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Dr Stefano Pluchino

Research Interests

The development of cell-based therapies aimed to promote tissue repair in central nervous system (CNS) diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Several cell-replacement strategies have been developed in the last few years. Recent evidence from our own and other laboratories indicates that somatic neural stem/precursor cells (NPCs) might very efficiently protect the CNS from chronic degeneration induced by inflammation both in small rodents as well as in primates. However, before envisaging any potential human applications of such innovative therapies we need to confront with some preliminary and still unsolved questions that include also the identification of the mechanisms of stem cell-instructed tissue repair, whether it is to be cell replacement or tissue protection (rescue).

 

The current projects in the our Lab are further exploring the cellular and molecular mechanisms regulating the therapeutic plasticity of NPCs in complex CNS diseases such as multiple sclerosis, and spinal cord injury. While keeping an eye on next generation stem cells, either induced pluripotent stem (iPS) or induced neural stem (iNS) cells that are being tested via classical experimental cell therapy approaches, we are also devoting special attention to the study of the different modalities by which stem cells speak with the brain and with the immune system (neuro/immune interactions).

 

As first and principal strand of investigation, we are focusing at a novel mechanism of intercellular communication that works through the cell-to-cell transfer of extracellular membrane vesicles (EMVs). We are attempting on defining whether this form of communication exists for stem cells of the brain, and on elucidating its molecular signature and potential therapeutic relevance. We are very excited about our current preliminary data, as they suggest that EMV-mediated transfer of small non-coding nucleic acids – including microRNAs – is very likely be a major mechanism responsible for the functional instruction of neighbouring (target) immune cells by transplanted stem cells. In our experiments we are using state-of-the-art technologies to (i) investigate the EMV small RNAome; and (ii) demonstrate that ncRNAs from stem cells affect the expression of several genes and protein, and ultimately the function, of target immune cells. Then, we aim at (iii) demonstrating the therapeutic potential of the transfer of individual EMV-carried small ncRNAs in vitro and in vivo in rodents with experimental neurological diseases where the adaptive or innate immune response play a major role.

 

Understanding how this communication occurs will allow us to identify both the stem cell molecular makeup and their therapeutic benefits. Using computational analysis, bioinformatics techniques and rodent models, this project hopes to determine how stem cell behavior can be translated into treatments for neurological disorders that include multiple sclerosis and spinal cord injuries.

Key Publications

Pluchino S, Cossetti C. How stem cells speak with host immune cells in inflammatory brain diseases. Glia. 2013, 61:1379-401.

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: 447-60

G Martino, S Pluchino, L Bonfanti, M Schwartz. Brain regeneration in physiological and pathological conditions: the therapeutic plasticity of neural stem cells. Physiol Rev 2011, 91: 1281-1304

F Cimadamore, K Fishwick, E Giusto, K Gnedeva, G Cattarossi, A Miller, S Pluchino, L M. Brill, M Bronner-Fraser, AV Terskikh. Human ESC-Derived Neural Crest Model Reveals A Key Role For Sox2 In Sensory Neurogenesis. Cell Stem Cell 2011; 8: 538-51

M Bacigaluppi, S Pluchino, L Peruzzotti Jametti, E Kilic, U Kilic, G Salani, E Brambilla,MJ West, G Comi,G Martino and D M Hermann. Delayed post- ischemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain 2009, 132: 2239-51

S Pluchino, L Muzio, J Imitola, M Deleidi, C Alfaro-Cervello, G Salani, C Porcheri, E Brambilla, F Cavasinni, A Bergamaschi, J Manuel Garcia-Verdugo, G Comi, S J Khoury, G Martino. Persistent inflammation induces dysfunction of the endogenous brain stem cell compartment. Brain 2008, 131: 2564-78

S Pluchino, L Zanotti, B Rossi, E Brambilla, L Ottoboni, G Salani, M Martinello, A Cattalini, A Bergami, R Furlan, G Comi, G Constantin and G Martino. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005, 436: 266-271

Morphology and ultrastructure of atypical perivascular NPC niches that are established in vivo after focal NPC transplantation at the level of the severely contused mouse spinal cord (from Cusimano et al. Brain 2012; 135: 447-60).

Intravital microscopy showing systemically-injected NPCs (bright intravascular dots) firmly adhering to inflamed brain vessels in mice with experimental autoimmune encephalomyelitis (from Pluchino et al. Nature 2005, 436: 266-271).