Rhenish Westphalian Technical University

Aachen, Germany

Rhenish Westphalian Technical University

Aachen, Germany

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Liu X.,Chinese Institute of Basic Medical Sciences | Ren S.,Chinese Institute of Basic Medical Sciences | Ge C.,Chinese Institute of Basic Medical Sciences | Cheng K.,Chinese Institute of Basic Medical Sciences | And 4 more authors.
Journal of Immunology | Year: 2015

Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs) and exert broadly immunomodulatory effects on immune cells. However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood. In this study, we show that mouse bone marrow-derived Sca-1+Lin-CD117- MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8-controlled regDC population (Sca+ BM-MSC-driven DC [sBM-DCs]) when cocultured without exogenous cytokines. The Notch pathway plays a critical role in the generation of the sBM-DCs by controlling IRF8 expression in an RBP-J-dependent way. We observed a high level of H3K27me3 methylation and a low level of H3K4me3 methylation at the Irf8 promoter during sBM-DC induction. Importantly, infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4+CD25+ regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders. Copyright © 2015 by The American Association of Immunologists, Inc.


PubMed | University of Toronto, Rhenish Westphalian Technical University and Chinese Institute of Basic Medical Sciences
Type: Journal Article | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2015

Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs) and exert broadly immunomodulatory effects on immune cells. However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood. In this study, we show that mouse bone marrow-derived Sca-1(+)Lin(-)CD117(-) MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8-controlled regDC population (Sca(+) BM-MSC-driven DC [sBM-DCs]) when cocultured without exogenous cytokines. The Notch pathway plays a critical role in the generation of the sBM-DCs by controlling IRF8 expression in an RBP-J-dependent way. We observed a high level of H3K27me3 methylation and a low level of H3K4me3 methylation at the Irf8 promoter during sBM-DC induction. Importantly, infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4(+)CD25(+) regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders.


Cantarella G.,Fondazione IRCCS Ca Granda | Mazzola R.F.,Fondazione IRCCS Ca Granda | Mazzola R.F.,University of Milan | Mantovani M.,Fondazione IRCCS Ca Granda | And 4 more authors.
Journal of Craniofacial Surgery | Year: 2012

The aim of this article was to describe the technical details of a fat injection procedure for the treatment of mild to moderate velopharyngeal insufficiency (VPI). Before surgery, the velopharyngeal gap is assessed by means of flexible nasoendoscopy, and speech intelligibility, hypernasality, and nasal air escape are perceptually evaluated and scored by independent raters; nasal airflow during speech is objectively measured. The lipoaspirate is centrifuged at 1200g for 3 minutes to separate and remove blood, cell debris, and the oily layer. Patients are injected with 3.5 to 8 mL of fat in the posterior and lateral pharyngeal walls and soft palate under general anesthesia. The fat is placed within the superior constrictor muscle on the posterior pharyngeal wall to avoid injection behind the prevertebral fascia and possible intraoperative or postoperative fat displacement in a caudal direction. A 19-gauge malleable, blunt, single-hole cannula is used for fat grafting, and the operative field is exposed by means of a Digman mouth gag. Two Nelaton probes are inserted through the nostrils and retracted from the mouth under moderate tension to favor visualization of the nasopharynx. No donor-site or injection-site morbidity has been observed so far, and the 12 patients (aged 5-48 y) treated so far have not manifested snoring or nasal obstruction at any time after surgery. Improved voice resonance is audible soon after the operation, and no hyponasality can be detected. The patients are discharged the day after surgery. Subsequent fat grafting procedures can be performed to achieve further improvement.Correctly performed fat injections improve voice resonance and reduce nasal air escape in VPI, as demonstrated by nasoendoscopy, speech perceptual evaluation, and the objective measurement of nasal airflow and represent an alternative to velopharyngoplasty for mild to moderate VPI. Copyright © 2012 by Mutaz B. Habal, MD.


Rieg A.D.,Rhenish Westphalian Technical University | Rossaint R.,Rhenish Westphalian Technical University | Verjans E.,Rhenish Westphalian Technical University | Maihofer N.A.,Rhenish Westphalian Technical University | And 2 more authors.
PLoS ONE | Year: 2013

Introduction:Levosimendan is approved for left heart failure and is also used in right heart failure to reduce right ventricular afterload. Despite the fact that pulmonary arteries (PAs) and pulmonary veins (PVs) contribute to cardiac load, their responses to levosimendan are largely unknown.Materials and Methods:Levosimendan-induced vasorelaxation of PAs and PVs was studied in precision-cut lung slices from guinea pigs by videomicroscopy; baseline luminal area was defined as 100%. Intracellular cAMP- and cGMP-levels were measured by ELISA and NO end products were determined by the Griess reaction.Results:Levosimendan relaxed control PVs (116%) and those pre-constricted with an endothelinA-receptor agonist (119%). PAs were only relaxed if pre-constricted (115%). Inhibition of KATP-channels (glibenclamide), adenyl cyclase (SQ 22536) and protein kinase G (KT 5823) largely attenuated the levosimendan-induced relaxation in control PVs, as well as in pre-constricted PAs and PVs. Inhibition of BKCa 2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine) only contributed to the relaxant effect of levosimendan in pre-constricted PAs. In both PAs and PVs, levosimendan increased intracellular cAMP- and cGMP-levels, whereas NO end products remained unchanged. Notably, basal NO-levels were higher in PVs. The KATP-channel activator levcromakalim relaxed PAs dependent on cAMP/PKA/PKG and increased cAMP-levels in PAs.Discussion:Levosimendan initiates complex and divergent signaling pathways in PAs and PVs. Levosimendan relaxes PAs and PVs primarily via KATP-channels and cAMP/cGMP; in PAs, BKCa 2+- and Kv-channels are also involved. Our findings with levcromakalim do further suggest that in PAs the activation of KATP-channels leads to the production of cAMP/PKA/PKG. In conclusion, these results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of PVs. © 2013 Rieg et al.


PubMed | Rhenish Westphalian Technical University
Type: Journal Article | Journal: PloS one | Year: 2016

Levosimendan is approved for left heart failure and is also used in right heart failure to reduce right ventricular afterload. Despite the fact that pulmonary arteries (PAs) and pulmonary veins (PVs) contribute to cardiac load, their responses to levosimendan are largely unknown.Levosimendan-induced vasorelaxation of PAs and PVs was studied in precision-cut lung slices from guinea pigs by videomicroscopy; baseline luminal area was defined as 100%. Intracellular cAMP- and cGMP-levels were measured by ELISA and NO end products were determined by the Griess reaction.Levosimendan relaxed control PVs (116%) and those pre-constricted with an endothelinA-receptor agonist (119%). PAs were only relaxed if pre-constricted (115%). Inhibition of KATP-channels (glibenclamide), adenyl cyclase (SQ 22536) and protein kinase G (KT 5823) largely attenuated the levosimendan-induced relaxation in control PVs, as well as in pre-constricted PAs and PVs. Inhibition of BKCa (2+)-channels (iberiotoxin) and Kv-channels (4-aminopyridine) only contributed to the relaxant effect of levosimendan in pre-constricted PAs. In both PAs and PVs, levosimendan increased intracellular cAMP- and cGMP-levels, whereas NO end products remained unchanged. Notably, basal NO-levels were higher in PVs. The KATP-channel activator levcromakalim relaxed PAs dependent on cAMP/PKA/PKG and increased cAMP-levels in PAs.Levosimendan initiates complex and divergent signaling pathways in PAs and PVs. Levosimendan relaxes PAs and PVs primarily via KATP-channels and cAMP/cGMP; in PAs, BKCa (2+)- and Kv-channels are also involved. Our findings with levcromakalim do further suggest that in PAs the activation of KATP-channels leads to the production of cAMP/PKA/PKG. In conclusion, these results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of PVs.

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