Pluchino's Group

RESEARCH CENTER
 

Cambridge Centre for Brain Repair and Stem Cell Institute

Dept of Clinical Neurosciences, University of Cambridge

ED Adrian Building

Robinson way (Forvie site)

CB2 0PY Cambridge, UK

Group Leader

Stefano Pluchino, MD, PhD

Email: spp24@cam.ac.uk

Laboratory website: www.pluchinolab.org

Members
 
 
Adaoha Elizabeth C. Ihekwaba, PhD; post-doctoral fellow
Chiara Cossetti, BSc; PhD student
Melania Cusimano, PhD; post-doctoral fellow
Elena Giusto, BSc; PhD student
Giulia Tyzack, BSc; PhD student
Edoardo Gaude, MSc, undergraduate student
Tommaso Leonardi, MSc, undergaduate student
Elena Antonini, BSc, lab technician
Matteo Donegà, BSc, lab technician
Xiaoling He, BSc, lab technician
Scientific interests

Somatic and embryonic stem cells

Neural stem cells

Oligodendrocyte progenitors

Experimental cell therapies and cell transplantation

CNS regeneration

Mechanisms and molecules of neuroprotection

Extracellular membrane vesicles, including exosomes, and horizontal RNA transfer

Morphogens and morphogenesis

Multiple Sclerosis and experimental autoimmune encephalomyelitis

Nanotechnologies and Synthetic Biology

Experimental stroke

Experimental spinal cord injury

Mobile small ncRNAs

Tissue and cell engineering

Clinic
 General Neurology and Chronic MS Clinics (10 hours/week)
Expertise
 
 

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:

1.The ideal stem cell source for transplantation, whether it has to be from pluripotent or multipotent sources;

2.The ideal route of cell administration, whether it has to be focal or systemic;

3.The ideal balance between differentiation and persistence of stem cells into the targeted tissue and – last but not least –

4.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.

 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) 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 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. 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 inuries (http://erc.europa.eu/succes-stories/world-multiple-sclerosis-day-erc-funded-research).

 As follow up (and integration) of this first strand of highly translational research, we are also pursuing a more basic (fundamental) approach that focuses at the discovery of the cellular machinery controlling the mobility of small nucleic acid sequences (known to regulate the translation into protein products, and ultimately functions) from within the cell to the extracellular space/compartment. We have started from some datasets that we have generated in the laboratory in the last couple of years and now attempting to define the genetic loci; verify the functions of potential cellular binders and/or identify the molecular carriers of these mobile small nucleic acids. This is a key and strategic strand of research that will provide evidence and mechanisms whose understanding has profound implications towards both the elucidation of the pathophysiology of major neurodegenerative diseases as well as the designing of next generation therapeutics mimicking (or interfering with) the sophisticated cellular intercourse that orchestrates the shift from homeostasis to disease.

 A third recent strand of investigation is the iONE-FP7 project that will focus at the definition of the safety and efficacy profiles of next generation implantable organic nano-electronics for spinal cord regeneration, both in vitro and in vivo in mice with experimental spinal cord traumas. The idea behind the iONE-FP7 project comes from a recently established consortium of 11 international (academic and non-academic) teams that will work together under the support of the European Union Seventh Framework Programme during the next three years. There is great expectation that within the iONE-FP7 framework these 11 teams will develop and test for the first time Active Multifunctional Implantable Devices (AMIDs) leading to treatment of Spinal Cord Injury (SCI). This project has the ambition to lead to device(s) that have (a) long-term stability associated to high biocompatibility and safety; (b) reduced risk of a host versus graft immune responses; (c) ability to mimic the local microenvironment for stem/precursor cell recruitment and differentiation; (d) ability to monitor the local functionality of the regenerated nerve cells (e.g. to intervene with loco-regional therapies); (e) ability to perform local stimulation with tunable electric fields; and (f) flexibility to deliver at the lesion site growth factors, neurotransmitters, and/or active drugs. This is again a highly strategic line of research that will advance the state-of-the-art of implantable devices for brain/spinal cord injuries from passive into active layouts that will promote nerve regeneration by a combination of local stimuli delivered on demand, will sense inflammation, and potentially control the immune-inflammatory response (http://ione-fp7.eu/).

 A fourth strand of investigation aims at the design, development, synthesis and testing of next generation RNA nanotherapeutics that will deliver short hairpin RNA (shRNA), microRNAs (miRs), aptamers, rybozimes, or other small RNAs to specific neural and non-neural cells in vitro and in vivo, for the treatment of inflammation-driven chronic neurological damage, such as that accumulating in multiple sclerosis and spinal cord injuries. We have recently launched collaboration with Professor Peixuan Guo at the University of Kentucky (UK) in applying RNA nanotechnologies for brain repair in syndromes where persistent inflammation leads to irreversible neural damage, such as multiple sclerosis, cerebral stroke and spinal cord injury. Professor Peixuan Guo is the William S. Farish Fund Endowed Chair in Nanobiotechnology at the UK College of Pharmacy and Markey Cancer Center, has established himself as one of the lead’s premier nanobiotechnology experts for his work in cancer therapeutics and RNA nanotechnology. Our backgrounds come from different ends of the scientific spectrum, which was one of the major factors in the partnership. We are constantly searching for innovative investigative approaches, and it was after we read a review on the emerging field of RNA nanotechnology published by Guo in Nature Nanotechnology that we became interested in how we could apply Guo’s approach to cancer to our own vision of creating novel nanomedicines to test in experimental neuroscience. As part of the collaboration, Jayden A. Smith, a post-doctoral scholar supported by our laboratory at Cambridge is spending six months in Guo’s lab at UK. Jayden will be specifically working at the construction of RNA nanostructures (from the conception, to the refinement of the assembly, to the final characterization) and learning how to apply Guo’s novel methods to neuroscience. The first translational phase of this project will encompass the test of RNA-nanostructures laboratory animals suffering from experimental multiple sclerosis, or contusion spinal cord injuries. Successful attempts in rodents will provide a strong rationale towards the development of clinical-grade next generation nanomedicines for the treatment of inflammation-driven neural damage in humans (See news releases at http://www.pluchinolab.org/PluchinoLab/News/Entries/2012/3/17_Entry_1.html;http://www.neuroscience.cam.ac.uk/news/article.php?permalink=61ea8fd398;http://pharmacy.mc.uky.edu/display.php?id=854). 

relevant publications
 
 
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;
2.     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;
3.     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;
4.     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 Manfrediand 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;
S Pluchino*¥, A Gritti*, E Blezer, S Amadio, E Brambilla, G Borsellino, C Cossetti, U Del Carro, G Comi, B ‘t Hart, A Vescovi¥, G Martino¥. Neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol, 2009, 66: 343-354 *equal contribution;¥corresponding author;
Scientific instruments
 
Cell culture; Cell transplantation; Computational modeling; Confocal microscopy; Electron microscopy (scanning and transmission); Flow cytometry; Fluorescence microscopy; hES cells; Immunohistochemistry; In situ hybridization; In vitro co-cultures; Magnetic resonance imaging (MRI); Mathematical modeling; Microscopy; Non viral delivery technologies (nanoparticles; liposomes); Reverse engineering; RNA deep sequencing; Semi-quantitative real time RT-PCR; siRNA; Unbiased stereology; Viral vector technology for cell engineering and in vivo gene silencing.

 
 
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