Lucia Zanotti

San Raffaele Scientific Institute, Milano, Lombardy, Italy

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Publications (8)56.97 Total impact

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    ABSTRACT: Neural stem cells represent a heterogeneous population of mitotically active, self-renewing and multipotent cells of both the developing and the adult central nervous system (CNS) showing complex patterns of gene expression that may vary in both space and time. Endogenous stem cells residing within CNS germinal niches might concur to nervous system repair owing to their ability to drive neurogenesis and gliogenesis during adulthood. Nevertheless, self-renewal, proliferation, migration and differentiation of CNS stem cells may significantly vary upon different types (e.g. acute vs chronic, focal vs multifocal) of CNS injury. In this chapter we address several aspects of neural stem cell pathophysiology. KeywordsNeural progenitor cells-Neurogenesis-Neurons-Glia-Neural stem cell transplantation-Nervous system disorders
    12/2009: pages 71-78;
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    ABSTRACT: Physiological (spontaneous) and reactive (reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells - and in particular on those of neural origin - in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.
    Neuroscience Letters 07/2009; 456(3):101-6. · 2.03 Impact Factor
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    ABSTRACT: The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation. The study described herein, identifies the first member of the TGF beta/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.
    PLoS ONE 02/2009; 4(6):e5959. · 3.53 Impact Factor
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    ABSTRACT: The adult mammalian brain harbours multi-potent stem/precursor cells supporting self-renewal and differentiation within specialised niches, namely the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. In response to different environmental cues, these neural stem/precursor cells (NPCs) may differentiate into neurons, astrocytes or oligodendrocytes. Due to their intrinsic plasticity, these cells are considered an attractive therapeutic tool for the treatment of several neurological disorders. We have shown that syngenic NPCs, injected systemically in mice with chronic central nervous system (CNS) inflammation, reduce tissue damage and improve functional recovery. NPCs express constitutively activated integrins, which enable them to enter the CNS. Once in the site of tissue injury, transplanted NPCs promote brain repair through several mechanisms of action. They can induce apoptosis of CNS-infiltrating T cells as well as foster remyelination driven by endogenous oligodendrocyte progenitors. Neuroprotective and immunomodulatory molecules released principally from undifferentiated NPCs at the site of tissue damage mediate these effects. This bystander (or paracrine) ability of transplanted NPCs to protect the CNS from different types of injury suggests that such therapeutic procedure could be of great interest in the future therapeutic armamentarium of inflammatory demyelinating diseases of the CNS. Key words Multiple sclerosis-inflammation-demyelination-stem cells-oligodendrocytes
    Journal of Neurology 02/2007; 254:I23-I28. · 3.58 Impact Factor
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    ABSTRACT: In degenerative disorders of the central nervous system (CNS), transplantation of neural multipotent (stem) precursor cells (NPCs) is aimed at replacing damaged neural cells. Here we show that in CNS inflammation, NPCs are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions. In a mouse model of chronic CNS inflammation, systemically injected adult syngeneic NPCs use constitutively activated integrins and functional chemokine receptors to selectively enter the inflamed CNS. These undifferentiated cells survive repeated episodes of CNS inflammation by accumulating within perivascular areas where reactive astrocytes, inflamed endothelial cells and encephalitogenic T cells produce neurogenic and gliogenic regulators. In perivascular CNS areas, surviving adult NPCs induce apoptosis of blood-borne CNS-infiltrating encephalitogenic T cells, thus protecting against chronic neural tissue loss as well as disease-related disability. These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection.
    Nature 08/2005; 436(7048):266-71. · 38.60 Impact Factor
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    ABSTRACT: Spontaneous neural tissue repair occurs in patients affected by inflammatory and degenerative disorders of the central nervous system (CNS). However, this process is not robust enough to promote a functional and stable recovery of the CNS architecture. The development of cell-based therapies aimed at promoting brain repair, through damaged cell-replacement, is therefore foreseen. Several experimental cell-based strategies aimed at replacing damaged neural cells have been developed in the last 30 years. Although successful in promoting site-specific repair in focal CNS disorders, most of these therapeutic approaches have failed to foster repair in multifocal CNS diseases where the anatomical and functional damage is widespread. Stem cell-based therapies have been recently proposed and might represent in the near future a plausible alternative strategy in these disorders. However, before envisaging any human applications of stem cell-based therapies in neurological diseases, we need to consider some preliminary and still unsolved issues: (i) the ideal stem cell source for transplantation, (ii) the most appropriate route of stem cell administration, and, last but not least, (iii) the best approach to achieve an appropriate, functional, and long-lasting integration of transplanted stem cells into the host tissue.
    Brain Research Reviews 05/2005; 48(2):211-9. · 7.82 Impact Factor
  • Ernst Schering Research Foundation workshop 02/2005;
  • S Pluchino, L Zanotti, G Martino
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    ABSTRACT: Polyreactive (auto)antibodies are frequently found in healthy subjects and are bona fide considered to be nonpathogenic. However, autoreactive B cells and circulating (auto)antibodies have been associated with several neurological syndromes, including demyelinating disorders. Whether these antibodies can have a real impact on disease development is still a matter of debate. Here, we briefly summarize some of the most recently published data on both the deleterious and the protective effects of antibodies in autoimmune demyelinating disorders of the central nervous system.
    Neurological Sciences 11/2003; 24 Suppl 4:S231-3. · 1.41 Impact Factor