Characterization of Monoamine Oxidases in Mesenchymal Stem Cells: Role in Hydrogen Peroxide Generation and Serotonin-Dependent Apoptosis

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Evaluation of alginate microspheres for mesenchymal stem cell engraftment on solid organ

Mesenchymal stem cells (MSCs) may be used as a cell source for cell therapy of solid organs due to their differentiation potential and paracrine effect. Nevertheless, optimization of MSC-based therapy needs to develop alternative strategies to improve cell administration and efficiency. One option is the use of alginate microencapsulation, which presents an excellent biocompatibility and an in vivo stability. As MSCs are hypoimmunogenic, it was conceivable to produce microparticles with [alginate-poly-L-lysine-alginate (APA) microcapsules] or without (alginate microspheres) a surrounding protective membrane. Therefore, the aim of this study was to determine the most suitable microparticles to encapsulate MSCs for engraftment on solid organ. First, we compared the two types of microparticles with 4 × 106 MSCs/ml of alginate. Results showed that each microparticle has distinct morphology and mechanical resistance but both remained stable over time. However, as MSCs exhibited a better viability in microspheres than in microcapsules, the study was pursued with microspheres. We demonstrated that viable MSCs were still able to produce the paracrine factor bFGF and did not present any chondrogenic or osteogenic differentiation, processes sometimes reported with the use of polymers. We then proved that microspheres could be implanted under the renal capsule without degradation with time or inducing impairment of renal function. In conclusion, these microspheres behave as an implantable scaffold whose biological and functional properties could be adapted to fit with clinical applications

058 The ongoing MESAMI translational research program

PurposeDespite the improvement of pharmacological and surgical therapies, the mortality related to ischemic heart failure remains high. During the last years, bone marrow-mesenchymal stem cell (BM-MSC) therapy has been proposed as a novel approach for the prevention and therapy of heart failure. Intramyocardial injection allows concentration of grafted cells within the injured zone. However, a major problem of with intraparenchymal route of administration is the early death of most of grafted cells. The goal of the MESAMI program is to evaluate the effect of intramyocardial administration of BM-MSC preconditioned or not with the pineal hormone melatonin in ischemic cardiomyopathy.Methods and ResultsOur preclinical investigations have designed a preconditioning strategy of BM-MSCs with the melatonin that significantly increases survival and efficacy of grafted cells in animal models of myocardial ischemia. Melatonin treatment significantly ameliorates the beneficial effects of BM-MSC on the recovery of cardiac function. In the mean time, we started a phase I clinical trial in patients with severe ischemic cardiomyopathy and no option of revascularization, using the NOGA XP system to guide injections into the myocardium. Based on our basic research results, we are developing a multicenter phase II trial on the effects of intramyocardial administration of melatonin-preconditioned BM-MSC in patients with chronic ischemic cardiomyopathy.ConclusionThe ongoing MESAMI program is representative of a translational research program in France

Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment

Three-dimensional (3D) scaffolds hold great potential for stem cell-based therapies. Indeed, recent results have shown that biomimetic scaffolds may enhance cell survival and promote an increase in the concentration of therapeutic cells at the injury site. The aim of this work was to engineer an original polymeric scaffold based on the respective beneficial effects of alginate and chitosan. Formulations were made from various alginate/chitosan ratios to form opposite-charge polyelectrolyte complexes (PECs). After freeze-drying, the resultant matrices presented a highly interconnected porous microstructure and mechanical properties suitable for cell culture. In vitro evaluation demonstrated their compatibility with mesenchymal stell cell (MSC) proliferation and their ability to maintain paracrine activity. Finally, the in vivo performance of seeded 3D PEC scaffolds with a polymeric ratio of 40/60 was evaluated after an acute myocardial infarction provoked in a rat model. Evaluation of cardiac function showed a significant increase in the ejection fraction, improved neovascularization, attenuated fibrosis as well as less left ventricular dilatation as compared to an animal control group. These results provide evidence that 3D PEC scaffolds prepared from alginate and chitosan offer an efficient environment for 3D culturing of MSCs and represent an innovative solution for tissue engineering

Alginate-chitosan PEC scaffolds: A useful tool for soft tissues cell therapy

In this study we evaluate macroporous scaffolds made of alginate-chitosan polyelectrolyte complexes (PEC) as tools to optimize the results of soft tissues cell therapy. Cell therapy using mesenchymal stem cells (MSC) has become attractive for tissue repair and regeneration in a number of acute and chronic injuries. Unfortunately their low retention and/or survival after injection limit their beneficial effects. A biomaterial-assisted implantation, providing cells a three-dimensional (3D) microenvironment is a promising strategy. To this purpose, we designed a family of PEC scaffolds, and studied if they could meet the requirement of such application. Xray tomography showed that all PEC scaffolds present an interconnected macroporosity, and both rheology and tensile measurements reveal optimized mechanical properties (higher storage moduli and Young moduli) compared to alginate reference scaffolds. In vitro assays demonstrated their ability to allow MSC retention (higher than 90%), long-term viability and FGF2 secretion. Then, we used a skeletal muscle implantation model to assess the biological response to scaffolds graft, and showed that they support in vivo vascular formation within the implant-derived tissue. The combination of alginate/chitosan PEC scaffolds architecture and angiogenic potential make them appear as interesting tools to optimize MSC therapy results in soft tissues

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN)

Background Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. Methods This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed >= 12, and proximal and distal free resection margins length >= 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. Results A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to infinity). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to infinity). Conclusions Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection

Postoperative pain management in non-traumatic emergency general surgery: WSES-GAIS-SIAARTI-AAST guidelines

Background Non-traumatic emergency general surgery involves a heterogeneous population that may present with several underlying diseases. Timeous emergency surgical treatment should be supplemented with high-quality perioperative care, ideally performed by multidisciplinary teams trained to identify and handle complex postoperative courses. Uncontrolled or poorly controlled acute postoperative pain may result in significant complications. While pain management after elective surgery has been standardized in perioperative pathways, the traditional perioperative treatment of patients undergoing emergency surgery is often a haphazard practice. The present recommended pain management guidelines are for pain management after non-traumatic emergency surgical intervention. It is meant to provide clinicians a list of indications to prescribe the optimal analgesics even in the absence of a multidisciplinary pain team. Material and methods An international expert panel discussed the different issues in subsequent rounds. Four international recognized scientific societies: World Society of Emergency Surgery (WSES), Global Alliance for Infection in Surgery (GAIS), Italian Society of Anesthesia, Analgesia Intensive Care (SIAARTI), and American Association for the Surgery of Trauma (AAST), endorsed the project and approved the final manuscript. Conclusion Dealing with acute postoperative pain in the emergency abdominal surgery setting is complex, requires special attention, and should be multidisciplinary. Several tools are available, and their combination is mandatory whenever is possible. Analgesic approach to the various situations and conditions should be patient based and tailored according to procedure, pathology, age, response, and available expertise. A better understanding of the patho-mechanisms of postoperative pain for short- and long-term outcomes is necessary to improve prophylactic and treatment strategies