Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles

Arasu, Uma Thanigai; Kärnä, Riikka; Härkönen, Kai; Oikari, Sanna; Koistinen, Arto; Kröger, Heikki; Qu, Chengjuan; Lammi, Mikko J.; Rilla, Kirsi

doi:10.1016/j.matbio.2017.05.001

Cited by 57 publications

(46 citation statements)

References 42 publications

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“…In fact, we have shown that the expression of CD44, a well‐known factor involved in cell adhesion and migration, is increased after the incorporation of MSC‐EV into CD34 + cells. These results are consistent with findings that MSC‐EV carry mRNA for CD44 , we also have confirmed that MSC‐EV express CD44 protein on their surface. The effects may not involve CXCR4, another important factor for homing and engraftment, as we have not observed changes in its expression after the incorporation of MSC‐EV, although some groups have described an increase in its expression .…”

Section: Discussionsupporting

confidence: 93%

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

et al. 2019

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Mesenchymal stromal cells (MSC) may exert their functions by the release of extracellular vesicles (EV). Our aim was to analyze changes induced in CD34 + cells after the incorporation of MSC-EV. MSC-EV were characterized by flow cytometry (FC), Western blot, electron microscopy, and nanoparticle tracking analysis. EV incorporation into CD34 + cells was confirmed by FC and confocal microscopy, and then reverse transcription polymerase chain reaction and arrays were performed in modified CD34 + cells. Apoptosis and cell cycle were also evaluated by FC, phosphorylation of signal activator of transcription 5 (STAT5) by WES Simple, and clonal growth by clonogenic assays. Human engraftment was analyzed 4 weeks after CD34 + cell transplantation in nonobese diabetic/severe combined immunodeficient mice. Our results showed that MSC-EV incorporation induced a downregulation of proapoptotic genes, an overexpression of genes involved in colony formation, and an activation of the Janus kinase (JAK)-STAT pathway in CD34 + cells. A significant decrease in apoptosis and an increased CD44 expression were confirmed by FC, and increased levels of phospho-STAT5 were confirmed by WES Simple in CD34 + cells with MSC-EV. In addition, these cells displayed a higher colony-forming unit granulocyte/macrophage clonogenic potential. Finally, the in vivo bone marrow lodging ability of human CD34 + cells with MSC-EV was significantly increased in the injected femurs. In summary, the incorporation of MSC-EV induces genomic and functional changes in CD34 + cells, increasing their clonogenic capacity and their bone marrow lodging ability. STEM CELLS 2019;37:1357-1368 SIGNIFICANCE STATEMENTIn the current study, the authors validate for the first time that preincubating human CD34 + cells with extracellular vesicles derived from human mesenchymal stromal cells not only modifies the gene expression of the recipient cells (inducing a downregulation of proapoptotic genes and overexpression of genes involved in colony formation and JAK-STAT pathway) but also significantly increases their in vitro clonogenic ability and, most importantly, increases their 4-week bone marrow lodging ability in vivo in a standard xenotransplantation model. This strategy could potentially be exploited to increase the hematopoietic engraftment in the clinical setting.

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Section: Discussionsupporting

confidence: 93%

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

et al. 2019

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“…In addition, HA is considered one of the key players in the tissue regeneration process [26]. Arasu et al, 2017, demonstrated that human mesenchymal stem cells can secrete HA-coated vesicles, contributing to the mechanisms of HA-mediated tissue regeneration. After incubating the tissues with lipopolysaccharide, the authors demonstrated induced filopodial growth, plasma membrane bleeding, and HA secretion, which can contribute to ECM remodeling, directly or indirectly by interacting with ECM-producing cells [27].…”

Section: Discussionmentioning

confidence: 99%

“…Arasu et al, 2017, demonstrated that human mesenchymal stem cells can secrete HA-coated vesicles, contributing to the mechanisms of HA-mediated tissue regeneration. After incubating the tissues with lipopolysaccharide, the authors demonstrated induced filopodial growth, plasma membrane bleeding, and HA secretion, which can contribute to ECM remodeling, directly or indirectly by interacting with ECM-producing cells [27]. The production of hyaluronan induced by cannabinoids can increase the ability of the collagen bundles inside the fasciae to glide with respect to others, and consequently to improve tissue adaptability.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue

Fede

Pirri

Petrelli

et al. 2020

IJMS

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The demonstrated expression of endocannabinoid receptors in myofascial tissue suggested the role of fascia as a source and modulator of pain. Fibroblasts can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and pharmacological. In this work, fascial fibroblasts were isolated from small samples of human fascia lata of the thigh, collected from three volunteer patients (two men, one woman) during orthopedic surgery. This text demonstrates for the first time that the agonist of cannabinoid receptor 2, HU-308, can lead to in vitro production of hyaluronan-rich vesicles only 3–4 h after treatment, being rapidly released into the extracellular environment. We demonstrated that these vesicles are rich in hyaluronan after Alcian blue and Toluidine blue stainings, immunocytochemistry, and transmission electron microscopy. In addition, incubation with the antagonist AM630 blocked vesicles production by cells, confirming that release of hyaluronan is a cannabinoid-mediated effect. These results may show how fascial cells respond to the endocannabinoid system by regulating and remodeling the formation of the extracellular matrix. This is a first step in our understanding of how therapeutic applications of cannabinoids to treat pain may also have a peripheral effect, altering the biosynthesis of the extracellular matrix in fasciae and, consequently, remodeling the tissue and its properties.

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“…In addition, it would be interesting to see if inhibitors of hedgehog signaling combined with the available immune therapeutics improve the survival of melanoma patients. Since HA coated EVs originate from HAS3 expressing cells [10], from primary cells such as mesothelial cells [92] and from human mesenchymal stem cells [93], their role as messengers in the extracellular space can be acknowledged. As shown in this study, HA-coated EVs are associated with the release of tumor promoting IHH mitogen from melanoma and these EVs could influence its surrounding microenvironment to melanoma progression.…”

Section: Discussionmentioning

confidence: 99%

HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells

Arasu

Deen

Pasonen‐Seppänen

et al. 2019

Cell. Mol. Life Sci.

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Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.

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Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles

Cited by 57 publications

References 42 publications

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue

HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells

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