Head:	Maria Pia Abbracchio (Full professor; Pharmacology)
Team members:	Davide Lecca (Assistant professor; Pharmacology) Davide Marangon (Research associate; Pharmacology) Marta Boccazzi (Postdoctoral fellow; Pharmacology) Juliana Helena Castro E Silva (PhD student) Marta Fumagalli (Associate professor; Pharmacology; DiSFeB) Stefano Raffaele (Postdoctoral fellow; DiSFeB)

 

GENERAL DESCRIPTION

The research group has a wide expertise in studying glial cell functions, many of which are mediated by purinergic receptors. Glial cells play important roles in mechanical, metabolic, and trophic support for neurons, they contribute to neurotransmission, affect differentiation, proliferation, and neuronal death. In particular, the activities of the lab are focused on the identification of pharmacological strategies to foster remyelination in experimental models of demyelinating diseases, such as multiple sclerosis (MS), brain ischemia, amyotrophic lateral sclerosis (ALS), acting on targets expressed by oligodendrocytes, namely the myelin producing cells in the central nervous system, and their precursors, called OPCs. These strategies are aimed at activating or inhibiting purinergic or P2Y-like receptors, at repositioning drugs already marketed for other diseases, at identifying microRNAs that hamper remyelination and may thus represent new targets for innovative drugs.
Part of the research activity of the group is also aimed at understanding the mechanisms by which the inflammatory response associated with pathological conditions of the central nervous system hinders OPC maturation. Focus is given to the contribution of astrocytes and immune cells, like microglia, to identify new approaches to control the response of these cells and redirect them toward protective functions. Furthermore, based on recent studies demonstrating that also a subpopulation of OPCs can participate in the inflammatory and immunological response that characterizes MS, studies are ongoing to unveil the mechanisms involved in this process and their impact on surrounding cells.
The group takes advantage of both in vitro systems (primary cultures of rodent glial cells and human oligodendrocytes derived from iPSCs), and in vivo models of demyelinating disease (experimental autoimmune encephalomyelitis, focal demyelination induced by lysolecithin and toxic demyelination by cuprizone).

RESEARCH TOPICS

1. The oligodendroglial receptor GPR17 as a pharmacological target in multiple sclerosis
2. Identification of new remyelinating compounds through drug repurposing strategies
3. Identification of post-transcriptional mechanisms underpinning oligodendrocyte maturation and remyelination
4. Mechanisms by which neuroinflammation hinders efficient OPC maturation in experimental models characterized by myelin damage
5. Strategies to delay motor neuron degeneration by enhancing trophic functions and remyelinating capabilities of OPCs in experimental models of ALS
6. Investigation of the immunological properties of OPCs

DESCRIPTION OF THE RESEARCH TOPICS

1. The oligodendroglial receptor GPR17 as a pharmacological target in multiple sclerosis
GPR17 is a P2Y-like purinergic receptor mainly expressed in OPCs. In several models of acute and chronic disease, the receptor is aberrantly expressed in OPCs, thus impairing their maturation to oligodendrocytes, and hampering remyelination attempts. The projects on this topic are aimed at elucidating the physiological functions of GPR17 by means of -omics approaches and to develop new pharmacological agents to block its overactivation. These studies are performed on rat OPC cultures, in mice subjected to experimental autoimmune encephalomyelitis and cuprizone-induced toxic demyelination. The lab has also developed a transgenic line of inducible reporter mice (GPR17-iCreERT2-GFP) in which GPR17-expressing cells and their progeny can be traced by means of a green fluorescent protein.

Main collaborations:

• • Prof. Nico Mitro, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano
• • Prof. Ivano Eberini, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano
• Prof. Letizia Trincavelli, Department of Pharmacy, Università degli Studi di Pisa
• Dr. Andrea Rivera, Department of Neuroscience, Università degli Studi di Padova
• Dr. Leda Dimou, University of Ulm, Germany
• Prof. Arthur Butt, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, UK

2. Identification of new remyelinating compounds through drug repurposing strategies
Repositioning strategies (“drug repurposing”) are based on the off-label use of already marketed drugs. This strategy opens new opportunities for the treatment of chronic and severe diseases, including multiple sclerosis and other neurodegenerative diseases, since it considerably reduces time and costs compared to the development of completely new drugs.

Main collaborations:

• Prof. Marco De Amici, Department of Pharmaceutical Sciences, Università degli Studi di Milano
• Prof. Gianvito Martino e Dr. Roberto Furlan, Ospedale San Raffaele, Milan
• Prof. Marco Salvetti, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Università degli Studi di Roma “La Sapienza”
• Dr. Cristina Agresti, Istituto Superiore di Sanità, Rome

3. Identification of post-transcriptional mechanisms underlying oligodendrocyte maturation and remyelination
In the last years, the research group has been focusing on miRNAs as physiological regulators of differentiation and potential inhibitory remyelination factors. MiRNAs represent interesting pharmacological targets. The projects on this topic aim at identifying miRNAs altered in disease models, understanding their pathogenetic role in vitro and in vivo through rescue experiments and identifying cross-talk mechanisms between distinct cell types via extracellular vesicles.

Main collaborations:

• Prof. Enrica Boda, Istituto di Neuroscienze Cavalieri Ottolenghi, Università degli Studi di Torino
• Dr. Claudia Verderio, Istituto di Neuroscienze, CNR, Vedano al Lambro (MB)
• Dr. Corinna Giorgi, Istituto di Biologia e Patologie Molecolari, CNR, Roma
• Prof. Patrizia Riso, Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, Università degli Studi di Milano

4. Mechanisms by which neuroinflammation hinders efficient OPC maturation in experimental models characterized by myelin damage
In addition to the role of "patrols" of the nervous tissue, microglia have numerous specific functions with important implications for neurodegeneration and demyelination associated with neurological diseases, such as cerebral ischemia and multiple sclerosis. The primary objectives of the projects related to this research aim at understanding the mechanisms by which the activation of microglia during disease conditions hinders efficient remyelination and at identifying strategies to direct these cells to protective functions. A particular focus is given to the crosstalk between microglia and OPCs mediated by extracellular vesicles.

Main collaborations:

• Dr. Claudia Verderio, Istituto di Neuroscienze, CNR, Vedano al Lambro (MB)
• Prof. Luigi Sironi, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano
• Prof. Kate Lykke Lambertsen, Department of Neurobiology Research, University of Southern Denmark, Odense, Danimarca
• Prof. Roberta Brambilla, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL (USA)

5. Strategies to delay motor neuron degeneration by enhancing trophic functions and remyelinating capabilities of OPCs in experimental models of ALS
Recent studies revealed that motor neuron degeneration in ALS is strictly associated with oligodendrocyte dysfunction. Increasing the regenerative capacities of OPCs may therefore represent an innovative approach to treat this disease. We have recently shown the presence of an abnormal increase in the expression of the GPR17 receptor in the spinal cord of ALS SOD1G93A mice, in parallel with altered numbers of mature oligodendrocytes. Furthermore, OPCs isolated from the same tissues show maturation defects, which can be rescued by ligands active on GPR17. On this basis, the project aims to analyze the therapeutic activity of GPR17 ligands in the SOD1G93A model. In parallel, a new GPR17-CreERT2:eGFP/SOD1G93A inducible reporter line will be generated, which will allow to label the GPR17 expressing OPCs and their progeny with the fluorescent protein GFP and to follow their fate during disease progression and after pharmacological treatment. Finally, oligodendrocyte cultures from induced pluripotent stem cells derived from ALS patients will be set up to analyze the therapeutic effects of GPR17 ligands in human cells.

Main collaborations:

• Prof. Giambattista Bonnano, Prof. Marco Milanese, Dr. Tiziana Bonifacino, Dipartimento di Farmacia, Università degli Studi di Genova
• Prof. Vincenzo Silani, Prof. Antonia Ratti, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano
• Prof. Loris Rizzello, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano

6. Investigation of the immunological properties of OPCs
Recent evidence show that OPCs are able to participate in the inflammatory and immunological response that characterizes MS. This project aims at unveiling the pathways involved in the immunological functions of OPCs and the mechanisms that mediate their immunomodulatory effects on surrounding cells.

Main collaborations:

• Prof. Pierre Gressens, INSERM U1141, Paris
• Dr. Claudia Verderio, Istituto di Neuroscienze, CNR, Vedano al Lambro (MB)

 

NETWORK PARTECIPATION

Maria P. Abbracchio is the coordinator of the National Interest Research Project PRIN 2017NSXP8J, is a member of the BRAVEinMS international network for the study of multiple sclerosis and is responsible for two national research projects funded by the Italian Multiple Sclerosis Foundation (FISM). The laboratory is part of the MIND FoodS HUB network, an innovative agri-food research project funded by Regione Lombardia.
Marta Fumagalli is coordinator of the research project GPR17ALS-1 funded by the Italian AriSLA Foundation and Head of Unit in the SEED2020 project for the study of the anti-inflammatory properties of antidiabetic drugs in a murine experimental model of maternal immune activation.
MPA, MF and DL are collaborators of the IUPHAR Pages (International Union of Basic and Clinical Pharmacology) for their contribution to the drafting and updating of the database managed by the Committee on Receptor Nomenclature and Drug Classification, in the section of P2Y receptors for nucleotides (www.guidetopharmacology.org).