The mammalian central nervous system (CNS) is characterized by the richest assortment of cell types amongst vertebrate tissues. Fundamental players in this tremendous complexity are neural stem cells (NSCs) that during development serve as the ultimate origin of all three major neural cell types composing the mature CNS. NSCs are specified to a vast array of subtypes at topologically well-defined locations and precise developmental stages. This highly coordinated cell genesis represents a crucial step in the assemblage and consequent functions of the complex neural circuitry. The central goal of our laboratory is to decipher the molecular and cellular codes underlying the neural specification and neuronal differentiation programmes during neural development and understand how the same programmes are impaired in brain diseases. This knowledge is pivotal to cell replacement approaches to the damaged brain and to the generation of cellular models of brain diseases mandatory for disclosing the molecular bases of diseases and for establishing effective drug discovery programmes.
Research activity in the lab is directed toward the understanding of mechanisms regulating self-renewal, fate decision and neuronal maturation of NSCs. In particular we are dissecting the roles of specific signal transduction molecules and transcription factors in the molecular circuitries that control the physiologic maintenance of normal NSCs and their specific alteration underlying tumorigenesis processes and neurodevelopmental diseases. The final aims are to exploit this knowledge in order to develop molecular and cellular tools for prospect cellular and pharmacological therapeutic interventions in the diseased brain. We pursue these goals by using both mammalian neural tissues and neuralizing processes applied to human and mouse pluripotent stem cell systems. We routinely combine a variety of techniques and tools to conduct our research including in vitro culture of mouse and human NSCs and pluripotent stem cells, molecular biology, biochemistry and cell-based assays.
There are currently three major areas of interest in the lab:
- Explore the molecular mechanisms that regulate pluripotent stem cells developmental-relevant conversion into specific NSC populations and their neuronal subtype specification and functional maturation. Defined stage- and region-specific NSC populations are generated in a coordinate fashion during brain development and following neural induction protocols applied to pluripotent stem cells. We aim at disclosing the molecules important for the induction and stable maintenance of specific NSC populations characterized by high developmental plasticity (i.e. the potential to generate a wide range of neuronal subtypes) and to develop protocols for achieving their appropriate neuronal maturation.
- Modelling human brain disorders with iPS cells and NSCs in order to understand the molecular mechanisms of diseases, disclose pathological-relevant phenotypes and develop drug screening platforms. Our aim is to model human brain diseases by reprogramming patient-derived somatic cells with neurodevelopmental diseases. The iPS cell lines are subjected to differentiation into patient-specific NSCs and disease-relevant neurons and are interrogated in order to disclose the molecular mechanisms causing and/or driving the particular disease. To this end, assays monitoring self-renewal and differentiation potential, as well as the function of neuronal subtypes are used.
- Identify molecular determinants that control maintenance and tumorigenic competence of Brain Tumor Stem cells (BTSCs) in order to develop target therapies directed to the malignant stem cell component. Our focus here is on Glioblastoma Multiforme (GBM), the most aggressive human brain tumor. We have generated BTSC lines from human GBM biopsies and we are currently investigating the role of specific transcription factors in the maintenance of self-renewal and tumorigenic competence of these cells. The aim is to define new potential targets for the development of new brain tumor therapeutics.
- Luciano Conti, PI
- Jacopo Zasso, PhD student
- Isabella Lucini, Master student
A postdoctoral position is currently available in the lab. Motivated candidates interested in stem cell biology are invited to contact the PI (luciano.conti [at] unitn.it) for informal inquiries. Candidates with experience in cell reprogramming, procedures for human pluripotent stem cells and NSCs maintenance and neuronal differentiation will be preferred. Undergraduate students interested in stem cell research as theme for experimental theses are also encouraged to contact the PI.
- Roberto Maggi, Elio Messi, Dept. Pharmacological and Biomolecular Sciences, University of Milano, Italy
- Giorgio Merlo, Molecular Biotechnology Center, University of Torino, Italy
- Pietro Luigi Poliani, Dept. Molecular and Translational Medicine, University of Brescia, Italy
- Steve Pollard, Cancer Research Centre, University of Edinburgh, UK
- Maurizio Popoli, Dept. Pharmacological and Biomolecular Sciences, University of Milano, Italy
- Leonid Schneider, Dept. Biology, Technical University Darmstadt, Germany
- Ada Maria Tata, Dept. Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Italy
- Yvan Torrente, Dept. Neurological Sciences, University of Milano, Italy
- Ileana Zucchi, Institute of Biomedical Technologies, National Research Council, Italy
Gorba T and Conti L (2013). Neural Stem Cells as Tools for Drug Discovery: novel platforms and approaches. Expert Opinion on Drug Discovery 8(9), 1083-94.
Brilli E*, Reitano E*, Conti L*, Conforti P*, Gulino R, Consalez G, Smith A, Rossi F, Cattaneo E (2013). Neural stem cells engrafted in the adult brain fuse with endogenous neurons. Stem Cells and Development 22(4): 538-47.
Conti L, Crisafulli L, Caldera V, Tortoreto M, Brilli E, Conforti P, Zunino F, Magrassi L, Schiffer D, Cattaneo E (2012). REST controls self-renewal and tumorigenic competence of human glioblastoma cells. PLoS ONE 7: e38486.
Onorati M, Binetti M, Conti L, Camnasio S, Calabrese G, Albieri I, Di Febo F, Toselli M, Biella G, Martynoga B, Guillemot F, Consalez G, Cattaneo E (2011). Preservation of positional identity in fetus-derived neural stem (NS) cells from different mouse central nervous system compartments. Cellular and Molecular Life Sciences 68: 1769-83.
Conti L, Cattaneo E (2010). Neural stem cell systems: Physiological players or in vitro entities? Nature Reviews Neuroscience 11: 176-87.
Ponti G, Reitano E, Aimar P, Cattaneo E, Conti L, Bonfanti L (2010). Neural-specific inactivation of ShcA functions results in anatomical disorganization of subventricular zone neural stem cell niche in the adult brain. Neuroscience 168: 314-22.
Spiliotopoulos D*, Goffredo D*, Conti L*, Di Febo F, Biella G, Toselli M, Cattaneo E (2009). An optimized experimental strategy for efficient conversion of embryonic stem (ES)-derived mouse neural stem (NS) cells into a nearly homogeneous mature neuronal population. Neurobiology of Disease 34: 320-31.
Papadimou E, Moiana A, Goffredo D, Koch P, Bertuzzi S, Brüstle O, Cattaneo E, Conti L (2009). p66ShcA adaptor molecule accelerates ES cell neural induction. Molecular and Cellular Neuroscience 41: 74-84.
Goffredo D*, Conti L*, Di Febo F, Biella G, Tosoni A, Vago G, Biunno I, Moiana A, Bolognini D, Toselli M, Cattaneo E (2008) Setting the conditions for efficient, robust and reproducible generation of functionally active neurons from adult subventricular zone-derived neural stem cells. Cell Death and Differentiation 15:1847-56.
Sun Y, Pollard S, Conti L, Toselli M, Biella G, Parkin G, Willatt L, Falk A, Cattaneo E, Smith A (2008). Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture. Molecular and Cellular Neuroscience 38: 245-258.
Pollard SM, Conti L (2007). Investigating radial glia in vitro. Progress in Neurobiology 83: 53-67.
Pollard S, Conti L, Sun Y, Goffredo D, Smith A (2006). Adherent neural stem (NS) cells from fetal and adult forebrain. Cerebral Cortex 16: i112-20.
Conti L, Pollard S, Gorba T, Reitano E, Toselli, M, Biella G, Sun Y, Sanzone S, Ying Q-L, Cattaneo E, Smith A (2005). Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biology 3: 1594-606.
Magrassi L, Conti L, Lanterna A, Zuccato C, Marchionni M, Cassini P, Arienta C, Cattaneo E (2005). Shc3 affects human high-grade astrocytomas survival. Oncogene 24: 5198-206.
Conti L, Sipione S, Magrassi L, Bonfanti L, Rigamonti D, Pettirossi V, Peschanski M, Haddad B, Pelicci P, Milanesi G, Pelicci G, Cattaneo E. (2001). Shc signaling in differentiating neural progenitor cells. Nature Neuroscience 4: 579-86.
Conti L, De Fraja C, Gulisano M, Migliaccio E, Govoni S, Cattaneo E (1997). Expression and activation of SH2/PTB-containing ShcA adaptor protein reflects the pattern of neurogenesis in the mammalian brain. PNAS 94: 8185-90.
“Neural Stem Cells” Publication Number: WO/2005/121318; International Application No.: PCT/GB2005/002289, Publication Date: 22.12.2005.