is crucial for upregulating EPC levels in circulation, elevating the number of the cells recruited in ischemic regions and increasing vessel growth and blood supply in damaged tissues, thereby provide a promising therapeutic target for improving efficacy of stem cell therapy (Table 2).

Table 2.

Regulation of SDF-1 in EPC-mediated vascular repair and tissue regeneration

Clinical models	EPC mobilization	Recruitment	Vessel density	Tissue regeneration	References
Ischemic stroke
SDF-1 secretion	Increase	Elevation	Augment	Promotion	[76, 77]
SDF-1 application	Increase	Elevation	Augment	Promotion	[66]
Myocardial infarction
SDF-1 secretion	Increase	Elevation	Augment	Promotion	[132]
SDF-1 application	Increase	Elevation	Augment	Promotion	[150, 151]
Diabetic wound
SDF-1 downregulation	Decrease	Impairment	Decrease	Delay	[96]
SDF-1 application	Increase	Elevation	Augment	Promotion	[96]

SDF-1 in EPC survival

EPCs during endothelial repair and neovascularization are exposed to the high levels of reactive oxygen species and inflammatory stress produced by the injured tissues, which contribute to apoptosis and dysfunction of the cells [135–137]. The vascular risk factors such as diabetes, hypertension, smoking and hypercholesterolemia also decrease the number of EPCs and impair their reparative function [136, 138–140]. The dysfunction could be partially reversed through increasing the expressing levels of SDF-1 [141, 142]. Recent studies revealed a second SDF-1 receptor CXCR7 expressed on surface of EPCs. SDF-1/CXCR7 is a survival signal for the cells under pathological conditions [142, 143]. EPCs treated with oxidative low-density lipoprotein (ox-LDL) or high glucose (HG) decrease CXCR7 expression, reduce tube formation, increase oxidative stress and apoptosis of the progenitor cells, which can be reversed by SDF-1 pretreatment in EPCs transduced with CXCR-7 lentivirus, indicating SDF-1/CXCR7 axis promotes EPCs survival and functional capacity [136]. Diabetes is associated with the defective functions of EPCs and delayed wound healing after injury, and administration of SDF-1 promotes the progenitor cell migration into the sites of injury and enhances blood supply and tissue repair [96]. Further studies have revealed that the dysfunctional capacity of diabetic and hypertensive EPCs is associated with the decline in CXCR7 levels on the cell surface, and increase the expression of SDF-1 and CXCR7 markedly reduce these damage effect through Nrf2 activation via AKt/GSK-3β/Fyn pathway [136, 142].

Application of SDF-1

The efficiency of EPCs therapy is dependent on their functional capacity in mobilization, migration and adhesion. Increasing the number of the progenitor cells recruited to the sites of ischemia is crucial for repairing endothelium and facilitating new blood vessel formation, and defection is related closely to impaired vascular regeneration and poor outcome after injury [144]. This may explain the modest effect of autologous EPC transplantation and EPC mobilization through pharmacological agents on tissue regeneration in several clinical trials [145, 146]. G-CSF, for example, is frequently used agent for mobilizing angiogenic progenitor cells to restore blood supply and recover damaged tissues. However, the mobilizing proteases activated by G-CSF can also cleave surface adhesion molecules of the progenitor cells, resulting in decreased retention of the cells in ischemic tissues and poor recovery after ischemia [147]. SDF-1 plays a crucial role in mobilizing stem and progenitor cells from BM into circulation and promoting accumulation and retention of the circulating cells into ischemic tissues; thus has been considered as a critical target for improving EPC-mediated endothelial repair and tissue regeneration [125, 148, 149]. In vitro studies revealed that SDF-1 modification of EPCs improved their function in migration, adhesion and tube formation. Transplantation of these progenitor cells have shown greatly increased blood vessel density and better functional outcome in ischemic mice [56]. Moreover, increasing local SDF-1 levels in damaged tissue displayed beneficial effects on functional recovery by attracting angiogenic stem cells to ischemic areas [150]. Administration of SDF-1 into diabetic lesions enhanced EPC mobilization, homing and wound healing [96]. SDF-1 transgene delivery increased the homing of stem and progenitor cells to the sites of ischemia, activated cell survival signaling and promoted neovascularization and myocardial regeneration in the infarcted heart [151]. Application of exogenous SDF-1 increased recruitment and incorporation of CXCR4⁺stem and progenitor cell into the ischemic myocardium, and improved blood supply and cardiac function after myocardial infarction [132]. S-SDF-1 (also known as S4V) is a variant of SDF-1 that is resistant to matrix metalloproteinase-2 and exopeptidase cleavage activated by damaged tissue. Intramyocardial delivery of S-SDF-1(S4V) promotes angiogenic progenitor cell homing, and improved cardiac function after myocardial infarction [150]. However, the efficiency of local SDF-1 delivery is partially reduced by the rapid diffusion of the cytokine from the wound into peripheral regions. HIF-1 is a key inducer of SDF-1 production. Strategies to increase the levels of HIF in injured tissues would promote 

the release and accumulation of SDF-1 in ischemic areas, and improve the recruitment and retention of EPCs into the damaged tisues. This hypothesis required to be elucidated in EPC-based therapy. Taken together, Increasing SDF-1 levels in ischemic regions can improve the efficacy of EPC-based cell therapy in ischemic vascular disease.

Conclusion

EPCs are a BM-derived precursor cell population. They participate in endothelial repair and postnatal neovascularization by direct incorporating into endothelium and paracrine function; thus provide a novel and promising therapy for the treatment of vascular disease. The abilities of EPCs to repair injured vessels and tissues depend on their number and functional capacity. Multifunctional SDF-1 plays crucial role in mobilizing EPCs from BM into peripheral circulation, recruiting of the progenitor cells into ischemic regions, and consequently promoting EPC-based vessel formation and tissue regeneration. Strategy to increasing SDF-1levels in ischemic regions can increase the number of EPCs located in damaged tissues and promote functional capacity of EPCs in tissue regeneration, and the therapeutic approaches using SDF-1for improving therapeutic efficacy of the progenitor cell to need further exploraion.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical statement

There are no animal experiments carried out for this article.