The central nervous system (CNS) has the intrinsic capability to repair itself when injured. Over the years a series of molecular and cellular innate repair mechanisms have been discovered and their ability to prevent irreversible tissue damage and irreversible neurological deficits has been characterized. Among cellular mechanisms, those sustained by neural stem/precursor cells (NPCs); the self-renewing and multipotent cells of the CNS capable of driving neurogenesis and gliogenesis during development and adult life; play a crucial role. On one hand, endogenous NPCs maintain CNS homeostasis via a series of different mechanisms of action among which the most important ones are the production of newly generated neuronal and glial cells and the release of neuroprotective substances.
The Unit research activity is mainly focused on the study of the molecular and cellular pathways sustaining both spontaneous and reparative CNS regenerative processes in both the healthy and pathological conditions such as inflammation and neurodegeneration. The ultimate main goal of the unit is to develop more efficacious therapeutic strategies to combat still incurable CNS pathological conditions.
- Analyze which are the molecular pathways that support the development of the brain during embryonic life and to understand whether or not those pathways are recapitulated after an inflammatory and/or degenerative insult in order to promote the regeneration of the CNS
- Understand the molecular mechanisms that alter synaptic function during inflammatory processes and/or degenerative CNS processes
- Develop genetic tools to study the function of endogenous NPCs residing within the CNS during the development and in the adult life, both in physiological and pathological conditions
- Analyze the role of endogenous NPCs in maintaining the homeostasis of the CNS and/or to induce tissue repair by developing genetic and molecular tools capable of marking or effectively eliminate these cells
- Establish alternative therapeutic strategies based on the transplantation of adult or reprogrammed NPCs or aimed at fostering the reparative potential of endogenous NPCs in acute and chronic CNS inflammatory disorders leading to irreversible neurodegeneration (i.e. multiple sclerosis, stroke and spinal cord injury)
De Feo D, Merlini A, Brambilla E, Ottoboni L, Laterza C, Menon R, Srinivasan S, Farina C, Manteiga JMG, Butti E, Bacigaluppi M, Comi G, Greter M, Martino G. Neural precursor cell-secreted tgf-β2 redirects inflammatory monocyte-derived cells in cns autoimmunity. J Clin Inv. 2017 Nov 1;127(11):3937-3953.
Bacigaluppi M, Russo G*, Peruzzotti-Jametti L*, Rossi S, Sandrone S, Gallizioli M, De Ceglia R, Butti E, Studer V, Colombo E, Reitmeir R, Motta C, Muzio L, Comi G, Farina C, Letterio Politi L, Invernizzi RW, Hermann DM*, Centonze D*, Martino G. Neural stem cell transplantation promotes post-ischemic neuronal plasticity by regulating the expression of glutamate transporters. J Neurosci. 2016 Oct 12; 36(41):10529–10544. (*equally contributed)
Mozafari S, Laterza C, Roussel D, Bachelin C, Marteyn A, Deboux C, Martino G. Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice. J Clin Inv. 2015 Sep;125(9):3642-56.
Onorati M*, Castiglioni V*, Iasci D**, Cesana E**, Menon R**, Vuono R, Talpo F, Goya RL, Lyons P, Bulfamante GP, Muzio L, Martino G, Toselli M, Farina C, Barker RA, Biella G, Cattaneo E. Molecular and functional definition of the developing human striatum. Nat Neurosci. 2014 Dec;17(12):1804-15. (*,**equally contributed)
Arnò B, Grassivaro F, Rossi C, Bergamaschi A, Greter M, Favaro R, Comi G, Becher B, Martino G*, Muzio L*. Neural progenitors cells orchestrate microglia migration and positioning into the developing cortex. Nat Comm. 2014 Nov 26;5:5611. (*equally contributed)
Martino G, Butti E, Bacigaluppi M. Neurogenesis or non-neurogenesis: this is the question. J Clin Invest. 2014 Mar;124(3):970-3.
Laterza C, Merlini A, De Feo D, Ruffini F, Menon R, Onorati M, Fredrickx E, Muzio L, Lombardo A, Comi G, Quattrini A, Taveggi AC, Farina C, Cattaneo E, Martino G. Ipsc-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of leukemia inhibitory factor. Nat. Commun. 2013;4:2597.
Kokaia Z*, Martino G*, Schwartz M*, Lindvall O. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci. 2012 Jul 26;15(8):1078-87. (*equally contributed)
Butti E, Bacigaluppi M, Rossi S, Cambiaghi M, Bari M, Cebrian Silla A, Brambilla E, Musella A, De Ceglia R, Teneud L, De Chiara V, D’Adamo P, Garcia-Verdugo JM, Comi G, Muzio L, Quattrini A, Leocani L, Maccarrone M, Centonze D, Martino G. Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitoxicity. Brain 2012;115(11):3320-3335.
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 Oct;91(4):1281-304.
Martino G, Franklin RJ, Van Evercooren AB, Kerr DA. Stem cells in multiple sclerosis (STEMS) consensus group. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010 May;6(5):247-55.
Pluchino S*, Gritti A*, Blazer 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;66:343-354. (*equally contributed).
Bacigaluppi M*, Pluchino S*, Kilic E, Peruzzotti-Jametti L, Kilic U, Salani G, Brambilla E, Comi G, Martino G*, Hermann DM*. Delayed post-ischemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain 2009 Aug;132(Pt 8):2239-51. (*equally contributed).
Centone D*, Muzio L*, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, Marcello D’Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Concioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009 Mar 18;29(11):3442-52. (*equally contributed).
Martino G, Pluchino S. The therapeutic potential of neural stem cells. Nat Rev Neurosci. 2006;7:395-406.
Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005 Jul 14;436(7048):266-71.
Martino G. How the brain repairs itself: perspectives for new therapeutic strategies for inflammatory and degenerative cns disorders. Lancet Neurol. 2004;3:372-378.
Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Bergami A, Furlan R, Delcarro U, Amadio S, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induce clinical recovery in a chronic model of multiple sclerosis. Nature 2003;422:688-694.
Akram Mokhtarzadeh Khanghahi
Luca De Feo