Dr. Pluchino have carried out an intense teaching activity in the Faculties of Medicine and Biological Technologies at the University Vita-Salute San Raffaele (Milan, Italy; since 2005), at The University of Vermont College of Medicine (VT, USA; since 2008), at the University of Cambridge (UK; since 2010), and more recently at Guangzhou Medical University (China).
Dr. Pluchino's also has a team at Cambridge University with a long-standing interest towards the understanding of the cellular and molecular (including metabolic) determinants of chronic inflammation. The team overall aim at establishing whether the accumulation of neurological disability observed in patients with progressive forms of multiple sclerosis (PMS) can be slowed down using innovative molecular therapies that include small molecules, gene therapy vectors (both integrating and non-integrating), and stem cell medicines. In particular, their aim is to understand the basic mechanisms that allow exogenously delivered neural stem cells (NSCs) to create an environment that preserves damaged axons or prevents neurons from dying.
Using stem cells as a model to identify the critical factors that prevent neurodegeneration is an exciting new frontier of regenerative medicine, which is just being tested in humans. After having provided compelling evidence that support the [constitutive vs inducible] immune modulatory functions of somatic neural stem cells (NSCs), Dr. Pluchino's laboratory major recent focus has been the exploitation of the cellular and molecular mechanisms regulating the therapeutic plasticity of NSCs in inflammatory CNS diseases such as multiple sclerosis, ischemic stroke and spinal cord injury. Current projects in his laboratory are further exploiting the mechanisms that regulate the therapeutic plasticity of NSCs, clarifying the role of mitochondrial metabolism in chronic neuroinflammation, while working at the development of a full bench-to-bedside phase I clinical trial consisting of the transplantation of (patient-specific) stably expandable directly induced NSC in people with progressive MS. By understanding the mechanisms of intercellular (stem cell) signalling, diseases of the central nervous system (CNS) may be treated more effectively, and significant neuroprotection may be achieved with new tailored NSC therapeutics.
Dr. Pluchino have been first or senior author in seminal papers that have established the potential of somatic NSC-based experimental therapies for PMS. His early studies identified a critical role around the route of cell injection and the mechanisms of NSC accumulation in the chronically inflamed CNS, as well as revealing an unexpected ability of NSC therapies to provide neurotrophic support and inhibit detrimental host immune responses in vivo.
His team has also focused on defining the nature and function of intercellular signalling mediated by extracellular membrane vesicles (EVs) from NSCs. Using a series of computational analyses and high-resolution imaging techniques, they demonstrated that EVs deliver functional IFN-g/Ifngr1 complexes to target cells. His team also discovered that EVs harbour L-asparaginase activity catalysed by the enzyme Asparaginase-like protein 1. While the translation of EV therapies into clinical regenerative therapies is still some way from being fully achievable, both these studies on NSC EVs serve as complementary models of how stem cell grafts might signal to the host to mediate repair through a range of complementary actions. Their current work describes a delayed accumulation of the pro-inflammatory tricarboxylic acid (TCA) cycle intermediate succinate in the cerebrospinal fluid (CSF) of mice with experimental autoimmune encephalomyelitis (EAE), a model of chronic MS. He has identified a new complementary mechanism by which directly induced NSCs (iNSCs) respond to endogenous inflammatory metabolic signals to inhibit the activation of type-1 mononuclear phagocytes (MPs) in vivo after transplantation. Transplanted iNSCs respond to the succinate released by type-1 inflammatory macrophages and microglia in the CSF, which then signals to iNSCs via succinate receptor 1 (SUCNR1) and initiates the secretion of prostaglandin E2 and the scavenging of extracellular succinate.
Dr. Pluchino's research has therefore recalibrated the classical view that neural grafts only function through structural cell replacement, and opened up a new therapeutic avenue by which to use exogenously delivered NSCs.