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Summary 3rd meeting

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3rd FIRST meeting Report - Milan, April 18th 2011

On April 18th 2011, FIRST third meeting was held in Milan, Italy, at Palazzo delle Stelline with the participation of more than 100 attendees from 5 European Countries and particular emphasis was put on the contribution of young researchers who were also awarded for the best abstracts. Presentations included studies on neuroregenerative properties of MSC and kidney repair, on MSC senescence, on mechanisms underlying MSC multipotency and their immunomodulatory properties. Moreover, the limits and bottlenecks of induced pluripotent stem cells (iPS) have been reviewed, with particular attention to cardiovascular applications.

Mesenchymal stem cells and neuroregenerative properties

MSC have been proposed to contrast the progressive dopaminergic depletion caused by the selective death of neuronal subpopulations that is responsible of the symptoms in Parkinson's Disease (PD). In the study presented by Patrizia Bossolasco (Fondazione Matarelli, Milan, Italy), undifferentiated human MSCs have been implanted into the striatum of rats bearing a lesion of the nigrostriatal pathway induced by local injection of 6-hydroxydopamine (6-OHDA), a widely recognized rodent model of PD. MSCs expressed markers of neural cells, but no glial markers were detected. After transplantation, some transplanted cells acquired a glial-like phenotype in animals bearing the nigrostriatal lesion, but no differentiation toward a dopaminergic phenotype was observed. Interestingly, transplanted animals showed increased survival of both cell bodies and terminals of dopaminergic neurons and a reduction of the behavioral abnormalities associated with the lesion. These results suggest that MSCs could stimulate the surrounding microenvironment to support damaged neurons substitution. It was also demonstrated that grafted MSCs sustained the survival of striatal/nigral dopaminergic terminals and enhanced neurogenesis in the subventricular zone and neuroblasts migration. Moreover, MSC protected the murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-OHDA in a co-culture system and multiplex human angiogenic array analysis on the conditioned media demonstrated a modulation of released cytokines. The neuroregenerative properties of MSC have also been investigated in the context of peripheral nerve gap injuries that are currently repaired with an autologous nerve graft or biocompatible nerve conduits. The combination of biomaterials and MSC may facilitate improved nerve regeneration. The results presented by Giorgio Terenghi (University of Manchester, UK) demonstrate that adult adipose-derived MSC differentiated towards the expression of phenotypic and functional characteristics of Schwann cells and transplanted into bioengineered nerve conduits, have beneficial effects in promoting enhanced nerve regeneration.

MSC and kidney regeneration

Important advances have recently been made in understanding the mechanisms underlying the effects of MSC in renal regeneration. Several studies support the paracrine action of MSC. It has also been demonstrated that microvesicles (MVs) derived from human bone marrow MSCs may be responsible for the observed effects of MSC. In particular, Benedetta Bussolati (University of Turin, Italy) demonstrated that MVs are as effective as the cells themselves in accelerating the recovery in models of glycerol-induced acute kidney injury and of acute and chronic ischemia-reperfusion damage. MVs released from MSC may reprogram target cells by transferring various bioactive molecules including specific subsets of mRNA and microRNA.

Induced pluripotent stem cells and cardiovascular repair

Massimiliano Gnecchi (IRCCS Policlinico San Matteo, Pavia, Italy) discussed the ability of MSC to mobilize and activate endogenous stem/progenitor cells in diseased organs or to introduce exogenous stem cells for tissue regeneration/repair and how this might impact on many diseases, including those affecting the brain, skeletal muscle, pancreas and heart. The current basic science that is the foundation of future clinical approaches of MSC therapy for heart diseases has been discussed. Furthermore, it has been demonstrated that MSC exert powerful beneficial paracrine effects on native cardiomyocytes through the release of soluble factors. Martin Ulrich (Hannover Medical School, Germany) discussed the current basic science, the techniques, potential and possible risks of iPS in the light of needs for patient-derived pluripotent stem cells. Data concerning generation, efficient genetic modification, scalable expansion and cardiorespiratory differentiation of iPS cells were presented. Their application for myocardial restoration and tissue engineering, together with the first encouraging results of iPS cells in pharmacological research, were reviewed, suggesting fascinating perspectives for future developments in biotechnology and regenerative medicine.

Molecular pathways for multipotency in MSC

Donald Phinney (The Scripps Research Institute, Jupiter, Florida) showed recent results on the role of different molecules in maintaining the undifferentiated state of MSC. FGF2 reversibly inhibits multi-lineage differentiation of primary mouse MSC. Moreover, the pre-treatment of MSCs with FGF2 specifically up regulates TWIST2 and SPRY4, which suppresses ERK1/2 activation in response to osteo-inductive stimuli and results in suppression of bone specific gene expression. FGF2 also induces expression of FGFR1 and FGFR4 and suppresses expression of FGFR2 and FGFR3 whereas BMP2, which increases osteogenic differentiation, has the opposite effect. Moreover, FGF2 has dramatic effects on cytokine gene expression in MSCs, such as IL-1? and IL-1?. FGF2-induced up regulation of IL-1? also strongly correlates with suppression of TWIST1 expression as well as several anti-inflammatory proteins belonging or related to the IL-1 family. Collectively, these data suggest that TWIST proteins integrate external signals in MSCs to regulate differentiation and cytokine gene expression, thereby providing a critical link between the stem-like and stromal-like functions of the cells.

MSC and immunomodulatory effects

A general overview on the effects of MSC from different sources was discussed. The results presented by Cedric Menard (INSERM U917, Rennes, France) were collected in the context of two current European Consortia, the CASCADE and the REBORNE projects, aimed at establishing common standards for the production, control and clinical use of MSC in skin, cornea and bone regeneration.

Young researchers - FIRST award

Several interesting and innovative abstracts have been received for poster and oral presentations. Six of them have been selected for oral presentations and the most outstanding works received one of the three awards which have been granted on the meeting day. These are the winners:

1) Riccardi Maria, University of Sacred Heart , Policlinico "A. Gemelli", Department of Obstetrics and Gynecology, Roma, Italy "New hepatic regeneration scenario involving amniotic fluid-derived mesenchymal stem cells and Wharton's jelly- mesenchymal stem cells: when the fetus heals the fetus"
2) Matuskova Miroslava, Laboratory of Molecular Oncology, Cancer Research Institute of SAS, Bratislava, Slovakia "Combined mesenchymal stromal cell-mediated enzyme/prodrug therapy represents efficient treatment for human metastatic disease"
3) Dander Erica, Dipartimento di Neuroscienze e Tecnologie Biomediche, UniversitÓ di Milano-Bicocca, Monza (MB), Italy "Immunomonitoring of Transplanted Patients infused with Mesenchymal Stromal Cells (MSC) for treating Steroid-Refractory GvHD"

This 3rd FIRST meeting has been, as expected, an open, interactive occasion to be in touch with outstanding scientists all over the world in a one-day workshop on mesenchymal stem and stromal cells, moving from the very last experimental data supporting the definition of their identity to the results of pre-clinical studies in view of their clinical use in regenerative medicine. 0ur most sincere thanks to Fondazione Cariplo for the support given to the realization of the meeting. Taken together, the information presented during the 3rd FIRST meeting defines a new framework of MSC research in which their mechanisms are better clarified, thus opening new options in the fascinating field of regenerative medicine.



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