Next Article in Journal
Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury
Next Article in Special Issue
Cardiac Extracellular Vesicles (EVs) Released in the Presence or Absence of Inflammatory Cues Support Angiogenesis in Different Manners
Previous Article in Journal
Plant DNA Polymerases
Previous Article in Special Issue
Challenges in Exosome Isolation and Analysis in Health and Disease
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 20
Issue 19
10.3390/ijms20194813
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition

by
Sevindzh Kletukhina
1,†,
Olga Neustroeva
1,†,
Victoria James
2,
Albert Rizvanov
1,2,3,* and
Marina Gomzikova
1,3,*
1
OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
2
School of Veterinary Medicine and Science, University of Nottingham, Nottingham LE12 5RD, UK
3
M.M. Shemyakin–Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(19), 4813; https://doi.org/10.3390/ijms20194813
Submission received: 29 August 2019 / Revised: 22 September 2019 / Accepted: 25 September 2019 / Published: 27 September 2019
(This article belongs to the Special Issue Extracellular Vesicles and Cell–Cell Communication)
Browse Figures
Versions Notes

Abstract

:
Epithelial–mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.

1. Introduction

Extracellular vesicles (EVs) are membrane-surrounded structures that act as paracrine effectors, as they are released by cells to deliver signals to other cells. EVs can be characterized by size and the mechanism of their biogenesis. The majority of studies investigating intercellular communication focus on an admixture of plasma membrane-released microvesicles (microparticles) and endosome-derived exosomes. Exosomes have sizes ranging from 40 to 150 nm [1,2], microvesicles have a heterogeneous size: from 40 to 2000 nm [3,4]. They impact a variety of biological processes, transferring biologically active molecules and are secreted by virtually all cells of the body [5].
EVs contain in their composition mRNA, microRNA, various proteins, and lipids, which they deliver to neighboring cells and systemically (via the blood and lymphatic system) [6,7]. EVs mediate the connection between cells of the body through receptor–ligand-mediated interactions and/or direct fusion with target cells. Mesenchymal stem cell (MSC)-derived EVs have been shown to alter the phenotype of target cells and modulate the microenvironment [8]. Furthermore, it was shown that EVs derived from embryonic stem cells mediate a horizontal transfer of bioactive molecules and genetic material (including mRNA [9] and microRNA [10]) leading to the reprogramming of target cells.
Epithelial–mesenchymal transition (EMT) occurs in embryonic development, in the adult it can be observed during wound healing, regeneration, organ fibrosis, and cancer [11,12,13,14]. However, the specific stimulus and mechanism of EMT induction in epithelial cells is still unknown. It is known that inflamed tissue and the tumor microenvironment contains a range of cell populations, which include immune cells, endothelial cells, fibroblasts, and mesenchymal stroma/stem cells [15]. We believe that intercellular communication between stem, stromal cells (tissue-specific progenitor cells, mesenchymal stem cells), and epithelial cells contribute to the induction of EMT reprogramming and the acquisition of a MSC phenotype.

2. Epithelial–Mesenchymal Transition

The architecture of epithelial cells is usually in the form of a sheet, with tight connections via surface adhesion proteins and apical–basal polarity [16,17]. The key events during EMT are the loss of this apical–basal polarity, cell–cell junctions, and adherence to the basement membrane by epithelial cells, and the appearance of mesenchymal cell properties [17]. The epithelial cells show a reduction in proteins related to apical dense compounds, such as occlusion, claudins, desmoplakin, and plakophilin, as well as inhibition of E-cadherin expression during the EMT [18,19]. In contrast, the epithelial cells increase expression of vimentin and N-cadherin and show traits characteristic of mesenchymal cells including migration and invasion [13], supporting their ability to develop into specific tissues and organs to mediate repair and regeneration [20,21].
Induction of EMT is regulated at the molecular level by a variety of growth factor signals, in particular transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), Wnt proteins, IL-6, and hypoxia-inducible factor (HIF)-1α [22,23,24,25,26,27,28]. These initial signals lead to changes in gene expression mediated by factors such as Twist1, Twist2, Snail, Zeb1, Zeb2, Slug, which consequently result in mesenchymal-like changes within the epithelial cells [29]. For example, TGF-β is a multifunctional cytokine that is considered the main inducer of EMT. The TGF-β signaling pathway plays an important role in the regulation of cell proliferation, differentiation, invasion, migration, apoptosis, and modification of the microenvironment and also stimulates pathophysiological EMT and metastasis [22,23,24]. HGF activates the c-Met signaling pathway, together they increase invasive and metastatic potential and ensure the survival of cancer cells in the bloodstream in the absence of cell-to-cell contact [26]. EGF and Snail2 play an important role in wound healing, during which signaling through the EGF receptor predominantly activates extracellular signal-regulated kinase (ERK) pathways. It was found that the Erk5 pathway specifically enhances Snail2 promoter activity and controls wound healing in vitro [25]. Other researchers have shown that EGF-stimulated Smad2/3 activation promotes EMT, activates several key EMT markers, inhibits E-cadherin expression, and improves invasion and migration in breast cancer cells [27]. FGF is involved in the formation of the mesenchyme and during EMT in the adult it acts similarly to increase the expression of vimentin and fibroblast-specific protein 1 (FSP1), as well as inducing matrix metallopeptidase 2 (MMP-2) activity increasing cell mobility. FGF is also capable of causing changes in the actin cytoskeleton capable of enabling anchorage-independent growth [28].
EMTs occur in three distinct biological processes. The first type of EMT is associated with implantation, embryo formation, organ development, and formation of a variety of cell types with mesenchymal phenotypes. This type of EMT generates mesenchymal cells (primary mesenchyme), which can later undergo mesenchymal–epithelial transition (MET) with formation of secondary epithelium [30]. EMT type 1 is detected during the formation of the neural crest, gastrulation in the primitive deforming somatic recession, the formation of the heart valve, and other embryological phenomena [31].
EMT type 2 is associated with wound healing, tissue regeneration, and organ fibrosis. This type of EMT is induced by repair-related events that usually generate fibroblasts and other related cells, in order to repair the tissues after trauma and inflammation [32]. During wound healing at the edges of the damaged zone, cells that have undergone EMT are found [33]. For example, keratinocytes located in the border of a wound acquire an intermediate phenotype, which is called a “metastable” state, and gain the ability to move around. In addition, they have markers that are characteristic of MSCs, while in the deeper layers of the skin, this phenomenon is not observed [33].
EMT type 3 occurs in neoplastic cells that have undergone genetic or epigenetic changes. Carcinoma cells that have undergone EMT are able to metastasize, thereby inducing the progression of cancer. Cancer cells may undergo EMT to differing extents, retaining epithelial features and acquiring some mesenchymal traits, or losing all epithelial features and acquiring completely mesenchymal properties. The rate of proliferation, metastasis, likelihood of relapse, and individual response to chemotherapy are all influenced by the switching between MET and EMT states [34]. Recovery of epithelial features allows the proliferation of tumor cells in these secondary tumor clusters in metastases [35]. Stress (toxic, infectious, hemodynamic, metabolic, hypoxia, nutrient deprivation, and inflammation) promotes tumor cells to secrete a spectrum of cytokines and chemokines that favor EMT [36]. In parallel, MSCs are recruited to inflammation sites by chemotaxis [37], communication between tumor cells and MSCs within the tumor microenvironment may impact on EMT and is currently under study.

3. Extracellular Vesicles of Stem Cells

The composition of EVs depends on the type of parental cell and conditions under which vesicle release occurs [38] and often reflects the specific expression profile and changes in epigenetic regulation of the EV-producing cell [39,40,41].
Previous studies have shown that MSCs do not require direct contact with neighboring cells to induce regeneration [42,43,44]. In this regard, the stem cell paracrine hypothesis was developed which postulates the paracrine action of transplanted stem cells on target cell by secreting soluble and insoluble factors into the extracellular space [45,46,47,48]. Growing evidence points that EVs possess biological activity similar to that of the parental cell. For example, platelet-derived EVs transfer coagulation factors and participate in blood clotting [49], embryonic stem cell-derived EVs increase survival and improve expansion of recipient cells [9,41,50], cancer cell-derived EVs contain oncogenic molecules and contribute to the remodeling of tumor microenvironment [51]. MSC-derived EVs are of particular interest due to their ability to stimulate regeneration and induce angiogenesis [52,53,54,55].
Cells within a damage site secrete huge amounts of cytokines which attract MSCs toward these areas of inflammation [56,57]. Previous studies have shown that MSC-derived EVs demonstrate similar therapeutic effects to parental MSCs by delivery of biological active molecules to target cells. For example, human embryonic MSC-derived EVs promote osteochondral repair [58]. Human fetal MSC EVs promote liver regeneration by activation the IL-6/STAT3 signaling pathway and cell cycle progression in hepatocytes after CCl4-induced injury in rats [59]. The protective effect of EVs derived from human umbilical cord MSCs was observed using a cisplatin-induced rat nephrotoxicity model [60]. These and other studies have placed MSC-derived EVs as therapeutic tools with significant potential in regenerative medicine.
It is known, that on the surface of EVs is present phosphotidylserine (PS) [61]. Due to the presence of PS and tissue factor in them, EVs have procoagulant and prothrombic properties [62,63]. They also regulate wound healing, inflammation, and vascular integrity [64,65]. Since the tumor niche resembles the site of chronic wound healing [66], and viable cancer cells have high PS levels on the outer surface and exhibit a wide range of surface PSs [67], EVs could be used as a therapeutic tool for treating/detecting a tumor.
Beside protein and lipids, stem cell-derived EVs contain genetic material (mRNA, microRNA, siRNA, DNA) [50,68] and are able to reprogram target cells by horizontal transfer of mRNA [9]. Ratajczak et al. showed that embryonic stem cell-derived EVs increase the pluripotency of target cells by inducing the expression of early pluripotent (Oct-4, Nanog, and Rex-1) and early hematopoietic stem cell (Scl, HoxB4, and GATA 2) markers [9]. MSC-derived EVs deliver RNA into injured tubular cells, altering their gene expression, and inducing dedifferentiation [69]. The accumulating data indicates that stem cell-derived EVs carry biologically active molecules, including transcription factors, and other genetic material capable of inducing viability and reprogramming of target cells toward a stem cell phenotype.

4. Migration of MSCs toward Injury, Inflammation Site, and Cancerous Tissues

MSC migrate in response to chemotaxic factors including inflammatory cytokines, growth factors, and chemokines produced by the injured tissue [70]. In fact, it was shown that adipose tissue-derived mesenchymal stem cells (AD-MSCs) and bone marrow-MSCs (BM-MSCs) show enhanced migration capacity toward chemokines and growth factors: platelet-derived growth factor-AB (PDGF-AB), insulin-like growth factor-1 (IGF-1), stromal-derived factor-1 (SDF-1), macrophage-derived chemokine (MDC), TGF-β1, and tumor necrosis factor alpha (TNF-α)—the most active MSC’s chemoattractant [71,72,73]. It is known that inflammation is the reason MSCs migrate from adipose tissue and bone marrow (stem cells niches) to blood and lymph nodes by CXCL12 (SDF-1)/CXCR4-dependent mechanisms [72].
The phenomenon of MSC mobilization in injury sites is utilized in the treatment of many diseases. In inflammation areas, MSCs show beneficial effects on neighboring cells via paracrine stimulation improving cell expansion and survival and preventing apoptosis. For instance, intravenous injection of human MSCs increases corneal allograft engraftment and prevents their rejection through the secretion of anti-inflammatory molecule TNFα-stimulated gene (TSG) 6 [74]. BM-MSCs contribute to reducing wound size by paracrine effects on angiogenesis and fibroblast migration [75]. Nakanishi et al. showed that conditioned medium (CM) taken from MSCs promotes cardiac progenitor cell proliferation and inhibits their apoptosis [76]. In addition, Linero and Chaparro demonstrated that MSC CM promoted bone callus formation [77]. These studies demonstrated that paracrine stimulation of neighboring cells is responsible for the beneficial effects of MSC therapy.
As a tumor is often described as being like a “chronic wound” [78,79,80], the hypoxic conditions and high concentration of cytokines and growth factors IL-1α, IL-1β, IL-6, FGF-2, IGF-1, TGF-β, VEGF-A, HIF-1α, EGF, TGF-α are a likely trigger for MSCs recruitment to tumor microenvironments [79,81,82]. These same factors, which act to control wound healing, are critical not only in MSC recruitment but also in their function. For example, TGF-β1 expressed by prostate cancer cells mediates MSC transdifferentiation into tumor-supporting carcinoma-associated fibroblasts (CAFs) [83,84,85]. Other studies demonstrate some MSCs integrate in a tumor and subsequently transform into tumor-associated MSCs (TA-MSCs). TA-MSCs show a stronger tumor-promoting capacity through microenvironment modulation [86]. MSCs migrate to the tumor microenvironment in much the same way as observed at sites of inflammation and in both cases, they effect to resident cells via paracrine stimulation [37,70,71,72,73,74,75,76,77,79,81,82,87,88,89,90,91,92,93,94,95] (Figure 1). MSC tropism to tumors has been utilized as a means of delivering an antitumor therapy. Ren et al. showed that i.v. injection of MSC-overexpressing lipocalin-2 led to the significant reduction of tumor volume in a model of lung cancer [96]. Intranasal injection of MSCs was found to have strong tropism to gliomas and potentially could be used to target brain tumors [97]. The potential of MSCs to deliver drugs has been demonstrated in a number of tumor types. Systemic delivery of MSC-overexpressing IL-12 significantly inhibited the growth of established subcutaneous renal tumors [98]. Furthermore, modification of MSCs to express TRAIL led to long-term remission of renal cell carcinoma [99].
Tumor-infiltrating MSCs (TA-MSCs) are thought to be important contributors to EMT via direct cell–cell contact and through paracrine mechanisms such as the secretion of bioactive molecules and extracellular vesicles EVs [15].

5. Mesenchymal Stem Cells in Epithelial–Mesenchymal Transition and Related Processes

Ectopic expression of EMT transcription factors (TFs), including Twist1 and Snail1 was conducted in order to assess the contribution of EMT to the process of metastasis. It was observed that expression of Twist1 is associated with the acquisition of stemness properties by tumor cells and increased metastasis [100,101]. However these factors did not contribute to the metastatic progression [102,103]. Constitutive expression of EMT-TFs induces a permanent state of EMT and blocks the proposed MET, which is necessary for the development of metastatic sites [100]. Indeed, suppression of Snail1, Twist1, or Prrx1 attenuates the EMT and promotes the colonization of the metastatic site by tumor-initiating cells [102,104,105].
The molecular changes occurring during EMT have been well studied. However, the driver of EMT remains unclear. The presence of MSCs in the tumor stroma is able to stimulate EMT of cancer cells. In models of breast cancer, bone marrow-derived MSCs promote de novo lysyl oxidase (LOX) production from breast tumor cells, this in turn stimulates Twist transcription and triggers EMT. The acquisition of stemness properties through Twist-induced EMT results in increased metastasis to both the lungs and bones [106]. Similarly, TGF-β1 secreted by human AD-MSCs has been shown to regulate EMT in MCF7 (breast cancer cells) by targeting the ZEB/miR-200 regulatory loop [107]. Research has shown that direct co-culture of breast or gastric cancer cells with human BM-MSCs resulted in the upregulation of EMT markers N-cadherin, vimentin, Twist, and Snail and the downregulation of E-cadherin [108,109]. The authors showed that the factors secreted by MSCs are responsible for changes in epithelial/mesenchymal cell markers, the morphology and growth pattern of breast cancer cells, the increased expression of genes associated with invasion and migration, angiogenesis, and anti-apoptosis [108]. MSC supernatant has been used to induce EMT in human hepatocellular carcinoma cells (HCC). HCC cells were grown in CM from MSCs pretreated with TNF-α and IFN-γ. HCC cells showed marked changes in molecular markers and functional characteristics associated with EMT, such as increased migration and invasion in both in vitro and in vivo [110]. CM of spheroid MSC cultures has also been used to demonstrate the effects of MSC-secreted factors. Klopp et al. treated human mammary epithelial cells (HMECs), MCF-7 and SUM149 (breast cancer cells), with MSC-CM. This led to an increase in the formation of the mammosphere by 6.4–21 times. The mammospheres had lower levels of cell adhesion protein, E-cadherin, increased expression of N-cadherin, vimentin, Snail, and Slug, all characteristic of a pro-invasive mesenchymal phenotype [111]. A previous study demonstrated that the CM of human MSCs (hMSCs) promoted the proliferation, migration, and invasion of PC-3 (prostate cancer cells) by upregulating of the expression of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). Blocking TGF-β blunted the pro-oncogenic function of hMSCs. These results suggest that hMSCs play a pro-oncogenic role in the growth of human prostate cancer by producing TGF-β [112].
Cell-to-cell contact and factors secreted by MSCs have a significant effect on tumor cells and mediating EMT. EVs form an important element of the factors secreted by MSCs. These unique mediators of MSC cell-to-cell communication contain inducers of EMT, such as TGF-β, TNF-a, IL-6, TSG101, RAC-alpha serine/threonine-protein kinase (AKT), integrin-linked kinase (ILK) 1, b-catenin, casein kinase II (CK2), annexin A2, integrin-3, caveolin-1, and matrix metalloproteinases [113,114,115,116,117,118,119,120]. Luga et al. found that EVs produced by breast cancer-associated fibroblasts in the tumor microenvironment contain WNT signaling pathway proteins and are able to activate the migration and metastasis of breast tumor cells [121]. Aga et al. demonstrated that EVs carrying latent membrane protein 1 (LMP1) modulate the expression of EMT markers in recipient cells (N-cadherin expression is increased and E-cadherin is decreased) [122] (Figure 2). Whilst Zhou et al. showed EVs produced by human umbilical cord MSCs significantly enhance the proliferative, migratory, and invasive properties of breast cancer cells (MDA-MB-231 and MCF-7) through the induction of EMT via the ERK pathway in vitro [123].
In metastatic sites, a reversal to a more epithelial state, mesenchymal–epithelial transition, is usually necessary [124]. As with EMT, the drivers of MET are yet to be fully determined [125]. Potentially the loss of secreted factors such as EVs from TA-MSCs may be one drivers of the reversal MET process, as once the cancer cells have migrated from the primary tumor, they no longer face the signals they experienced within the primary tumor microenvironment.
The understanding of the trigger mechanism of EMT of cancer cells is essential for the successful antitumor therapy. To prevent tumor dissemination, drugs and strategies targeted on the EMT program might be developed. Thus, the possible use of natural or modified/loaded EV MSCs to inhibit factors inducing EMT will provide an opportunity to control the process of tumor metastasis For example, in the future, in EVs, you can try to download the compounds: apigenin [126], melatonin [127], miR-711 [127], which have already shown the ability to inhibit migration and invasion, as well as the emergence of EMT of tumor cells. Moreover, to increase the efficiency of the delivery of EV contents, one can use targeting with recombinant proteins without affecting the integrity of the EVs, as was shown in the article by Kooijmans et al. [38].

6. Conclusions

Current evidence clearly supports a role for MSCs in the EMT process via both direct cell contact and through secreted factors. However, the full extent of MSCs and their paracrine effects, particularly via EVs, in the process of driving EMT and MET requires further scrutiny. A thorough study of the components of the molecular composition of EVs will help determine which of them contribute most to the induction and progression of EMT and MET. This is an important area of research since the potential of utilizing MSC EVs to manipulate EMT/MET transitions offers a potentially significant therapeutic opportunity to target both metastatic cancer and other chronic inflammatory diseases including chronic, non-healing wounds.

Author Contributions

Conceptualization, M.G.; writing manuscript and drawing figures, S.K. and O.N.; editing manuscript, V.J. and M.G.; editing figures, M.G. and A.R.

Funding

The reported study was funded by RSF according to the research project no. 18-75-00090. This work was supported by the Russian Government Program of Competitive Growth of Kazan Federal University. A.R. was supported by state assignments 20.5175.2017/6.7 and 17.9783.2017/8.9 of the Ministry of Science and Higher Education of the Russian Federation.

Conflicts of Interest

The authors declare no conflict of interest. Authors declare that there are no competing financial and/or non-financial interests regarding the publication of this paper. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Li, T.; Yan, Y.; Wang, B.; Qian, H.; Zhang, X.; Shen, L.; Wang, M.; Zhou, Y.; Zhu, W.; Li, W.; et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis. Stem Cells Dev. 2013, 22, 845–854. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Zhao, Y.; Sun, X.; Cao, W.; Ma, J.; Sun, L.; Qian, H.; Zhu, W.; Xu, W. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury. Stem Cells Int. 2015, 2015. [Google Scholar] [CrossRef] [PubMed]
  3. Kim, H.-S.; Choi, D.-Y.; Yun, S.J.; Choi, S.-M.; Kang, J.W.; Jung, J.W.; Hwang, D.; Kim, K.P.; Kim, D.-W. Proteomic Analysis of Microvesicles Derived from Human Mesenchymal Stem Cells. J. Prot. Res. 2012, 11, 839–849. [Google Scholar] [CrossRef] [PubMed]
  4. Bruno, S.; Grange, C.; Collino, F.; Deregibus, M.C.; Cantaluppi, V.; Biancone, L.; Tetta, C.; Camussi, G. Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury. PLoS ONE 2012, 7, e33115. [Google Scholar] [CrossRef] [PubMed]
  5. Morhayim, J.; Rudjito, R.; van Leeuwen, J.P.; van Driel, M. Paracrine Signaling by Extracellular Vesicles via Osteoblasts. Curr. Mol. Bio. Rep. 2016, 2, 48–55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Gomzikova, M.; Kletukhina, S.; Kurbangaleeva, S.; Rizvanov, A. Evaluation of Cytochalasin B-Induced Membrane Vesicles Fusion Specificity with Target Cells. BioMed Res. Int. 2018, 2018. [Google Scholar] [CrossRef]
  7. Gomzikova, M.O.; Zhuravleva, M.N.; Miftakhova, R.R.; Arkhipova, S.S.; Evtugin, V.G.; Khaiboullina, S.F.; Kiyasov, A.P.; Persson, J.L.; Mongan, N.P.; Pestell, R.G.; et al. Cytochalasin B-induced membrane vesicles convey angiogenic activity of parental cells. Oncotarget 2017, 8, 70496–70507. [Google Scholar] [CrossRef]
  8. Nawaz, M.; Fatima, F.; Vallabhaneni, K.C.; Penfornis, P.; Valadi, H.; Ekström, K.; Kholia, S.; Whitt, J.D.; Fernandes, J.D.; Pochampally, R.; et al. Extracellular Vesicles: Evolving Factors in Stem Cell Biology. Stem Cells Int. 2016, 2016. [Google Scholar] [CrossRef]
  9. Ratajczak, J.; Miekus, K.; Kucia, M.; Zhang, J.; Reca, R.; Dvorak, P.; Ratajczak, M.Z. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: Evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006, 20, 847–856. [Google Scholar] [CrossRef]
  10. Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J.J.; Lötvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659. [Google Scholar] [CrossRef] [Green Version]
  11. Iwano, M.; Plieth, D.; Danoff, T.M.; Xue, C.; Okada, H.; Neilson, E.G. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Investig. 2002, 110, 341–350. [Google Scholar] [CrossRef] [PubMed]
  12. Lepilina, A.; Coon, A.N.; Kikuchi, K.; Holdway, J.E.; Roberts, R.W.; Burns, C.G.; Poss, K.D. A Dynamic Epicardial Injury Response Supports Progenitor Cell Activity during Zebrafish Heart Regeneration. Cell 2006, 127, 607–619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Eastham, A.M.; Spencer, H.; Soncin, F.; Ritson, S.; Merry, C.L.R.; Stern, P.L.; Ward, C.M. Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation. Cancer Res. 2007, 67, 11254–11262. [Google Scholar] [CrossRef] [PubMed]
  14. Arnoux, V.; Nassour, M.; L’Helgoualc’h, A.; Hipskind, R.A.; Savagner, P. Erk5 Controls Slug Expression and Keratinocyte Activation during Wound Healing. MBoC 2008, 19, 4738–4749. [Google Scholar] [CrossRef] [Green Version]
  15. Melzer, C.; Yang, Y.; Hass, R. Interaction of MSC with tumor cells. Cell Commun. Signal. 2016, 14, 20. [Google Scholar] [CrossRef] [PubMed]
  16. Lechler, T.; Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 2005, 437, 275–280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Huang, R.Y.-J.; Guilford, P.; Thiery, J.P. Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J. Cell Sci. 2012, 125, 4417–4422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Trivanović, D.; Krstić, J.; Jauković, A.; Bugarski, D.; Santibanez, J.F. Mesenchymal stromal cell engagement in cancer cell epithelial to mesenchymal transition: MSC Modulate EMT in Cancer Cells. Dev. Dyn. 2018, 247, 359–367. [Google Scholar] [CrossRef]
  19. Suh, Y.; Yoon, C.-H.; Kim, R.-K.; Lim, E.-J.; Oh, Y.S.; Hwang, S.-G.; An, S.; Yoon, G.; Gye, M.C.; Yi, J.-M.; et al. Claudin-1 induces epithelial–mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene 2013, 32, 4873–4882. [Google Scholar] [CrossRef]
  20. Cheng, F.; Shen, Y.; Mohanasundaram, P.; Lindström, M.; Ivaska, J.; Ny, T.; Eriksson, J.E. Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β–Slug signaling. Proc. Natl. Acad. Sci. USA 2016, 113, E4320–E4327. [Google Scholar] [CrossRef]
  21. Klingener, M.; Chavali, M.; Singh, J.; McMillan, N.; Coomes, A.; Dempsey, P.J.; Chen, E.I.; Aguirre, A. N-Cadherin Promotes Recruitment and Migration of Neural Progenitor Cells from the SVZ Neural Stem Cell Niche into Demyelinated Lesions. J. Neurosci. 2014, 34, 9590–9606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Pang, M.-F.; Georgoudaki, A.-M.; Lambut, L.; Johansson, J.; Tabor, V.; Hagikura, K.; Jin, Y.; Jansson, M.; Alexander, J.S.; Nelson, C.M.; et al. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene 2016, 35, 748–760. [Google Scholar] [CrossRef] [PubMed]
  23. Ripka, S.; Konig, A.; Buchholz, M.; Wagner, M.; Sipos, B.; Kloppel, G.; Downward, J.; Gress, T.; Michl, P. WNT5A-target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 2007, 28, 1178–1187. [Google Scholar] [CrossRef] [PubMed]
  24. Škovierová, H.; Okajčeková, T.; Strnádel, J.; Vidomanová, E.; Halašová, E. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis. Int. J. Mol. Med. 2017, 41, 1187–1200. [Google Scholar] [CrossRef] [PubMed]
  25. Savagner, P.; Kusewitt, D.F.; Carver, E.A.; Magnino, F.; Choi, C.; Gridley, T.; Hudson, L.G. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J. Cell. Physiol. 2005, 202, 858–866. [Google Scholar] [CrossRef] [PubMed]
  26. Jiao, D.; Wang, J.; Lu, W.; Tang, X.; Chen, J.; Mou, H.; Chen, Q. Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer. Mol. Ther. Oncolytics 2016, 3. [Google Scholar] [CrossRef] [PubMed]
  27. Kim, J.; Kong, J.; Chang, H.; Kim, H.; Kim, A. EGF induces epithelial-mesenchymal transition through phospho-Smad2/3-Snail signaling pathway in breast cancer cells. Oncotarget 2016, 7, 85021–85032. [Google Scholar] [CrossRef] [Green Version]
  28. Ranieri, D.; Rosato, B.; Nanni, M.; Magenta, A.; Belleudi, F.; Torrisi, M.R. Expression of the FGFR2 mesenchymal splicing variant in epithelial cells drives epithelial-mesenchymal transition. Oncotarget 2016, 7, 5440–5460. [Google Scholar] [CrossRef]
  29. Vu, T.; Datta, P. Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis. Cancers 2017, 9, 171. [Google Scholar] [CrossRef]
  30. Ohta, S.; Suzuki, K.; Tachibana, K.; Tanaka, H.; Yamada, G. Cessation of gastrulation is mediated by suppression of epithelial-mesenchymal transition at the ventral ectodermal ridge. Development 2007, 134, 4315–4324. [Google Scholar] [CrossRef] [Green Version]
  31. Acloque, H.; Adams, M.S.; Fishwick, K.; Bronner-Fraser, M.; Nieto, M.A. Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease. J. Clin. Investig. 2009, 119, 1438–1449. [Google Scholar] [CrossRef] [PubMed]
  32. Kalluri, R.; Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Investig. 2003, 112, 1776–1784. [Google Scholar] [CrossRef] [PubMed]
  33. Hahn, J.M.; McFarland, K.L.; Combs, K.A.; Supp, D.M. Partial epithelial-mesenchymal transition in keloid scars: Regulation of keloid keratinocyte gene expression by transforming growth factor-β1. Burn. Trauma 2016, 4, 30. [Google Scholar] [CrossRef] [PubMed]
  34. Gurzu, S. Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update. WJCC 2015, 3, 393. [Google Scholar] [CrossRef] [PubMed]
  35. Hugo, H.J.; Gunasinghe, N.P.A.D.; Hollier, B.G.; Tanaka, T.; Blick, T.; Toh, A.; Hill, P.; Gilles, C.; Waltham, M.; Thompson, E.W. Epithelial requirement for in vitro proliferation and xenograft growth and metastasis of MDA-MB-468 human breast cancer cells: Oncogenic rather than tumor-suppressive role of E-cadherin. Breast Cancer Res. 2017, 19, 86. [Google Scholar] [CrossRef] [PubMed]
  36. Jolly, M.K. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front. Oncol. 2015, 5. [Google Scholar] [CrossRef] [PubMed]
  37. Karnoub, A.E.; Dash, A.B.; Vo, A.P.; Sullivan, A.; Brooks, M.W.; Bell, G.W.; Richardson, A.L.; Polyak, K.; Tubo, R.; Weinberg, R.A. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007, 449, 557–563. [Google Scholar] [CrossRef] [PubMed]
  38. Kooijmans, S.A.A.; Gitz-Francois, J.J.J.M.; Schiffelers, R.M.; Vader, P. Recombinant phosphatidylserine-binding nanobodies for targeting of extracellular vesicles to tumor cells: A plug-and-play approach. Nanoscale 2018, 10, 2413–2426. [Google Scholar] [CrossRef] [PubMed]
  39. Sincennes, M.-C.; Brun, C.E.; Rudnicki, M.A. Concise Review: Epigenetic Regulation of Myogenesis in Health and Disease: Epigenetic Regulation of Myogenesis. Stem Cells Transl. Med. 2016, 5, 282–290. [Google Scholar] [CrossRef]
  40. Katsman, D.; Stackpole, E.J.; Domin, D.R.; Farber, D.B. Embryonic Stem Cell-Derived Microvesicles Induce Gene Expression Changes in Müller Cells of the Retina. PLoS ONE 2012, 7, e50417. [Google Scholar] [CrossRef]
  41. Yuan, A.; Farber, E.L.; Rapoport, A.L.; Tejada, D.; Deniskin, R.; Akhmedov, N.B.; Farber, D.B. Transfer of MicroRNAs by Embryonic Stem Cell Microvesicles. PLoS ONE 2009, 4, e4722. [Google Scholar] [CrossRef] [PubMed]
  42. Ling, L.; Feng, X.; Wei, T.; Wang, Y.; Wang, Y.; Wang, Z.; Tang, D.; Luo, Y.; Xiong, Z. Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation improves ovarian function in rats with premature ovarian insufficiency (POI) at least partly through a paracrine mechanism. Stem Cell Res. Ther. 2019, 10, 46. [Google Scholar] [CrossRef] [PubMed]
  43. Schlosser, S.; Dennler, C.; Schweizer, R.; Eberli, D.; Stein, J.V.; Enzmann, V.; Giovanoli, P.; Erni, D.; Plock, J.A. Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin. Microvasc. Res. 2012, 83, 267–275. [Google Scholar] [CrossRef] [PubMed]
  44. Jiang, Z.; Liu, G.; Meng, F.; Wang, W.; Hao, P.; Xiang, Y.; Wang, Y.; Han, R.; Li, F.; Wang, L.; et al. Paracrine effects of mesenchymal stem cells on the activation of keratocytes. Br. J. Ophthalmol. 2017, 101, 1583–1590. [Google Scholar] [CrossRef] [PubMed]
  45. Gnecchi, M.; Danieli, P.; Malpasso, G.; Ciuffreda, M.C. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. In Mesenchymal Stem Cells; Gnecchi, M., Ed.; Springer: New York, NY, USA, 2016; pp. 123–146. [Google Scholar]
  46. Tögel, F.; Hu, Z.; Weiss, K.; Isaac, J.; Lange, C.; Westenfelder, C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am. J. Physiol. Ren. Physiol. 2005, 289, F31–F42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Danieli, P.; Malpasso, G.; Ciuffreda, M.C.; Gnecchi, M. Testing the Paracrine Properties of Human Mesenchymal Stem Cells Using Conditioned Medium. In Mesenchymal Stem Cells; Gnecchi, M., Ed.; Springer: New York, NY, USA, 2016; pp. 445–456. [Google Scholar]
  48. Cai, M.; Shen, R.; Song, L.; Lu, M.; Wang, J.; Zhao, S.; Tang, Y.; Meng, X.; Li, Z.; He, Z.-X. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects. Sci. Rep. 2016, 6, 28250. [Google Scholar] [CrossRef] [PubMed]
  49. Sandberg, H.; Bode, A.P.; Dombrose, F.A.; Hoechli, M.; Lentz, B.R. Expression of coagulant activity in human platelets: Release of membranous vesicles providing platelet factor 1 and platelet factor 3. Thromb. Res. 1985, 39, 63–79. [Google Scholar] [CrossRef]
  50. Ratajczak, M.Z.; Ratajczak, J. Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clin. Trans. Med. 2016, 5, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Al-Nedawi, K.; Meehan, B.; Micallef, J.; Lhotak, V.; May, L.; Guha, A.; Rak, J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 2008, 10, 619–624. [Google Scholar] [CrossRef]
  52. Dellett, M.; Brown, E.D.; Guduric-Fuchs, J.; O’Connor, A.; Stitt, A.W.; Medina, R.J.; Simpson, D.A. MicroRNA-containing extracellular vesicles released from endothelial colony-forming cells modulate angiogenesis during ischaemic retinopathy. J. Cell. Mol. Med. 2017, 21, 3405–3419. [Google Scholar] [CrossRef]
  53. Gong, M.; Yu, B.; Wang, J.; Wang, Y.; Liu, M.; Paul, C.; Millard, R.W.; Xiao, D.-S.; Ashraf, M.; Xu, M. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017, 8, 45200–45212. [Google Scholar] [CrossRef] [PubMed]
  54. Trinh, N.T.; Yamashita, T.; Tu, T.C.; Kato, T.; Ohneda, K.; Sato, F.; Ohneda, O. Microvesicles enhance the mobility of human diabetic adipose tissue-derived mesenchymal stem cells in vitro and improve wound healing in vivo. Biochem. Biophys. Res. Commun. 2016, 473, 1111–1118. [Google Scholar] [CrossRef] [PubMed]
  55. Merjaneh, M.; Langlois, A.; Larochelle, S.; Cloutier, C.B.; Ricard-Blum, S.; Moulin, V.J. Pro-angiogenic capacities of microvesicles produced by skin wound myofibroblasts. Angiogenesis 2017, 20, 385–398. [Google Scholar] [CrossRef] [PubMed]
  56. Wang, S.; Yang, H.; Tang, Z.; Long, G.; Huang, W. Wound Dressing Model of Human Umbilical Cord Mesenchymal Stem Cells-Alginates Complex Promotes Skin Wound Healing by Paracrine Signaling. Stem Cells Int. 2016, 2016. [Google Scholar] [CrossRef] [PubMed]
  57. Hodgkinson, C.P.; Gomez, J.A.; Bareja, A.; Dzau, V.J. Role of Paracrine Mechanisms. In Stem Cell and Gene Therapy for Cardiovascular Disease; Elsevier: Amsterdam, The Netherlands, 2016; pp. 39–48. [Google Scholar]
  58. Zhang, S.; Chu, W.C.; Lai, R.C.; Lim, S.K.; Hui, J.H.P.; Toh, W.S. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr. Cartil. 2016, 24, 2135–2140. [Google Scholar] [CrossRef] [Green Version]
  59. Tan, C.; Lai, R.; Wong, W.; Dan, Y.; Lim, S.-K.; Ho, H. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res. Ther. 2014, 5, 76. [Google Scholar] [CrossRef]
  60. Zhou, Y.; Xu, H.; Xu, W.; Wang, B.; Wu, H.; Tao, Y.; Zhang, B.; Wang, M.; Mao, F.; Yan, Y.; et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res. Ther. 2013, 4, 34. [Google Scholar] [CrossRef]
  61. Wei, X.; Liu, C.; Wang, H.; Wang, L.; Xiao, F.; Guo, Z.; Zhang, H. Surface Phosphatidylserine Is Responsible for the Internalization on Microvesicles Derived from Hypoxia-Induced Human Bone Marrow Mesenchymal Stem Cells into Human Endothelial Cells. PLoS ONE 2016, 11, e0147360. [Google Scholar] [CrossRef]
  62. Freyssinet, J.-M.; Toti, F. Formation of procoagulant microparticles and properties. Thromb. Res. 2010, 125, S46–S48. [Google Scholar] [CrossRef]
  63. Satta, N.; Toti, F.; Feugeas, O.; Bohbot, A.; Dachary-Prigent, J.; Eschwège, V.; Hedman, H.; Freyssinet, J.M. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J. Immunol. 1994, 153, 3245–3255. [Google Scholar]
  64. Varon, D.; Shai, E. Platelets and their microparticles as key players in pathophysiological responses. J. Thromb. Haemost. 2015, 13, S40–S46. [Google Scholar] [CrossRef] [PubMed]
  65. Vajen, T.; Mause, S.; Koenen, R. Microvesicles from platelets: Novel drivers of vascular inflammation. Thromb. Haemost. 2015, 114, 228–236. [Google Scholar] [CrossRef] [PubMed]
  66. Rybinski, B.; Franco-Barraza, J.; Cukierman, E. The wound healing, chronic fibrosis, and cancer progression triad. Physiol. Genom. 2014, 46, 223–244. [Google Scholar] [CrossRef] [PubMed]
  67. Davis, H.W.; Vallabhapurapu, S.D.; Chu, Z.; Vallabhapurapu, S.L.; Franco, R.S.; Mierzwa, M.; Kassing, W.; Barrett, W.L.; Qi, X. Enhanced phosphatidylserine-selective cancer therapy with irradiation and SapC-DOPS nanovesicles. Oncotarget 2019, 10, 856–868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Spees, J.L.; Olson, S.D.; Whitney, M.J.; Prockop, D.J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. Sci. USA 2006, 103, 1283–1288. [Google Scholar] [CrossRef] [Green Version]
  69. Ju, G.; Cheng, J.; Zhong, L.; Wu, S.; Zou, X.; Zhang, G.; Gu, D.; Miao, S.; Zhu, Y.; Sun, J.; et al. Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Tubular Epithelial Cell Dedifferentiation and Growth via Hepatocyte Growth Factor Induction. PLoS ONE 2015, 10, e0121534. [Google Scholar] [CrossRef] [PubMed]
  70. Spaeth, E.L.; Kidd, S.; Marini, F.C. Tracking Inflammation-Induced Mobilization of Mesenchymal Stem Cells. In Stem Cell Mobilization; Kolonin, M.G., Simmons, P.J., Eds.; Humana Press: Totowa, NJ, USA, 2012; pp. 173–190. [Google Scholar]
  71. Baek, S.J.; Kang, S.K.; Ra, J.C. In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors. Exp. Mol. Med. 2011, 43, 596. [Google Scholar] [CrossRef]
  72. Eggenhofer, E.; Luk, F.; Dahlke, M.H.; Hoogduijn, M.J. The Life and Fate of Mesenchymal Stem Cells. Front. Immunol. 2014, 5. [Google Scholar] [CrossRef]
  73. Ponte, A.L.; Marais, E.; Gallay, N.; Langonné, A.; Delorme, B.; Hérault, O.; Charbord, P.; Domenech, J. The In Vitro Migration Capacity of Human Bone Marrow Mesenchymal Stem Cells: Comparison of Chemokine and Growth Factor Chemotactic Activities. Stem Cells 2007, 25, 1737–1745. [Google Scholar] [CrossRef]
  74. Oh, J.Y.; Lee, R.H.; Yu, J.M.; Ko, J.H.; Lee, H.J.; Ko, A.Y.; Roddy, G.W.; Prockop, D.J. Intravenous Mesenchymal Stem Cells Prevented Rejection of Allogeneic Corneal Transplants by Aborting the Early Inflammatory Response. Mol. Ther. 2012, 20, 2143–2152. [Google Scholar] [CrossRef] [Green Version]
  75. Rodriguez-Menocal, L.; Shareef, S.; Salgado, M.; Shabbir, A.; Van Badiavas, E. Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing. Stem Cell Res. Ther. 2015, 6, 24. [Google Scholar] [CrossRef] [PubMed]
  76. Nakanishi, C.; Yamagishi, M.; Yamahara, K.; Hagino, I.; Mori, H.; Sawa, Y.; Yagihara, T.; Kitamura, S.; Nagaya, N. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2008, 374, 11–16. [Google Scholar] [CrossRef] [PubMed]
  77. Linero, I.; Chaparro, O. Paracrine Effect of Mesenchymal Stem Cells Derived from Human Adipose Tissue in Bone Regeneration. PLoS ONE 2014, 9, e107001. [Google Scholar] [CrossRef] [PubMed]
  78. Bergfeld, S.A.; DeClerck, Y.A. Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev. 2010, 29, 249–261. [Google Scholar] [CrossRef] [PubMed]
  79. Whiteside, T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008, 27, 5904–5912. [Google Scholar] [CrossRef] [Green Version]
  80. Flier, J.S.; Underhill, L.H.; Dvorak, H.F. Tumors: Wounds That Do Not Heal. N. Engl. J. Med. 1986, 315, 1650–1659. [Google Scholar] [CrossRef] [PubMed]
  81. Rattigan, Y.; Hsu, J.-M.; Mishra, P.J.; Glod, J.; Banerjee, D. Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp. Cell Res. 2010, 316, 3417–3424. [Google Scholar] [CrossRef]
  82. Andrejeva, G.; Rathmell, J.C. Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab. 2017, 26, 49–70. [Google Scholar] [CrossRef] [Green Version]
  83. Barcellos-de-Souza, P.; Comito, G.; Pons-Segura, C.; Taddei, M.L.; Gori, V.; Becherucci, V.; Bambi, F.; Margheri, F.; Laurenzana, A.; Del Rosso, M.; et al. Mesenchymal Stem Cells are Recruited and Activated into Carcinoma-Associated Fibroblasts by Prostate Cancer Microenvironment-Derived TGF-β1: PCa Recruits and Activates MSC into CAF via TGF-β1. Stem Cells 2016, 34, 2536–2547. [Google Scholar] [CrossRef]
  84. Padua, D.; Massagué, J. Roles of TGFβ in metastasis. Cell Res. 2009, 19, 89–102. [Google Scholar] [CrossRef]
  85. Santibañez, J.F.; Quintanilla, M.; Bernabeu, C. TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin. Sci. 2011, 121, 233–251. [Google Scholar] [CrossRef] [PubMed]
  86. McLean, K.; Gong, Y.; Choi, Y.; Deng, N.; Yang, K.; Bai, S.; Cabrera, L.; Keller, E.; McCauley, L.; Cho, K.R.; et al. Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J. Clin. Investig. 2011, 121, 3206–3219. [Google Scholar] [CrossRef] [PubMed]
  87. Yoon, B.S.; Moon, J.-H.; Jun, E.K.; Kim, J.; Maeng, I.; Kim, J.S.; Lee, J.H.; Baik, C.S.; Kim, A.; Cho, K.S.; et al. Secretory Profiles and Wound Healing Effects of Human Amniotic Fluid–Derived Mesenchymal Stem Cells. Stem Cells Dev. 2010, 19, 887–902. [Google Scholar] [CrossRef] [PubMed]
  88. Galindo, L.T.; Filippo, T.R.M.; Semedo, P.; Ariza, C.B.; Moreira, C.M.; Camara, N.O.S.; Porcionatto, M.A. Mesenchymal Stem Cell Therapy Modulates the Inflammatory Response in Experimental Traumatic Brain Injury. Neurol. Res. Int. 2011, 2011, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Rustad, K.C.; Wong, V.W.; Sorkin, M.; Glotzbach, J.P.; Major, M.R.; Rajadas, J.; Longaker, M.T.; Gurtner, G.C. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials 2012, 33, 80–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Yuan, F.; Lei, Y.; Fu, X.; Sheng, Z.; Cai, S.; Sun, T. Promotive effect of adipose-derived stem cells on the wound model of human epidermal keratinocytes in vitro. Chin. J. Surg. 2008, 46, 1575–1578. [Google Scholar]
  91. Hung, S.-C.; Pochampally, R.R.; Chen, S.-C.; Hsu, S.-C.; Prockop, D.J. Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. Stem Cells 2007, 25, 2363–2370. [Google Scholar] [CrossRef]
  92. Dawson, M.R.; Chae, S.-S.; Jain, R.K.; Duda, D.G. Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. Am. J. Cancer Res. 2011, 1, 144–154. [Google Scholar]
  93. Balakrishnan, K.; Burger, J.A.; Quiroga, M.P.; Henneberg, M.; Ayres, M.L.; Wierda, W.G.; Gandhi, V. Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells. Blood 2010, 116, 1083–1091. [Google Scholar] [CrossRef] [Green Version]
  94. Patel, S.A.; Meyer, J.R.; Greco, S.J.; Corcoran, K.E.; Bryan, M.; Rameshwar, P. Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β. J. Immunol. 2010, 184, 5885–5894. [Google Scholar] [CrossRef]
  95. Ramasamy, R.; Lam, E.W.-F.; Soeiro, I.; Tisato, V.; Bonnet, D.; Dazzi, F. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: Impact on in vivo tumor growth. Leukemia 2007, 21, 304–310. [Google Scholar] [CrossRef] [PubMed]
  96. Ren, G.; Zhang, L.; Zhao, X.; Xu, G.; Zhang, Y.; Roberts, A.I.; Zhao, R.C.; Shi, Y. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide. Cell Stem Cell 2008, 2, 141–150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Mangraviti, A.; Tzeng, S.Y.; Gullotti, D.; Kozielski, K.L.; Kim, J.E.; Seng, M.; Abbadi, S.; Schiapparelli, P.; Sarabia-Estrada, R.; Vescovi, A.; et al. Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials 2016, 100, 53–66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Gao, P.; Ding, Q.; Wu, Z.; Jiang, H.; Fang, Z. Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma. Cancer Lett. 2010, 290, 157–166. [Google Scholar] [CrossRef] [PubMed]
  99. Kim, S.W.; Kim, S.J.; Park, S.H.; Yang, H.G.; Kang, M.C.; Choi, Y.W.; Kim, S.M.; Jeun, S.-S.; Sung, Y.C. Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK. Clin. Cancer Res. 2013, 19, 415–427. [Google Scholar] [CrossRef] [PubMed]
  100. Mittal, V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu. Rev. Pathol. Mech. Dis. 2018, 13, 395–412. [Google Scholar] [CrossRef] [PubMed]
  101. Mani, S.A.; Guo, W.; Liao, M.-J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; et al. The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell 2008, 133, 704–715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Tsai, J.H.; Donaher, J.L.; Murphy, D.A.; Chau, S.; Yang, J. Spatiotemporal Regulation of Epithelial-Mesenchymal Transition Is Essential for Squamous Cell Carcinoma Metastasis. Cancer Cell 2012, 22, 725–736. [Google Scholar] [CrossRef] [Green Version]
  103. Celià-Terrassa, T.; Meca-Cortés, Ó.; Mateo, F.; Martínez de Paz, A.; Rubio, N.; Arnal-Estapé, A.; Ell, B.J.; Bermudo, R.; Díaz, A.; Guerra-Rebollo, M.; et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J. Clin. Investig. 2012, 122, 1849–1868. [Google Scholar] [CrossRef] [Green Version]
  104. Ocaña, O.H.; Córcoles, R.; Fabra, Á.; Moreno-Bueno, G.; Acloque, H.; Vega, S.; Barrallo-Gimeno, A.; Cano, A.; Nieto, M.A. Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition Inducer Prrx1. Cancer Cell 2012, 22, 709–724. [Google Scholar] [CrossRef] [Green Version]
  105. Tran, H.D.; Luitel, K.; Kim, M.; Zhang, K.; Longmore, G.D.; Tran, D.D. Transient SNAIL1 Expression Is Necessary for Metastatic Competence in Breast Cancer. Cancer Res. 2014, 74, 6330–6340. [Google Scholar] [CrossRef] [PubMed]
  106. El-Haibi, C.P.; Bell, G.W.; Zhang, J.; Collmann, A.Y.; Wood, D.; Scherber, C.M.; Csizmadia, E.; Mariani, O.; Zhu, C.; Campagne, A.; et al. Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc. Natl. Acad. Sci. USA 2012, 109, 17460–17465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Xu, Q.; Wang, L.; Li, H.; Han, Q.; Li, J.; Qu, X.; Huang, S.; Zhao, R.C. Mesenchymal stem cells play a potential role in regulating the establishment and maintenance of epithelial-mesenchymal transition in MCF7 human breast cancer cells by paracrine and induced autocrine TGF-β. Int. J. Oncol. 2012, 41, 959–968. [Google Scholar] [CrossRef] [PubMed]
  108. Martin, F.T.; Dwyer, R.M.; Kelly, J.; Khan, S.; Murphy, J.M.; Curran, C.; Miller, N.; Hennessy, E.; Dockery, P.; Barry, F.P.; et al. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: Stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res. Treat. 2010, 124, 317–326. [Google Scholar] [CrossRef] [PubMed]
  109. Xue, Z.; Wu, X.; Chen, X.; Liu, Y.; Wang, X.; Wu, K.; Nie, Y.; Fan, D. Mesenchymal Stem Cells Promote Epithelial to Mesenchymal Transition and Metastasis in Gastric Cancer Though Paracrine Cues and Close Physical Contact: MSCs promote EMT. J. Cell. Biochem. 2015, 116, 618–627. [Google Scholar] [CrossRef] [PubMed]
  110. Jing, Y.; Han, Z.; Liu, Y.; Sun, K.; Zhang, S.; Jiang, G.; Li, R.; Gao, L.; Zhao, X.; Wu, D.; et al. Mesenchymal Stem Cells in Inflammation Microenvironment Accelerates Hepatocellular Carcinoma Metastasis by Inducing Epithelial-Mesenchymal Transition. PLoS ONE 2012, 7, e43272. [Google Scholar] [CrossRef] [PubMed]
  111. Klopp, A.H.; Lacerda, L.; Gupta, A.; Debeb, B.G.; Solley, T.; Li, L.; Spaeth, E.; Xu, W.; Zhang, X.; Lewis, M.T.; et al. Mesenchymal Stem Cells Promote Mammosphere Formation and Decrease E-Cadherin in Normal and Malignant Breast Cells. PLoS ONE 2010, 5, e12180. [Google Scholar] [CrossRef]
  112. Ye, H.; Cheng, J.; Tang, Y.; Liu, Z.; Xu, C.; Liu, Y.; Sun, Y. Human Bone Marrow-Derived Mesenchymal Stem Cells produced TGFbeta Contributes to Progression and Metastasis of Prostate Cancer. Cancer Investig. 2012, 30, 513–518. [Google Scholar] [CrossRef]
  113. Webber, J.P.; Spary, L.K.; Sanders, A.J.; Chowdhury, R.; Jiang, W.G.; Steadman, R.; Wymant, J.; Jones, A.T.; Kynaston, H.; Mason, M.D.; et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 2015, 34, 290–302. [Google Scholar] [CrossRef]
  114. Chairoungdua, A.; Smith, D.L.; Pochard, P.; Hull, M.; Caplan, M.J. Exosome release of β-catenin: A novel mechanism that antagonizes Wnt signaling. J. Cell Biol. 2010, 190, 1079–1091. [Google Scholar] [CrossRef]
  115. Ramteke, A.; Ting, H.; Agarwal, C.; Mateen, S.; Somasagara, R.; Hussain, A.; Graner, M.; Frederick, B.; Agarwal, R.; Deep, G. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol. Carcinog. 2015, 54, 554–565. [Google Scholar] [CrossRef] [PubMed]
  116. Jeppesen, D.K.; Nawrocki, A.; Jensen, S.G.; Thorsen, K.; Whitehead, B.; Howard, K.A.; Dyrskjøt, L.; Ørntoft, T.F.; Larsen, M.R.; Ostenfeld, M.S. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors. Proteomics 2014, 14, 699–712. [Google Scholar] [CrossRef] [PubMed]
  117. Bijnsdorp, I.V.; Geldof, A.A.; Lavaei, M.; Piersma, S.R.; van Moorselaar, R.J.A.; Jimenez, C.R. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J. Extracell. Vesicles 2013, 2, 22097. [Google Scholar] [CrossRef] [PubMed]
  118. Felicetti, F.; Parolini, I.; Bottero, L.; Fecchi, K.; Errico, M.C.; Raggi, C.; Biffoni, M.; Spadaro, F.; Lisanti, M.P.; Sargiacomo, M.; et al. Caveolin-1 tumor-promoting role in human melanoma. Int. J. Cancer 2009, 125, 1514–1522. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Hakulinen, J.; Sankkila, L.; Sugiyama, N.; Lehti, K.; Keski-Oja, J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J. Cell. Biochem. 2008, 105, 1211–1218. [Google Scholar] [CrossRef] [PubMed]
  120. Vella, L.J. The Emerging Role of Exosomes in Epithelial—Mesenchymal—Transition in Cancer. Front. Oncol. 2014, 4. [Google Scholar] [CrossRef] [PubMed]
  121. Luga, V.; Zhang, L.; Viloria-Petit, A.M.; Ogunjimi, A.A.; Inanlou, M.R.; Chiu, E.; Buchanan, M.; Hosein, A.N.; Basik, M.; Wrana, J.L. Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration. Cell 2012, 151, 1542–1556. [Google Scholar] [CrossRef] [Green Version]
  122. Aga, M.; Bentz, G.L.; Raffa, S.; Torrisi, M.R.; Kondo, S.; Wakisaka, N.; Yoshizaki, T.; Pagano, J.S.; Shackelford, J. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene 2014, 33, 4613–4622. [Google Scholar] [CrossRef]
  123. Zhou, X.; Li, T.; Chen, Y.; Zhang, N.; Wang, P.; Liang, Y.; Long, M.; Liu, H.; Mao, J.; Liu, Q.; et al. Mesenchymal stem cell-derived extracellular vesicles promote the in vitro proliferation and migration of breast cancer cells through the activation of the ERK pathway. Int. J. Oncol. 2019, 54, 1843–1852. [Google Scholar] [CrossRef]
  124. Chaffer, C.L.; Brennan, J.P.; Slavin, J.L.; Blick, T.; Thompson, E.W.; Williams, E.D. Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2. Cancer Res. 2006, 66, 11271–11278. [Google Scholar] [CrossRef]
  125. Magbanua, M.J.M.; Park, J.W. (Eds.) Isolation and Molecular Characterization of Circulating Tumor Cells; Springer International Publishing: Cham, Switzerland, 2017. [Google Scholar]
  126. Tong, J.; Shen, Y.; Zhang, Z.; Hu, Y.; Zhang, X.; Han, L. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through NF-κB/Snail signaling pathway. Biosci. Rep. 2019, 39. [Google Scholar] [CrossRef] [PubMed]
  127. Chao, C.-C.; Chen, P.-C.; Chiou, P.-C.; Hsu, C.-J.; Liu, P.-I.; Yang, Y.-C.; Reiter, R.J.; Yang, S.-F.; Tang, C.-H. Melatonin suppresses lung cancer metastasis by inhibition of epithelial–mesenchymal transition through targeting to Twist. Clin. Sci. 2019, 133, 709–722. [Google Scholar] [CrossRef] [PubMed]
Ijms 20 04813 g001 550
Figure 1. Mesenchymal stem cell (MSC) migration toward tumor/injury site. Tumors or inflamed tissues release the chemokines and growth factors inducing MSC chemotaxis. Migrated MSCs demonstrate beneficial effects on resident cells [37,70,71,72,73,74,75,76,77,79,81,82,87,88,89,90,91,92,93,94,95].
Figure 1. Mesenchymal stem cell (MSC) migration toward tumor/injury site. Tumors or inflamed tissues release the chemokines and growth factors inducing MSC chemotaxis. Migrated MSCs demonstrate beneficial effects on resident cells [37,70,71,72,73,74,75,76,77,79,81,82,87,88,89,90,91,92,93,94,95].
Ijms 20 04813 g001
Ijms 20 04813 g002 550
Figure 2. Schematic representation of the epithelial–mesenchymal transition (EMT) mechanism. Tumor cell undergo EMT under the influence of MSC-derived extracellular vesicles (EVs), with subsequent migration to a metastatic niche, returning to the epithelial phenotype (mesenchymal–epithelial transition (MET)) and the formation of a new metastatic site.
Figure 2. Schematic representation of the epithelial–mesenchymal transition (EMT) mechanism. Tumor cell undergo EMT under the influence of MSC-derived extracellular vesicles (EVs), with subsequent migration to a metastatic niche, returning to the epithelial phenotype (mesenchymal–epithelial transition (MET)) and the formation of a new metastatic site.
Ijms 20 04813 g002

Share and Cite

MDPI and ACS Style

Kletukhina, S.; Neustroeva, O.; James, V.; Rizvanov, A.; Gomzikova, M. Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition. Int. J. Mol. Sci. 2019, 20, 4813. https://doi.org/10.3390/ijms20194813

AMA Style

Kletukhina S, Neustroeva O, James V, Rizvanov A, Gomzikova M. Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition. International Journal of Molecular Sciences. 2019; 20(19):4813. https://doi.org/10.3390/ijms20194813

Chicago/Turabian Style

Kletukhina, Sevindzh, Olga Neustroeva, Victoria James, Albert Rizvanov, and Marina Gomzikova. 2019. "Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition" International Journal of Molecular Sciences 20, no. 19: 4813. https://doi.org/10.3390/ijms20194813

APA Style

Kletukhina, S., Neustroeva, O., James, V., Rizvanov, A., & Gomzikova, M. (2019). Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition. International Journal of Molecular Sciences, 20(19), 4813. https://doi.org/10.3390/ijms20194813

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop