4th Annual Meeting of The Forum of Italian Researchers on Mesenchymal and Stromal cells (FIRST) Pavia (Italy).

This year the historical frame of Collegio Borromeo in Pavia hosted the participants of the 4th FIRST meeting, 122 delegates from 3 European Countries, who had the occasion to debate the most intriguing and recent developments in mesenchymal stem cell with some of the principal experts in the field. Surrounded by the fresco paintings of the main episodes of Saint Charles Borromeo life and warmly welcomed by the rector of the Collegio, the speakers discussed the futuristic aspects of mesenchymal stem cell research. Special attention has been given to the strategies to better exploit mesenchymal stem cell potential against the well-known killers of our era, namely heart diseases and cancer. A further step in heart disease treatment has been presented by Paolo Madeddu. He showed how a population of CD34+ cells, located around the aorta adventitia with typical pericyte, mesenchymal and stemness markers, and a robust regenerative potential in a mouse model of hind limb ischemia, can be also successfully isolated from saphenous vein leftovers of patients undergoing coronary artery bypass graft surgery and sustained long-term improvements in a mouse model of myocardial infarction. Carlo Ventura illustrated, in a multidisciplinary context, important chemical and physical strategies to empower mesenchymal stem cell pluripotentiality. Endorphin peptides, hyaluronan esters of butyric and retinoic acids, extremely low frequency magnetic fields (ELF-MF) and RF energy from Wi-Fi technologies are some of the new tools that can be applied in order to enhance the regenerative potential of mesenchymal stem cells, especially towards cardiomyocyte differentiation, as shown by his numerous in vitro and in vivo experiments. The dark side of mesenchymal stem cells has been explored by Paola Chiarugi who clearly summarized her experiments addressed to explore the role of cancer-associated fibroblasts (CAFs) in epithelial mesenchymal transition (EMT) of prostate carcinoma cells. Interleukine-6, metalloproteases (MMP)-2 and 9, cycloxygenase-2, nuclear factor-?B and hypoxia inducible factor-1 have been identified as the key-players in the reciprocal interplay between prostate carcinoma cells and CAFs. What happens to mesenchymal stem cells and tumor microenvironment when a patient receives chemotherapy? Which is the role of mesenchymal stem cells in establishing and maintaining chemoresistence? Emile Voest gave an important contribution to answer these questions. He showed how, after exposure to commonly used chemotherapeutics such as cisplatin, oxaliplatin and carboplatin, MSC become activated to secrete very specific fatty acids, the so-called platinum induced fatty acids (PIFA), with important in vivo effect on chemoresistance. Inhibitors of the enzymes involved in PIFA synthesis could therefore prevent PIFA-mediated chemoresistance but also enhance the anti-tumor activity of chemotherapy in vivo. A nano-scale view on the possibility to bioengineer mesenchymal stem cells: the lecture by Jeffrey M. Karp opened a new perspective on the methods to enhance the homing of systematically infused mesenchymal stem cells through cell surface engineering and to orchestrate mesenchymal stem cell-mediated drug delivery with an intracellular depot of phenotype altering agents. Moreover, he showed how cell surface sensors can be used to detect signals within the cellular nano-environment with unprecedented spatial and temporal resolution thus providing a useful tool for monitoring the cell secretome after transplantation. From the future to the past and back to the future: the lecture from Bruno Péault beautifully summarized the fascinating ancestry of mesenchymal stem cells from the potential of perivascular stem cells through their mechanisms of control in situ and towards clinical application of adipose tissue derived autologous perivascular cells in bone repair. And then, biomaterials: Nicola Elvassore translated in the mesenchymal stem cell language the word "mechanotransduction" so as the process converting mechanical stimuli into biochemical signals. He showed how microfabrication techniques and substrate engineering allow an accurate control of microenvironmental cues that is crucial in mediating a wide range of mesenchymal stem cell behaviours, including growth, proliferation, differentiation and migration. The role of microtechnologies is not limited to cell culture condition control, but can also improve the possibility to perform successful screening experiments of different conditions in short time and at reduced economical effort. Still in the nano-scale and in the future with a "braille" system for mesenchymal stem cells: the talk by Nikolaj Gadegaard summarized his innovative experiments on the development of a nano-scale system based on the use of electron beam lithography (EBL), an idea get by the semiconductor industry. In this systems the cells find an environment in which they maintain their multipotentiality for long time or, by introducing a small amount of noise in the system, they differentiate into bone forming cells. The potential impact of this discovery on artificial bone especially for aging population is impressive. Finally, as in the past editions, the choice of the scientific committee of the best three abstracts for the Young Investigators. Awarding was very difficult! Besides the many excellent researches presented and the six selected for presentation, works from Manuela Mura, Francesca Bianchi and Anne-Laure Gamblin have been prized: many compliments to the winners and see all of you next year!