Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes

Favaro, Enrica; Carpanetto, Andrea; Lamorte, Sara; Fusco, A; Caorsi, Cristiana; Deregibus, Maria Chiara; Bruno, Stefania; Amoroso, Antonio; Giovarelli, Mirella; Porta, Massimo; Perin, Paolo Cavallo; Tetta, Ciro; Camussi, Giovanni; Zanone, Maria M.

doi:10.1007/s00125-014-3262-4

Cited by 120 publications

(100 citation statements)

References 50 publications

(65 reference statements)

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“…Participants and DC generation Peripheral blood mononuclear cells (PBMCs) were obtained from nine white patients with recent-onset type 1 diabetes on the basis of a positive IFN-γ response to glutamic acid decarboxylase (GAD65; stimulation index [SI] ≥3; Table 1) by enzyme-linked immunosorbent spot (ELISPOT) analysis as previously described [12,21]. CD14 + monocytes were isolated by positive selection (CD14 microbeads, Miltenyi Biotec, Bergisch Gladbach, Germany) and CD14…”

Section: Methodsmentioning

confidence: 99%

“…EVs were obtained by differential ultracentrifugation and quantified by nanoparticle tacking analysis, as previously described [21]. A pool of approximately 2.5×10 8 /ml EV particles was labelled with 2 μl/ml Vybrant Dil (Life Technologies, OR, USA) for 15 min at 37°C and then washed, ultracentrifuged at 100,000 g and added to mDCs (2×10 5 ) for 24 h. After washing, EV internalisation was assessed by flow cytometry and confocal microscopy (LSM5-PASCAL, Zeiss, Oberkochen, Germany) analyses.…”

Section: Methodsmentioning

confidence: 99%

“…EVs obtained from human dermal fibroblasts (i.e. fibroblast-derived EVs; Lonza) served as controls [21]. In a limited set of experiments, mDCs from diabetic patients (n = 3) were cultured in MSC-conditioned medium or in EV-depleted conditioned medium.…”

Section: Methodsmentioning

confidence: 99%

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Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

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Aims/hypothesis Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 + cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14− cell were cocultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed.Results MSC-and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 + regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

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“…MSC-derived extracellular vesicles are able to inhibit proliferation and induce apoptosis of activated T cells while promoting secretion of anti-inflammatory cytokines [77]. In animal and in vitro studies, MSC-derived extracellular vesicles restored Th1/ Th2 balance and induced generation of Tregs, implementing the regulatory component of the adaptive immune system [77,78]. A dose-dependent inhibitory effect of MSC-derived extracellular vesicles on B-cell proliferation, differentiation and Ig production has been reported [58].…”

Section: Anti-inflammatory (M2) Mscs Inhibit the Cell Cycle Of Cytotmentioning

confidence: 98%

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

Pierro

Thébaud

2016

Curr Stem Cell Rep

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The imbalance of inflammatory and antiinflammatory responses in favor of inflammation plays a major role in the pathogenesis of many neonatal diseases. Inflammation in the perinatal period carries important longterm consequences, including neurodevelopmental and respiratory complications. Treatments able to restore immune homeostasis may reduce neonatal mortality and prevent longterm deleterious multi-organ consequences of unchecked inflammation. Mesenchymal stromal cells are a heterogenous group of progenitors cells with potent anti-inflammatory and immunomodulatory potential, among other diverse mechanisms of action. Thus, mesenchymal stromal cells (MSCs) may represent a novel and effective therapy for several neonatal diseases, potentially capable of preventing their longterm complications. This paper reviews the role of inflammation in the perinatal period and the therapeutic role of MSCs, focusing on their anti-inflammatory potential.

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“…Considering their immunosuppressive nature, MSC EVs are under investigation for a multitude of inflammatory conditions. For instance, in the field of auto-immune diseases, EVs shed by MSCs have shown to limit the pro-inflammatory response and induce a shift towards a beneficial regulatory T cell profile in type I diabetes [98] which is currently being investigated in a clinical setting (NCT02138331). As another example, MSC EVs are also successfully investigated in refractory graft-versus-host disease [99].…”

Section: Harnessing the Intrinsic Biological Effect Of Evsmentioning

confidence: 99%

Therapeutic and diagnostic applications of extracellular vesicles

Stremersch

Smedt

Raemdonck

2016

Journal of Controlled Release

153

103

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During the past two decades, extracellular vesicles (EVs) have been identified as important mediators of intercellular communication, enabling the functional transfer of bioactive molecules from one cell to another. Consequently, it is becoming increasingly clear that these vesicles are involved in many (patho)physiological processes, providing opportunities for therapeutic applications. Moreover, it is known that the molecular composition of EVs reflects the physiological status of the producing cell and tissue, rationalizing their exploitation as biomarkers in various diseases. In this review the composition, biogenesis and diversity of EVs is discussed in a therapeutic and diagnostic context. We describe emerging therapeutic applications, including the use of EVs as drug delivery vehicles and as cell-free vaccines, and reflect on future challenges for clinical translation. Finally, we discuss the use of EVs as a biomarker source and highlight recent studies and clinical successes.

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Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes

Cited by 120 publications

References 50 publications

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

Therapeutic and diagnostic applications of extracellular vesicles

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