**Abstract**

Tissue engineering and regenerative medicine are branches of biomedical sciences that facilitate the use of cells and biocompatible scaffolds in favor of tissue restoration. In this regard, restoration and maintenance of angiogenesis and blood supplementation could be an effective strategy for injured tissue removal, accelerating healing rate, and successful transplantation of cells and scaffolds into target sites. It has been elucidated that mesenchymal stem cells have the potency to promote angiogenesis via paracrine activity and trans-differentiation into the endothelial lineage. In this chapter, we highlighted the paracrine property of mesenchymal stem cells to modulate angiogenesis in the target tissues.

**Keywords:** mesenchymal stem cells, angiogenesis, paracrine activity, exosomes

### **1. Introduction**

Angiogenesis, termed as neovascularization, is defined as de novo vascularization from the pre-existing vascular network and activated in response to numerous pathological and physiological stimuli, playing critical roles during development and tissue repair [1]. Recent advances in the field of stem cell research, notably MSCs, have opened new horizons to human medicine in the promotion of angiogenesis and restoration and salvage of ischemic tissues [2]. MSCs actively participate in angiogenesis via direct differentiation, cell contact interaction with endothelial lineage, and releasing pro-angiogenic factors via a paracrine manner [3]. Due to the low survival and differentiation rate of MSCs posttransplantation into ischemic microenvironment, it is proposed that the paracrine activity is the principal mechanism for the therapeutic outcome [4]. It has been well-established that stem cell-secreted growth factors are responsible for, at least in part, therapeutic effects. As a matter of fact, MSC-derived secretome is thought to be a suitable alternative therapeutic modality to MSCs posttransplantation. At present, the underlying mechanisms by which MSC secretomes contribute to tissue healing and angiogenesis are not fully addressed and many efforts are needed to fill knowledge gaps by experimental animal research and clinical trials prior to application to human medicine [5, 6]. Paracrine factors could increase the blood supplement of damaged tissues via the activation and recruitment of resident/circulating stem cells and progenitor cells [7, 8]. Several experiments detected the pro-angiogenic

capacity of MSCs isolated from different sources [9, 10]. **Table 1** ELISA and liquidchip assays of cytokine content of umbilical cord MSCs revealed several angiogenesis factors, including interleukin-8 (IL-8), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) compared to mature cell types such as fibroblasts. These pro-angiogenic factors are able to form vascular networks and increase the migration of endothelial lineage in vitro [51]. In addition to the secretion of angiogenic factors by MSCs, it was revealed that various factors existing in secretome could activate the angiogenic behavior in endothelial cells (ECs). For instance, equine peripheral blood MSC angiocrine was found to stimulate endothelial functional behavior by the induction of VEGF-A signaling pathway via several factors such as endothelin-1, IL-8, platelet-derived growth factor-AA (PDGF-AA), and IGF-2 [52]. Due to the variety of factors released by MSCs such as VEGF, monocyte chemoattractant protein-1 (MCP-1), and IL-6, an increased angiogenesis rate was observed in the mouse model of hindlimb ischemia, and even the combination of VEGF, MCP-1, and IL-6 could be served as a commercial cocktail for the promotion of angiogenesis either in vivo or in vitro [53]. In addition to the existence of the pro-angiogenic factor in MSC secretome, some authorities, however, showed the anti-angiogenic properties of these cells (**Table 2**) [67]. In some circumstances, the dual effect of a distinct factor was proved related to angiogenesis status. For example, in VEGF-free condition, the attachment of angiopoietin-2 (Ang-2) to receptor tyrosine kinase (RTK), namely Tie-2, promotes vascular destabilization and regression by reduction of pericyte-EC interaction, while in normal condition Ang-2 could increase EC migration and tip cell formation required for neovascularization [68]. Commensurate with these comments, one could hypothesize that the dynamic balance of MSC secretome, cell source, purity, and preconditioning could predetermine the pro- and/or anti-angiogenic property of MSCs [67].

By modulating distinct signaling pathway/s inside the MSCs, cell bioactivity would be induced in favor of neovascularization. For instance, it was shown that the activation of sonic hedgehog (Shh) factor in Wharton's jelly-derived MSCs (WJ-MSCs) induced the production of pro-angiogenic factors such as angiogenin, angiopoietin-1, activin A, matrix metallopeptidase-9 (MMP-9), granulocytemacrophage colony-stimulating factor, and urokinase-type plasminogen activator, indicating WJ-MSCs an ideal cell source for the induction of vascularization [69]. An experiment conducted by Matluobi et al. showed an enhanced vascular formation capacity of human MSCs after treatment with carvacrol evaluated by chicken chorioallantoic membrane angiogenesis assay. The carvacrol-treated MSCs tended to trans-differentiate into endothelial lineage by the expression of VWF and VE-cadherin [70]. MSCs have the ability to adapt themselves with environmental condition increasing regenerative potential in different conditions [71]. Maintaining the MSC cross talk with other cells is required for cell hemostasis, stemness feature, and regenerative potential in the distinct niche. For example, the normal bioactivity of Hox gene, *Abdominal-B*, seems to be essential in Drosophila cystic stem cells to obtain multipotentiality [72].

Regarding issues related to isolation protocols and stem cell proliferation rate, a careful selection is essential for high-throughput results. Vizoso et al. demonstrated large-scale secretome production and release of a vast array of bioactive factors in human uterine cervical stem cells with considerable advantages over MSCs from other tissues for research and clinical application [73].

The emergence of some conditions could change the trans-differentiation capacity of MSCs into distinct phenotypes. In the case of the vicious cycle of abnormal placental development in intrauterine growth restriction, placental mesenchymal stromal cells lose angiogenic potential while acquiring adipogenic capacity which is coincided with a metabolic shift from aerobic to anaerobic state [71]. It seems that

**103**

Heparin binding-EGF

Hepatocyte growth factor

*The Angiogenic Paracrine Potential of Mesenchymal Stem Cells*

**bone marrow MSCs**

**Function**

Angiogenin **+/+** A pancreatic ribonuclease, known as ribonuclease 5, which

Angiopoietin-1 **+/+** Activates TEK/TIE2 receptor; promotes angiogenic processes,

development [12] Angiopoietin-2 **+/−** Binds to TEK/TIE2, in the presence of VEGF and Ang-2 and

epithelial cells [16] Artemin **+/−** Binds for the GFR-alpha-3-RET and GFR-alpha-1-RET receptor

Tissue factor **+/−** Stimulates PDGF receptor signaling pathway, angiogenesis,

CXCL16 **+/+** Encourages a chemotactic response, pro-angiogenic [19] DPPIV **+/−** A membrane-bound oligopeptidase acting on and modulating

EG-VEGF **+/−** Also called Prokineticin 1. Binds to PROKR1 and PROKR2, pro-angiogenic [22]

Endothelin-1 **+/+** Derived from the endothelium with vasoconstrictor and

Endoglin **+/−** Also called CD 105. Modulates TGF-β1 and β3 responses,

FGF-7 **+/+** Has positive effects on cell proliferation, migration and

Acidic FGF/FGF-1 **+/−** Binds to for FGFR1 and integrins and induces angiogenesis [26] Basic FGF/FGF-2 **+/−** Ligand for FGFR1, FGFR2, FGFR3, and FGFR4, Vascular

FGF-4 **+/−** Has positive effects in MSC proliferation, pro-angiogenic [28]

**+/+** Has positive effects in angiogenesis [32]

**+/−** Has positive effects in angiogenesis [33]

HIF-1α **+/+** Functions as a master transcriptional regulator of the adaptive

survival, and angiogenesis [34]

GDNF **+/−** Has positive effects in angiogenesis [29] GM-CSF **+/−** Has positive effects in angiogenesis [30] Heparanase **+/+** Has positive effects in angiogenesis [31]

and promotes angiogenesis [17]

the pro-angiogenic chemokine CXCL12 [20]

angiogenic effects, prolymphoangiogenic [23]

division, chemotaxis, and arteriogenesis [25]

angiogenesis, stimulates arteriogenesis [27]

vascular development, and angiogenic effects [24]

**+/−** Encourages the growth of epithelial tissues, is anti-apoptotic,

Angiopoietin-4 **+/+** Binds to TEK/TIE2, modulating ANGPT1 signaling, can

Amphiregulin **+/−** An EGF-like ligand that binds to the EGFR, enhanced

induces vascularization [11]

promotes neovascularization [13, 14]

endothelial cell survival, migration, proliferation, and stabilization; and during embryogenesis has a role in heart

induce tyrosine phosphorylation of TEK/TIE2, and promotes endothelial cell survival, migration, and angiogenesis [15]

lymphangiogenesis, and stimulates the growth of normal

endothelial cell migration, chemotaxis and proliferation, and coagulation factor III/CD142; improves transcription of VEGF; and reduces transcription of the thrombospondins [18]

induces lymphangiogenesis, and improves MSC survival [21]

regeneration; role in cell migration and proliferation involved in

response to hypoxia and influences cell metabolism, cell

*DOI: http://dx.doi.org/10.5772/intechopen.84433*

**Factor Amniotic fluid/**

Epidermal growth

factor


*Update on Mesenchymal and Induced Pluripotent Stem Cells*

capacity of MSCs isolated from different sources [9, 10]. **Table 1** ELISA and liquidchip assays of cytokine content of umbilical cord MSCs revealed several angiogenesis factors, including interleukin-8 (IL-8), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) compared to mature cell types such as fibroblasts. These pro-angiogenic factors are able to form vascular networks and increase the migration of endothelial lineage in vitro [51]. In addition to the secretion of angiogenic factors by MSCs, it was revealed that various factors existing in secretome could activate the angiogenic behavior in endothelial cells (ECs). For instance, equine peripheral blood MSC angiocrine was found to stimulate endothelial functional behavior by the induction of VEGF-A signaling pathway via several factors such as endothelin-1, IL-8, platelet-derived growth factor-AA (PDGF-AA), and IGF-2 [52]. Due to the variety of factors released by MSCs such as VEGF, monocyte chemoattractant protein-1 (MCP-1), and IL-6, an increased angiogenesis rate was observed in the mouse model of hindlimb ischemia, and even the combination of VEGF, MCP-1, and IL-6 could be served as a commercial cocktail for the promotion of angiogenesis either in vivo or in vitro [53]. In addition to the existence of the pro-angiogenic factor in MSC secretome, some authorities, however, showed the anti-angiogenic properties of these cells (**Table 2**) [67]. In some circumstances, the dual effect of a distinct factor was proved related to angiogenesis status. For example, in VEGF-free condition, the attachment of angiopoietin-2 (Ang-2) to receptor tyrosine kinase (RTK), namely Tie-2, promotes vascular destabilization and regression by reduction of pericyte-EC interaction, while in normal condition Ang-2 could increase EC migration and tip cell formation required for neovascularization [68]. Commensurate with these comments, one could hypothesize that the dynamic balance of MSC secretome, cell source, purity, and preconditioning could

predetermine the pro- and/or anti-angiogenic property of MSCs [67].

cystic stem cells to obtain multipotentiality [72].

other tissues for research and clinical application [73].

By modulating distinct signaling pathway/s inside the MSCs, cell bioactivity would be induced in favor of neovascularization. For instance, it was shown that the activation of sonic hedgehog (Shh) factor in Wharton's jelly-derived MSCs (WJ-MSCs) induced the production of pro-angiogenic factors such as angiogenin, angiopoietin-1, activin A, matrix metallopeptidase-9 (MMP-9), granulocytemacrophage colony-stimulating factor, and urokinase-type plasminogen activator, indicating WJ-MSCs an ideal cell source for the induction of vascularization [69]. An experiment conducted by Matluobi et al. showed an enhanced vascular formation capacity of human MSCs after treatment with carvacrol evaluated by chicken chorioallantoic membrane angiogenesis assay. The carvacrol-treated MSCs tended to trans-differentiate into endothelial lineage by the expression of VWF and VE-cadherin [70]. MSCs have the ability to adapt themselves with environmental condition increasing regenerative potential in different conditions [71]. Maintaining the MSC cross talk with other cells is required for cell hemostasis, stemness feature, and regenerative potential in the distinct niche. For example, the normal bioactivity of Hox gene, *Abdominal-B*, seems to be essential in Drosophila

Regarding issues related to isolation protocols and stem cell proliferation rate, a careful selection is essential for high-throughput results. Vizoso et al. demonstrated large-scale secretome production and release of a vast array of bioactive factors in human uterine cervical stem cells with considerable advantages over MSCs from

The emergence of some conditions could change the trans-differentiation capacity of MSCs into distinct phenotypes. In the case of the vicious cycle of abnormal placental development in intrauterine growth restriction, placental mesenchymal stromal cells lose angiogenic potential while acquiring adipogenic capacity which is coincided with a metabolic shift from aerobic to anaerobic state [71]. It seems that

**102**


#### **Table 1.**

*Comparison of angiogenic paracrine factors secreted by MSCs from amniotic fluid and bone marrow.*

external environmental influence could alter the therapeutic potency of MSCs by rendering epigenetic marks associated with cell differentiation capacity [74]. In support of this claim, Rezaie and co-workers found a decrease of angiogenic human MSC potential after exposure to diabetic sera. The diabetic MSCs showed a declined migration capacity by suppressing the transcription of MMP-2, MMP-9, and CXCR-4 and aborted the secretion of Ang-1, Ang-2, and VEGF [75]. The expression of CXC chemokine receptors such as CXCR-1, CXCR-2, and CXCR-4 was found to accelerate and direct MSC migration in response to the chemokine gradients. A blockade of CXCR chemokine such as CXCL6 had potential to abrogate cardiac stem cell migration and motility [76].

**105**

**Table 2.**

*The Angiogenic Paracrine Potential of Mesenchymal Stem Cells*

**bone marrow (MSCs)**

TGF-β1 **+/−** Angiogenic inhibitor [57] Platelet factor 4 (PF4) **+/−** Angiogenic inhibitor [58]

TIMP-1 **+/+** Angiogenesis inhibitor [62] TIMP-4 **+/+** Angiogenesis inhibitor [63]

**Function**

apoptosis in the absence of VEGF [54, 55]

migration and angiogenesis and induces endothelial

family and negative regulator of angiogenesis [59]

inhibitor of uPA; preserves the vascular integrity [60]

cell proliferation and migration [56]

Angiopoietin-2 **+/−** Binds to TEK/TIE2 and induces endothelial cell

Angiostatin **+/−** Angiogenic inhibitor. Acts as an inhibitor of endothelial

apoptosis [56]

Endostatin **+/−** Acts as inhibitor of endothelial cell proliferation and

Serpin B5 **+/−** Maspin. A member of the serine protease inhibitor

Serpin E1 **+/+** Serine protease inhibitor; inhibition of angiogenesis;

Serpin F1 **+/+** Serine protease inhibitor, inhibition of angiogenesis [61]

Thrombospondin-1 **+/+** Anti-angiogenic. Inhibits endothelial cell proliferation [64] Thrombospondin-2 **+/−** Anti-angiogenic. Inhibits endothelial cell migration and

Vasohibin **+/−** A negative feedback regulator of angiogenesis [66]

*Comparison of anti-angiogenic paracrine factors secreted by MSCs from the amniotic fluid and bone marrow.*

tubule formation [65]

At present, the combination of cell and tissue engineering techniques increased the restoration potential of a distinct cell type after transplantation [77]. In most of these approaches, the maintenance of cell-to-cell interaction in 3D microenvironment could increase survival signaling pathway and organotypic plasticity of cells. For instance, it seems that cell encapsulation by the mixture of alginate-gelatin promotes angiocrine cues and vascular network formation [77]. The introduction of MSC-alginate microbeads to ischemic hindlimb mouse model promoted arterial collaterals after the occlusion of the femoral artery by the modulation of VEGF-A signaling pathway [78]. A side-by-side comparison of MSCs expanded in 2D, and alginate microbeads revealed

enhanced angiogenic and chemotactic activity in cutaneous healing [79].

Regarding paracrine activity, MSC exosomes transfer various bioactive molecules, microRNAs, and protein factors with the ability to modulate angiogenesis

Exosomes are a subtype of extracellular vesicles (EVs, 40–200 nm) found in bio-fluids and released from all cell types. They maintain cell-to-cell communication through shuttling diverse biomolecules [80–82]. The first intracellular step

**2. Modulation of angiogenesis by exosomes**

behavior in the target cells.

**2.1 Exosomes biogenesis**

*DOI: http://dx.doi.org/10.5772/intechopen.84433*

**Factor Amniotic fluid/**


*The Angiogenic Paracrine Potential of Mesenchymal Stem Cells DOI: http://dx.doi.org/10.5772/intechopen.84433*

#### **Table 2.**

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

**bone marrow MSCs**

**Function**

IL-8 **+/−** Has a role of pro-angiogenic factor [37] Leptin **+/−** Stimulates vessel formation [38]

MIP-1α **+/−** CCL3. Induces vessel formation

PD-ECGF **+/−** Stimulates angiogenesis [44]

Persefin **+/−** Induces angiogenesis [3]

VEGF **+/+** Promotes angiogenesis [50] VEGF-C **+/−** Promotes lymphangiogenesis [50]

PlGF **+/+** Has a role of a pro-angiogenic factor [46]

MCP-1 **+/−** CCL2. Induces stabilization of new vessels [39]

NRG1-β1 **+/−** Promotes angiogenesis and arteriogenesis [42]

IL-1β **+/−** Has positive effects in angiogenesis and lymphangiogenesis [35] IL-6 **+/−** A potent pro-angiogenic cytokine which stimulates endothelial

MMP-8 **+/−** Known as collagenase 2. Breaks collagen types I, II, and III and

MMP-9 **+/−** Called as gelatinase B. Breaks both collagens and gelatins and

**+/+** Has a role of a pro-angiogenic agent [43]

**+/−** Induces neovascularization and arteriogenesis [27]

PDGF-AA **+/+** Has positive effects on MSC proliferation and stimulates angiogenesis [45]

Prolactin **+/−** Has a role of a pro-angiogenic factor in intact form [47]

SDF-1α **-/+** An important chemotactic factor for progenitor cells. Stimulates

TGF-β1 **+/−** Promotes angiogenesis at least in part via the secretion of the

uPA **+/+** Promotes endothelial cell proliferation and migration and has

stem cell migration, adhesion, and homing [3]

positive effects in vascular network formation [49]

survival factors TGF-α and VEGF [3]

**+/+** Promotes angiogenesis [48]

promotes neovascularization [36]

has positive effects on angiogenesis [40]

has positive effects on angiogenesis [41]

cell and smooth muscle cell proliferation and migration and

**Factor Amniotic fluid/**

Pentraxin-3 (PTX3)

PDGF-AB/ PDGF-BB

Sphingosine kinase 1

external environmental influence could alter the therapeutic potency of MSCs by rendering epigenetic marks associated with cell differentiation capacity [74]. In support of this claim, Rezaie and co-workers found a decrease of angiogenic human MSC potential after exposure to diabetic sera. The diabetic MSCs showed a declined

CXCR-4 and aborted the secretion of Ang-1, Ang-2, and VEGF [75]. The expression of CXC chemokine receptors such as CXCR-1, CXCR-2, and CXCR-4 was found to accelerate and direct MSC migration in response to the chemokine gradients. A blockade of CXCR chemokine such as CXCL6 had potential to abrogate cardiac stem

migration capacity by suppressing the transcription of MMP-2, MMP-9, and

*Comparison of angiogenic paracrine factors secreted by MSCs from amniotic fluid and bone marrow.*

**104**

**Table 1.**

cell migration and motility [76].

*Comparison of anti-angiogenic paracrine factors secreted by MSCs from the amniotic fluid and bone marrow.*

At present, the combination of cell and tissue engineering techniques increased the restoration potential of a distinct cell type after transplantation [77]. In most of these approaches, the maintenance of cell-to-cell interaction in 3D microenvironment could increase survival signaling pathway and organotypic plasticity of cells. For instance, it seems that cell encapsulation by the mixture of alginate-gelatin promotes angiocrine cues and vascular network formation [77]. The introduction of MSC-alginate microbeads to ischemic hindlimb mouse model promoted arterial collaterals after the occlusion of the femoral artery by the modulation of VEGF-A signaling pathway [78]. A side-by-side comparison of MSCs expanded in 2D, and alginate microbeads revealed enhanced angiogenic and chemotactic activity in cutaneous healing [79].

#### **2. Modulation of angiogenesis by exosomes**

Regarding paracrine activity, MSC exosomes transfer various bioactive molecules, microRNAs, and protein factors with the ability to modulate angiogenesis behavior in the target cells.

#### **2.1 Exosomes biogenesis**

Exosomes are a subtype of extracellular vesicles (EVs, 40–200 nm) found in bio-fluids and released from all cell types. They maintain cell-to-cell communication through shuttling diverse biomolecules [80–82]. The first intracellular step

#### *Update on Mesenchymal and Induced Pluripotent Stem Cells*

in exosome biogenesis involves the invagination of the membrane of the multivesicular body (MVB) to form membrane-bound vesicles in MVB lumens that are identified as intraluminal vesicles (ILVs) (**Figure 1**) [83, 84]. Various factors and signaling pathways have been considered in biogenesis, trafficking, and abscission of exosomes [85]. Of note, endosomal sorting complexes required for transport (ESCRT) machinery with four complexes, ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III, participate in exosome formation and packing cargo incorporation with different accessory proteins (**Figure 1**) [81, 85, 86]. Noteworthy, the formation of MVBs in the absence of the ESCRT machinery is aborted. In this condition, oligodendroglial cell ceramide is a key molecule to induce inward budding of the limiting membrane of MVBs [83, 87]. After MVB formation, intracellular trafficking of vesicle systems was orchestrated by Rab-GTPase family proteins [81]. As shown in **Figure 1**, several Rab proteins specifically contribute to the transfer of vesicles in definitive pathways. Along with these factors, soluble NSF attachment protein receptor (SNARE) has been suggested to control the fusion of MVBs with the plasma membrane (**Figure 1**) [88]. At the intracellular level, three possible fates are considered to involve MVBs such as secretory, lysosomal, and back fusion pathways. Once secreted, exosomes can be received by neighboring cells by three possible

#### **Figure 1.**

*Biogenesis, structure, and uptake of exosomes. Exosomes are producing during invagination process of MVB's membrane. ESCRT machinery and ESCRT-independent mechanisms (lipid rafts/tetraspanin) contribute to form exosomes and sort several molecules including proteins, miRNA, mRNA, DNA strands, and lipids into their lumen or limiting membrane of exosomes. Exosome cargoes are collected from materials received by endocytic pathway, Golgi apparatus, and cytoplasm. Rab-GTPase family proteins regulate intercellular trafficking and docking of MVBs. In the secretory pathway, MVBs actively fuse with the plasma membrane to release exosomes into the extracellular space. In alternative pathways, MVB could prefer binding to the lysosome or directly fuse back to the plasma membrane. Once secreted, exosomes enroll several mechanisms to arrive at the target cell: (I) enter through internalization process; (II) bind through receptor-ligand interactions, (III) direct fusion with the plasma membrane of the target cell. Exosomes are able to affect the biological processes of the target cells.*

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*The Angiogenic Paracrine Potential of Mesenchymal Stem Cells*

**2.2 Pro- and anti-angiogenic capacity of exosomes**

firmed in various in vivo experimental studies [89, 92, 93].

mechanisms: (i) internalization, (ii) direct fusion, and (iii) receptor-ligand interaction. Exosomal uptake results in triggering signaling pathways reprogramming fate, proliferation, survival, and morphology of recipient cells (**Figure 1**) [89, 90].

It was shown that a significant portion of MSC angio-activity drives from their potency to release exosomes that can affect the function of ECs, either by increasing the production of pro-angiogenic factors or decreasing the production of anti-angiogenic factors [91]. The fact that MSC exosomes promote angiogenesis, by delivering mediators such as miRNAs, protein factors to distinct cells, was con-

It seems that exosomal cargo such as cytokines and miRNAs could be easily transferred to recipient cells. Increasing evidence indicates that exosomal pro-angiogenic miRNAs (miRNA-125a, miRNA-30b, miRNA-30c, miRNA-424, miRNA-150, and let-7f) are important regulators of angiogenesis in the target sites [89, 94–96]. Data suggest that exosomal miR-150 is a key contributor to the pro-angiogenic activity of MSC exosomes following ischemic injuries [89, 96, 97]. In contrast, anti-angiogenic function on tumor cells was reported by a research group guided by Lee et al. They demonstrated the anti-angiogenic function of MSC exosomes on breast cancer cells governed by delivering miR-16 to suppress VEGF factor [91]. In a recent study conducted by Chen et al., they declared that exosome can be used as therapeutic transfer vesicles to carry miRNAs and genetic molecules to modulate VEGF content and control untamed angiogenesis in rheumatoid arthritis [98]. Based on the literature, the expression of VEGF, endothelial marker CD31, and matrix metalloproteinases-14 (MMP-14) activity is induced in patients with rheumatoid arthritis. The application of MSC-derived exosomes containing miRNA-150-5p (Exo-150) clearly decreased transcription of VEGF and MMP-14 in synovial fluid. Consistent with these changes, the pro-inflammatory response was blunted by decreasing IL-1β, transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) content in synovial fluid. This study has shown that MSC-derived Exo-150 can be used as bio-shuttle and magic bullet for inhibiting an exacerbated angiogenesis via the modulation of angiogenesis-related factors. However, some contradictory facts exist regarding the sole application of exosomes

MSCs can secret signal transducer and activator of transcription-3 (STAT3) mRNAs via exosomes that augment the transcription of hepatocyte growth factor (HGF), IL-6, and VEGF, promoting proliferation and migration of ECs [99]. In this context, MSC exosomes abundantly are enriched with VEGF factor that increases neovascularization through the Wnt4/β-catenin pathway in epithelial cells [100, 101]. The pro-angiogenic propriety of MSC exosomes has been previously shown in myocardial ischemia/reperfusion injury experiments following acute myocardial infarction [102–104]. In contrast, MSC exosomes may contain abundant anti-angiogenic factors that could regulate tumor angiogenesis rate. Lee et al. showed that exosomes from MSCs significantly downregulated the expression of VEGF in breast cancer cells, leading to the abortion of angiogenesis [91]. However, there are contradicting results. For example, human bone marrow MSC

*DOI: http://dx.doi.org/10.5772/intechopen.84433*

*2.2.1 miRNAs*

in the context of tumor cells.

*2.2.2 Exosomal pro- and anti-angiogenic factors*

mechanisms: (i) internalization, (ii) direct fusion, and (iii) receptor-ligand interaction. Exosomal uptake results in triggering signaling pathways reprogramming fate, proliferation, survival, and morphology of recipient cells (**Figure 1**) [89, 90].
