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Cambridge Immunology Network

 

Research

My team studies whether the accumulation of neurological disability observed in patients with progressive forms of multiple sclerosis (PMS) can be slowed down using stem cell therapies. In particular, our 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.

 

I have been first or senior author in seminal papers that have established the potential of somatic NSC-based experimental therapies for PMS. My early studies identified a critical role around the route of cell injection4 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.

My 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, we have demonstrated that EVs deliver functional IFN-g/Ifngr1 complexes to target cells.

We have 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.

Our most recent 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. We have 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.

Our 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.

 

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.

Publications

Key publications: 
  1. S Pluchino and JA Smith. Explicating Exosomes: reclassifying the rising stars in intercellular communication. Cell 2019 Apr 4;177(2):225-227
  2. L Peruzzotti-Jametti and S Pluchino. Targeting mitochondrial metabolism in neuroinflammation:towards a therapy for progressive multiple sclerosis? Trends Mol Med. 2018 Oct;24(10):838-855
  3. PP Amaral, T Leonardi, N Han, E Viré, DK Gascoigne, R Arias-Carrasco, M Buscher, A Zhang, S Pluchino, V Maracaja-Coutinho, HI Nakaya, Martin Hemberg, R Shiekhattar, AJ Enright, T Kouzarides. Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci. Genome Biol 2018 Mar 15; 19(1): 32
  4. L Peruzzotti-Jametti, JD Bernstock, N Vicario, ASH Costa, CK Kwok, T Leonardi, LM Booty, I Bicci, B Balzarotti, G Volpe, G Mallucci, G Manferrari, N Iraci, A Braga, JM Hallenbeck, MP Murphy, F Edenhofer, C Frezzaand S Pluchino. Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. Cell Stem Cell 2018 Mar 1; 22(3): 355-368
  5. N Iraci, E Gaude, T Leonardi, ASH Costa, C Cossetti,HK Saini,AJ Enright,C Frezza and S Pluchino. Extracellular vesicles are independent metabolic units delivering functional Asparaginase-like protein 1. Nat Chem Biol 2017 Sep;13(9):951-955
  6. C Cossetti, N Iraci,TR Mercer, T Leonardi,E Alpi,D Drago,C Alfaro-Cervello,H Saini,M Davis,J Schaeffer,W Muller,JM Garcia-Verdugo,S Mathivanan,A Bachi,A Enright,JS Mattick,S Pluchino. Extracellular vesicles from neural stem cells transfer IFN-g via Ifngr1 to activate Stat1 signalling in target cells. Mol Cell 2014 Oct 23;56(2):193-204
  7. D Drago,C Cossetti, N Iraci, E Gaude, G Musco, A Bachi and S Pluchino. The stem cell secretome and its role in brain repair. Biochimie 2013; 95(12): 2271-85
  8. Cusimano M, Biziato D, Brambilla E, Donegà M, Alfaro-Cervello C, Snider S, Salani G, Pucci F, Comi G, Garcia-Verdugo JM, De Palma M, Martino G, Pluchino S. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain. 2012; 135(Pt 2): 447-60
  9. Martino G, Pluchino S, Bonfanti L, Schwartz M. Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol Rev. 2011; 91(4): 1281-304
  10. Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, 't Hart B, Vescovi A, Martino G. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009; 66(3): 343-54
Dr Stefano  Pluchino
Takes PhD students
Not available for consultancy