Stefano Pluchino
University Lecturer in Brain Repair and Honorary Neurology Consultant, University of Cambridge, UK
Non-tenured Professor of Regenerative Neuroscience, Medical School, University Vita e Salute, Milano, Italy
Adjunct Associate Professor of Neurology, Department of Neurology, The University of Vermont College of Medicine, Burlington, VT, USA
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 undifferentiated 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:
- The ideal stem cell source for transplantation, whether it has to be from pluripotent or multipotent sources;
- The ideal route of cell administration, whether it has to be focal or systemic;
- The ideal balance between differentiation and persistence of stem cells into the targeted tissue and – last but not least –
- The ideal mechanism of tissue repair to foster, whether it has to be cell replacement or tissue protection (rescue).
Current projects in the laboratory 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. Besides some classical experimental cell therapy approaches with pluripotent stem cell-derived precursors/progenitors, we are devoting special attention to the different modalities by which NPCs engage programs of horizontal cell-to-cell communication with cells in the microenvironment. Our most recent work suggests that a key role in this might be attributed to a novel mechanism of intercellular communication through the transfer of secreted membrane vesicles (MVs; shown to contain RNAs) from donor to recipient cells. Recent years have seen many important regulatory functions ascribed to non-coding RNAs (ncRNAs), making direct and indirect consequences of ncRNA-directed transcriptional regulation significant. With the advent of next generation deep sequencing (DS) technologies, obtaining a comprehensive description of NPCs and MV transcriptome is now quite common place. Nevertheless, this convergence of DS technology and the potential regulatory roles of ncRNAs in NPCs would provide many opportunities as well as challenges in terms of data mining methodology in uncovering biological significance, identifying ncRNA targets as well as deciphering the exact mechanism of translational repression of messenger RNAs (mRNAs) by these ncRNAs. To this end, we aim to develop an extensive pipeline, dedicated towards discovery and annotation of both long and small ncRNAs on NPCs, which will then be exploited for modelling and simulation purposes. These computational approaches will develop our ability to produce mathematically sound hypotheses which can account for the way(s) NPCs communicate with each other by shuttling ncRNAs into secreted MVs.
We believe that the true innovation of this latter set of approaches lay in their ability to look into an innate (physiological) mechanism with the visionary focus of translating the knowledge of basal (vs reactive) stem cell functions into innovative highly clinical impact therapeutics.
People
1. Post-doctoral fellows
Clara Alfaro Cervello (ca386@cam.ac.uk)
Adaoha Elizabeth C. Ihekwaba (aeci3@cam.ac.uk)
2. PhD Students
Chiara Cossetti (cc608@cam.ac.uk)
Giulia Tyzack (get22@cam.ac.uk)
3. Undergraduate students
Tommaso Leonardi (tl344@cam.ac.uk)
4. Research Assistants/Lab Technicians
Xiaoling He (xlh20@ cam.ac.uk)
Selected Publications
Peer reviewed articles
R Furlan, E Brambilla, F Sanvito, L Roccatagliata, S Olivieri, A Bergami, S Pluchino, A Uccelli, G Comi, G Martino. Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57BL/6 mice. Brain 2003, 126: 1-7;
S Pluchino, A Quattrini, E Brambilla, A Gritti, G Salani, G Dina, R Galli, U Del Carro, S Amadio, A Bergami, R Furlan, G Comi, AL Vescovi, G Martino. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003, 422: 688-694;
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;
O Butovsky, Y Ziv, A Schwartz, G Landa, AE Talpalar, S Pluchino, G Martino, SM chwartz. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 2006, 31: 149-160;
Y Ziv, H Avidan, S Pluchino, G Martino and M Schwartz. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci U S A 2006, 103: 13174-13179;
LS Politi, M Bacigaluppi, E Brambilla, M Cadioli, A Falini, G Comi, G Scotti, G Martino, S Pluchino. Magnetic resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brain of mice with experimental multiple sclerosis. Stem Cells 2007, 5: 2583-2592;
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, E Brambilla, P Rovere-Querini, A Capobianco, C Alfaro-Cervello, G Salani, C Cossetti, G Borsellino, L Battistini, M Ponzoni, C Doglioni, JM Garcia-Verdugo, G Comi, AA Manfredi and G Martino¥. Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function. PLoS ONE 2009, 4(6): e5959 *corresponding author;
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 *equal contribution;
R Shechter, A London, C Varol, C Raposo, M Cusimano, G Yovel, A Rolls, M Mack, S Pluchino, G Martino, S Jung, M Schwartz. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 2009, 6(7): e1000113;