Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model

Montanari, Sonia; Dayan, Víctor; Yannarelli, Gustavo; Billia, Filio; Viswanathan, Sowmya; Connelly, Kim A.; Keating, Armand

doi:10.1016/j.healun.2015.05.008

Cited by 19 publications

(9 citation statements)

References 35 publications

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“…Bone marrow-derived MSCs have therapeutic benefits in other multiple applications where the effects of antibiotic treatment are unknown, and it would be beneficial to investigate the effects of minocycline treatment on these applications. For example, MSCs increase the thickness of the ventricular wall in a heart failure model, and they improve cardiac function with enhanced ventricular remodeling and reduced cardiac fibrosis in a heart transplantation model [37, 38]. This effect could be influenced by a minocycline-induced production of VEGF [17].…”

Section: Discussionmentioning

confidence: 99%

Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells

et al. 2017

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BackgroundMesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties due to their anti-inflammatory, angiogenic, and even antibacterial properties. We have shown previously that minocycline enhances the wound healing phenotype of MSCs, and MSCs encapsulated in poly(ethylene glycol) and gelatin-based hydrogels with minocycline have antibacterial properties against Staphylococcus aureus (SA). Here, we investigated the signaling pathway that minocycline modulates in MSCs which results in their enhanced wound healing phenotype and determined whether preconditioning MSCs with minocycline has an effect on antimicrobial activity. We further investigated the in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels in inoculated full-thickness cutaneous wounds.MethodsModulation of cell signaling pathways in MSCs with minocycline was analyzed via western blot, immunofluorescence, and ELISA. Antimicrobial efficacy of MSCs pretreated with minocycline was determined by direct and transwell coculture with SA. MSC viability after SA coculture was determined via a LIVE/DEAD® stain. Internalization of SA by MSCs pretreated with minocycline was determined via confocal imaging. All protein and cytokine analysis was done via ELISA. The in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels was determined in Sprague–Dawley rats inoculated with SA. Two-way ANOVA for multiple comparisons was used with Bonferroni test assessment and an unpaired two-tailed Student’s t test was used to determine p values for all assays with multiple or two conditions, respectively.ResultsMinocycline leads to the phosphorylation of transcriptional nuclear factor-κB (NFκB), but not c-Jun NH2-terminal kinase (JNK) or mitogen-activated protein kinase (ERK). Inhibition of NFκB activation prevented the minocycline-induced increase in VEGF secretion. Preconditioning of MSCs with minocycline led to a reduced production of the antimicrobial peptide LL-37, but enhanced antimicrobial activity against SA via an increased production of IL-6 and SA internalization. MSC and antibiotic-loaded hydrogels reduced SA bioburden in inoculated wounds over 3 days and accelerated reepithelialization.ConclusionsMinocycline modulates the NFκB pathway in MSCs that leads to an enhanced production of IL-6 and internalization of SA. This mechanism may have contributed to the in-vivo antibacterial efficacy of MSC and antibiotic-loaded hydrogels.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0623-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells

et al. 2017

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“…Cardiovascular diseases (CVD) are the leading cause of death worldwide [1] and deteriorate considerably the quality of many patient's life. To enhance prognosis and wellbeing of patients, a variety of cells were evaluated for their therapeutic potential in experimental and clinical studies, like cardiosphere-derived cells, cardiac progenitor cells, and mesenchymal stromal (MSC) cells from bone marrow, adipose tissue and other sources [2][3][4][5][6][7][8]. Another unique cardiac cell type are the human cardiacderived adherent proliferating (CardAP) cells, which are generated by outgrowth cultures of endomyocardial biopsies [9].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles from regenerative human cardiac cells act as potent immune modulators by priming monocytes

et al. 2019

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Background: Nano-sized vesicles, so called extracellular vesicles (EVs), from regenerative cardiac cells represent a promising new therapeutic approach to treat cardiovascular diseases. However, it is not yet sufficiently understood how cardiac-derived EVs facilitate their protective effects. Therefore, we investigated the immune modulating capabilities of EVs from human cardiac-derived adherent proliferating (CardAP) cells, which are a unique cell type with proven cardioprotective features. Results: Differential centrifugation was used to isolate EVs from conditioned medium of unstimulated or cytokinestimulated (IFNγ, TNFα, IL-1β) CardAP cells. The derived EVs exhibited typical EV-enriched proteins, such as tetraspanins, and diameters mostly of exosomes (< 100 nm). The cytokine stimulation caused CardAP cells to release smaller EVs with a lower integrin ß1 surface expression, while the concentration between both CardAP-EV variants was unaffected. An exposure of either CardAP-EV variant to unstimulated human peripheral blood mononuclear cells (PBMCs) did not induce any T cell proliferation, which indicates a general low immunogenicity. In order to evaluate immune modulating properties, PBMC cultures were stimulated with either Phytohemagglutin or anti-CD3. The treatment of those PBMC cultures with either CardAP-EV variant led to a significant reduction of T cell proliferation, pro-inflammatory cytokine release (IFNγ, TNFα) and increased levels of active TGFβ. Further investigations identified CD14 + cells as major recipient cell subset of CardAP-EVs. This interaction caused a significant lower surface expression of HLA-DR, CD86, and increased expression levels of CD206 and PD-L1. Additionally, EV-primed CD14 + cells released significantly more IL-1RA. Notably, CardAP-EVs failed to modulate anti-CD3 triggered T cell proliferation and pro-inflammatory cytokine release in monocultures of purified CD3 + T cells. Subsequently, the immunosuppressive feature of CardAP-EVs was restored when anti-CD3 stimulated purified CD3 + T cells were co-cultured with EV-primed CD14 + cells. Beside attenuated T cell proliferation, those cultures also exhibited a significant increased proportion of regulatory T cells. Conclusions: CardAP-EVs have useful characteristics that could contribute to enhanced regeneration in damaged cardiac tissue by limiting unwanted inflammatory processes. It was shown that the priming of CD14 + immune cells by CardAP-EVs towards a regulatory type is an essential step to attenuate significantly T cell proliferation and proinflammatory cytokine release in vitro.

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“…Thus, MSCs are expected to replenish the cellular component of damaged host tissue without disrupting the local microenvironment after transplantation. Currently, MSCs transplantation has been proposed as a promising therapeutic strategy for various degenerative diseases such as liver and heart ( Nhung et al, 2015 , Montanari et al, 2015 ). MSCs are isolated from the various locations in the body including bone marrow, skin, hair follicles, dental pulp, adipose tissue, umbilical cord, amniotic membrane, endometrium, placenta and synovium ( Li et al, 2014 , Beltrami et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Involvement of PI3K and MMP1 in PDGF-induced Migration of Human Adipose-derived Stem Cells

et al. 2017

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Human adult stem cells have widely been examined for their clinical application including their wound healing effect in vivo. To function as therapeutic cells, however, cells must represent the ability of directed migration in response to signals. This study aimed to investigate the mechanism of platelet-derived growth factor (PDGF)-induced migration of the human abdominal adipose-derived stem cells (hADSCs) in vitro. A general matrix metalloproteinase (MMP) inhibitor or a MMP2 inhibitor significantly inhibited the PDGF-induced migration. PDGF treatment exhibited greater mRNA level and denser protein level of MMP1. The conditioned medium of PDGF-treated cells showed a caseinolytic activity of MMP1. Transfection of cells with siRNA against MMP1 significantly inhibited MMP1 expression, its caseinolytic activity, and cell migration following PDGF treatment. Phosphatidylinositol 3-kinase (PI3K) inhibitor reduced the migration by about 50% without affecting ERK and MLC proteins. Rho-associated protein kinase inhibitor mostly abolished the migration and MLC proteins. The results suggest that PDGF might signal hADSCs through PI3K, and MMP1 activity could play an important role in this PDGF-induced migration in vitro.

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Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model

Cited by 19 publications

References 35 publications

Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells

Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells

Extracellular vesicles from regenerative human cardiac cells act as potent immune modulators by priming monocytes

Involvement of PI3K and MMP1 in PDGF-induced Migration of Human Adipose-derived Stem Cells

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