Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs)

Görgün, Cansu; Ceresa, Davide; Lesage, Raphaëlle; Villa, Federico; Reverberi, Daniele; Balbi, Carolina; Santamaria, Sara; Cortese, Katia; Malatesta, Paolo; Geris, Liesbet; Quarto, Rodolfo; Tasso, Roberta

doi:10.1016/j.biomaterials.2020.120633

Cited by 73 publications

(77 citation statements)

References 66 publications

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“…Hypoxia is a physiological characteristic of immunological niches [ 44 ], and changes to MSCs driven by HIF-1α can modulate innate and adaptive immunity, controlling the proliferation, differentiation and function of different immune cells [ 13 , 45 ]. Hypoxic preconditioning of MSCs is known to enhance the immunosuppressive properties of secreted EVs [ 46 , 47 ]. We show here that EV MSC-T-HIF C exhibits stronger immunoregulatory and anti-inflammatory properties than EV MSC-T C , which is supported by the following in vitro results: (I) superior differentiation of monocytes to Mφ2-like; (II) weakened adhesion of PBMCs to stimulated endothelium accompanied by partial restoration of the architecture of non-inflamed endothelium and reduced recruitment of immune cells to the tissues; (III) control of excessive fibrosis caused by impaired resolution of inflammation.…”

Section: Discussionmentioning

confidence: 99%

HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

Gómez

Amaro-Prellezo

Dorronsoro

et al. 2021

IJMS

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Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-β-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn’s disease and likely other immune-mediated inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

Gómez

Amaro-Prellezo

Dorronsoro

et al. 2021

IJMS

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“…Among these constituents, microRNAs are small non-coding RNA molecules that have a prominent role in gene regulation and biological functions. Both MSC-EV release and content are modified by environmental conditions (Gorgun et al, 2020). Xie et al (2017) observed that MSCderived EVs promote dose-dependent HUVEC proliferation, migration and tube formation.…”

Section: Extracellular Vesicles: a New Pathway Of Communicationmentioning

confidence: 99%

Cross-Talk Between Mesenchymal Stromal Cells (MSCs) and Endothelial Progenitor Cells (EPCs) in Bone Regeneration

Bouland

Philippart

Dequanter

et al. 2021

Front. Cell Dev. Biol.

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Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis, observed in both physiological and pathological situations. However, specific conditions (e.g., bone regeneration in large quantity, immunocompromised regenerative process) require additional support. Tissue engineering offers novel strategies. Bone regeneration requires a cell source, a matrix, growth factors and mechanical stimulation. Regenerative cells, endowed with proliferation and differentiation capacities, aim to recover, maintain, and improve bone functions. Vascularization is mandatory for bone formation, skeletal development, and different osseointegration processes. The latter delivers nutrients, growth factors, oxygen, minerals, etc. The development of mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) cocultures has shown synergy between the two cell populations. The phenomena of osteogenesis and angiogenesis are intimately intertwined. Thus, cells of the endothelial line indirectly foster osteogenesis, and conversely, MSCs promote angiogenesis through different interaction mechanisms. In addition, various studies have highlighted the importance of the microenvironment via the release of extracellular vesicles (EVs). These EVs stimulate bone regeneration and angiogenesis. In this review, we describe (1) the phenomenon of bone regeneration by different sources of MSCs. We assess (2) the input of EPCs in coculture in bone regeneration and describe their contribution to the osteogenic potential of MSCs. We discuss (3) the interaction mechanisms between MSCs and EPCs in the context of osteogenesis: direct or indirect contact, production of growth factors, and the importance of the microenvironment via the release of EVs.

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“…Therefore, MSCs have emerged as an attractive candidate therapy for many diseases, including IBD (Arranz et al, 2018;Silva et al, 2018;Kang et al, 2020). The previous investigations have indicated that the therapeutic efficacy of MSCs does not depend on cell-to-cell interactions, but on the effects mediated by the soluble active factors secreted by the cells (Eleuteri and Fierabracci, 2019;Gorgun et al, 2021). The components of MSCs, such as conditioned medium and extracellular vesicles, have been verified to ameliorate the experimental colitis in mice (Legaki et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats

Fan

Mao

et al. 2021

Front. Bioeng. Biotechnol.

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Adipose derived mesenchymal stem cells (AD-MSCs) have shown therapeutic potential in treatments of inflammatory bowel disease (IBD). Due to the harsh host environment and poor survival of the cells, controversy concerning the homing, proliferation and differentiation of MSCs in lesion tissue still remains. It has been reported that conditioned media from MSCs could improve the colitis, whereas the therapeutic efficiency could be significantly elevated by the stimulation of pro-cytokines. In this study, we pre-treated the adipose derived MSCs with the serum from colitis rats and then the activated conditioned media (CM-AcMSC) were collected. To compare the therapeutic effects of CM-MSC and CM-AcMSC on IBD, we constructed dextran sodium sulphate (DSS)-induced colitis rat models. The colitis was induced in rats by administrating 5% DSS in drinking water for 10 days, and the disease symptoms were recorded daily. The colon histopathological changes were observed by different staining methods (H&E and PAS). The expression levels of MUC2 and tight junctions (TJs) were determined by RT-qPCR. The levels of inflammatory cytokines were analyzed by ELISA and western blot analysis. Our findings suggested that CM-AcMSC was more effective in ameliorating the clinical features and histological damage scores. Treatment with CM-AcMSC significantly increased the expression of MUC2 and TJs and suppressed the production of pro-inflammatory cytokines in colonic tissues of colitis rats. The inhibitory effects of CM-AcMSC on inflammatory responses of colitis rats were mediated by NF-κB signaling pathway. These results suggested that pre-activation of MSCs with serum from colitis rats could promote the production of paracrine factors and improve the therapeutic effects of conditioned medium on colitis rats.

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Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs)

Cited by 73 publications

References 66 publications

HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

Cross-Talk Between Mesenchymal Stromal Cells (MSCs) and Endothelial Progenitor Cells (EPCs) in Bone Regeneration

The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats

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