Daniela Ferrari

Daniela Ferrari
Università degli Studi di Milano-Bicocca | UNIMIB · Department of Biotechnology and Biosciences

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74
Publications
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Publications

Publications (74)
Article
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Amyotrophic Lateral Sclerosis (ALS) is a fatal disease affecting both upper and lower motoneurons. The transactive response DNA binding protein (TARDBP) gene, encoding for TDP-43, is one of the most commonly mutated gene associated with familial cases of ALS (10%). We generated a human induced pluripotent stem cell (hiPSC) line from the fibroblasts...
Article
Full-text available
Mucopolysaccharidosis type II (Hunter Syndrome) is a rare X-linked inherited lysosomal storage disorder presenting a wide genetic heterogeneity. It is due to pathogenic variants in the IDS gene, causing the deficit of the lysosomal hydrolase iduronate 2-sulfatase, degrading the glycosaminoglycans (GAGs) heparan- and dermatan-sulfate. Based on the p...
Preprint
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disorder. There is no therapy to alleviate symptoms or delay disease onset. SMS is due to the haploinsufficiency of the retinoic-acid-induced-1 gene ( RAI1 ) caused by either chromosomal deletions (SMS-del) or RAI1 mi...
Chapter
The discovery of genomic rearrangements, known as copy number variations (CNVs), is relatively new; their contribution to genetic heterogeneity and their impact on human diseases is still largely unknown. CNVs within the human 15q13.3 region have been associated with neuropsychiatric and neurodevelopmental disorders such as schizophrenia, autism sp...
Chapter
NSCs have been demonstrated to be very useful in grafts into the mammalian central nervous system to investigate the exploitation of NSC for the therapy of neurodegenerative disorders in animal models of neurodegenerative diseases. To push cell therapy in CNS on stage of clinical application, it is necessary to establish a continuous and standardiz...
Article
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative condition with phenotypic and genetic heterogeneity. It is characterized by the selective vulnerability and the progressive loss of the neural population. Here, an induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of an individual carrying the p.G376...
Article
Full-text available
Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolat...
Article
Full-text available
Among the known causative genes of familial ALS, SOD1 mutation is one of the most common. It encodes for the ubiquitous detoxifying copper/zinc binding SOD1 enzyme, whose mutations selectively cause motor neuron death, although the mechanisms are not as yet clear. What is known is that mutant-mediated toxicity is not caused by loss of its detoxifyi...
Article
Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolat...
Article
Full-text available
Recent cutting-edge human genetics technology has allowed us to identify copy number variations (CNVs) and has provided new insights for understanding causative mechanisms of human diseases. A growing number of studies show that CNVs could be associated with physiological mechanisms linked to evolutionary trigger, as well as to the pathogenesis of...
Article
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Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a pati...
Article
Dentato-Rubral-pallidoluysian atrophy (DRPLA) is a rare autosomal, dominant, progressive neurodegenerative disease that causes involuntary movements, mental and emotional problems. DRPLA is caused by a mutation in the ATN1 gene that encodes for an abnormal polyglutamine stretch in the atrophin-1 protein. DRPLA is most common in the Japanese populat...
Article
Full-text available
The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervi...
Article
Full-text available
Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem...
Chapter
Clinical trials for Parkinson’s disease, which used primary brain fetal tissue, have demonstrated that neural stem cell therapy could be suitable for neurodegenerative diseases. The use of fetal tissue presents several issues that have hampered the clinical development of this approach. In addition to the ethical concerns related to the required co...
Article
Full-text available
CHRNA7, encoding the neuronal alpha7 nicotinic acetylcholine receptor (a7nAChR), is highly expressed in the brain, particularly in the hippocampus. It is situated in the 15q13.3 chromosome region, frequently associated with a Copy Number Variation (CNV), which causes its duplication or deletion. The clinical significance of CHRNA7 duplications is u...
Article
Full-text available
Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that matc...
Article
Introduction: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. Areas covered: This is an integra...
Article
Full-text available
Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3-10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about t...
Article
Full-text available
Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in complia...
Article
Full-text available
Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay, behavioural problems and circadian rhythm dysregulation. About 90% of SMS cases are due to a 17p11.2 deletion containing retinoic acid induced1 (RAI1) gene, 10% are due to heterozygous mutations affecting RAI1 coding region. Little is known about RAI1 r...
Article
Full-text available
Huntington's disease (HD) is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presympt...
Article
Full-text available
Huntington Disease (HD) is an autosomal dominant disorder characterized by motor, cognitive and behavioral features caused by a CAG expansion in the HTT gene beyond 35 repeats. The juvenile form (JHD) may begin before the age of 20years and is associated with expanded alleles as long as 60 or more CAG repeats. In this study, induced pluripotent ste...
Article
Full-text available
Joubert Syndrome (JS) is a rare autosomal recessive or X-linked condition characterized by a peculiar cerebellar malformation, known as the molar tooth sign (MTS), associated with other neurological phenotypes and multiorgan involvement. JS is a ciliopathy, a spectrum of disorders whose causative genes encode proteins involved in the primary cilium...
Article
Background & objective: Despite the great effort spent over recent decades to unravel the pathological mechanisms underpinning the development of central nervous system disorders, most of them still remain unclear. In particular, the study of rare CNS diseases is hampered by the lack of postmortem samples and of reliable epidemiological studies, t...
Article
Full-text available
We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità a...
Article
Full-text available
We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità a...
Article
Full-text available
Neuropathic pain (NP) is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed...
Article
A nonphysiological repair of the lesioned nerve leading to the formation of neurinomas, altered nerve conduction, and spontaneous firing is considered the main cause of the events underlying neuropathic pain. It was investigated whether neural stem cell (NSCs) administration could lead to a physiological nerve repair, thus to a reduction of neuropa...
Article
Full-text available
Cell therapy is reaching the stage of phase I clinical trials for post-traumatic, post-ischemic, or neurodegenerative disorders, and the selection of the appropriate cell source is essential. In order to assess the capacity of different human neural stem cell lines (hNSC) to contribute to neural tissue regeneration and to reduce the local inflammat...
Data
In vitro differentiation of IhNSC. (A–E) IhNSC-P used for transplantation contained early neuronal progenitors (Dcx+, A and NCAM+, B), neurons (β-Tub+, C and MAP2+, D), astrocytes (GFAP+, C), oligodendrocytes (GalC+, E) and a percentage of residual proliferating cells (Ki67+, A, B and D). (F) Quantification of the neural cell lineages in IhNSC-P. S...
Data
Experimental design. (A) Schematic representation showing the experimental plan with transplanted animals undergoing transient or constitutive immunosuppression. Healthy not transplanted animals (n = 4) have been excluded. (B) Table showing the numerosity of the transplanted animal groups. Abbreviations: cc: corpus callosum, hf: hippocampal fissure...
Article
Full-text available
Understanding the physiology of human neural stem cells (hNSCs) in the context of cell therapy for neurodegenerative disorders is of paramount importance, yet large-scale studies are hampered by the slow-expansion rate of these cells. To overcome this issue, we previously established immortal, non-transformed, telencephalic-diencephalic hNSCs (IhNS...
Article
This unit describes protocols for the derivation, characterization, and expansion of neural stem cell (NSC) lines from the adult mouse subventricular zone (mNSCs), embryonic mouse brain and from the human fetal brain (hNSCs). NSCs can be isolated by enzymatic digestion of specific regions (NSCs niches) of the central nervous system (CNS) and grown...
Data
Absolute numbers (A, B) and averages (A', B') used to calculate percentage values shown in Figure 3D (A and A') and Figure 6B (B and B') in the main text. Values in each row of A and B are the absolute numbers of nuclei (dapi; TOT) and of cells expressing a specific antigen counted in 4–6 randomly selected fields in one coverslip. The corresponding...
Data
Cartoon summarizing the cell type specific quantifications after the different cultivation and priming conditions used in this study. EF hNSCs: cells grown in EF medium FPN hNSCs: EF cells shifted to FPN medium and serially subcultured in this culture condition. Violet arrow indicates hours (h) or days (d) in culture, black and blue arrows indicate...
Data
Immunophenotypic signature of hNSC-derived oligodendrocytes. (A–D) Merged immunofluorescence pictures showing NG2+ cells (green), a fraction of them co-expressing GalCer (A) and O4 (B). NG2+ cells do not co-express the astrocytic marker GFAP (C) or the neuronal marker PSA-NCAM (D). NG2, green; GalCer, O4, GFAP, PSA-NCAM, red; yellow-orange indicate...
Data
FPN treatment allows the enrichment and expansion of an immature oligodendroglial progeny. Representative merged confocal pictures of FPN hNSCs exposed for 10-day to PDGF-AA+T3 showing PDGFRα+ (red) cells co-expressing Olig1(A, green), Sox10+ (B, green) and nestin (C, green). PDGFRα+ cells did not co-express PSA-NCAM (D, green) or GFAP (E, F; green...
Data
Human NSC transplantation in Shiverer mice. (A) Two months after unilateral injection in the right corpus callosum of post-natal day 20 Shiverer mice, LV.eGFP-T hNSCs are migrated along the corpus callosum in the controlateral hemisphere and show morphology and immunogenic features of undifferentiated neural cells. GFP, green; nestin, red; blue, da...
Data
Primer sequence and RT-PCR conditions. (0.46 MB DOC)
Data
Primary and secondary antibodies used. (0.06 MB DOC)
Data
Oligodendroglial potential of CTX-derived hNSCs. (A) Cortex (CTX)-derived human NSCs grown in EF medium were plated either in 2% FCS or in the presence of FPN for 7 days. After this priming time, medium was substituted with control medium containing 2% FCS or PDGF-AA+T3 and cultures were grown for additional 10 days. The cell type composition was q...
Article
Full-text available
Cell-based therapy holds great promises for demyelinating diseases. Human-derived fetal and adult oligodendrocyte progenitors (OPC) gave encouraging results in experimental models of dysmyelination but their limited proliferation in vitro and their potential immunogenicity might restrict their use in clinical applications. Virtually unlimited numbe...
Data
Severe hypoxia impairs differentiation of immortalized human neural stem cells (IhNSCs). IhNSCs were differentiated onto an adhesive substrate in medium without mitogens and fixed for immunocytochemical analysis at ten days. The graph shows the percentage of early undifferentiated IhNSCs (nestin+) over total nuclei (DAPI+ cells) at ten days during...
Article
Full-text available
Neural stem cells (NSCs) represent an optimal tool for studies and therapy of neurodegenerative diseases. We recently established a v-myc immortalized human NSC (IhNSC) line, which retains stem properties comparable to parental cells. Oxygen concentration is one of the most crucial environmental conditions for cell proliferation and differentiation...
Data
Asymmetric and symmetric divisions of T58A progenitor cells. Panel A-B: immunofluorescence analysis of T-IhNSC cells after 3 days in culture with FGF2 for glial (GFAP in green), neuronal (β-tubulinIII in red). DAPI nuclear staining (blue) is also shown. Panel A shows a symmetric division of a neuronal unipotent progenitor. Panel B shows the segrega...
Data
Analysis of neuronal and glial markers expression during differentiation. Immunofluorescence of hNSC (a–c), c-IhNSC (d–f), T-IhNSC (g–i) and v-IhNSCs (l–n) cell line, showing expression of cells lineage specific markers in cells differentiated for 10 days in adhesion on laminin in the absence of growth factors. Astroglial cell marker GFAP is shown...
Data
Proliferation and cell-cycle analyses. (A–D) BrdU incorporation assay of in hNSC (A), c-IhNSC (B), T-IhNSC (C) and v-IhNSC (D) cells. A pulse of BrdU was given to IhNSC cells for 20 min and then the percentage of cells in S-phase was identified by cytofluorimetric analysis. Actively proliferating cells (in S-phase) are shown in the chart as the per...
Data
The differentiation potential of T58A stem cells. Panel a–n: phase-bright microphotographs of hNSC (a–c), c-IhNSC (d–f), T-IhNSC (g–i) and v-IhNSCs (l–n) cells attached to a laminin-treated surface. Freshly dissociated neurospheres (a,d,g,l) were cultured for 3 days in the presence of FGF2 (b, e, h and m) and teminally differentiated in the absence...
Data
Soft agar colony formation assay. IhNSC (A) cells were seeded as a single cell suspension (1250 cells/well in a 24-wells culture dish) in soft agar (0.4% in growth medium) and incubated at 37°C, 5% CO2 as requested in the “Cell Transformation Detection Assay” kit (CHEMICON n. ECM570). Cells were analyzed using the cell stain solution included with...
Article
Full-text available
Human neural stem cells (hNSC) represent an essential source of renewable brain cells for both experimental studies and cell replacement therapies. Their relatively slow rate of proliferation and physiological senescence in culture make their use cumbersome under some experimental and pre-clinical settings. The immortalization of hNSC with the v-my...
Article
Cell degeneration and death, be it extensive and widespread, such as in metabolic disorders, or focal and selective as in Parkinson’s disease (PD), is the underlying feature of many neurological diseases. Thus, the replacement of cells lost by injury or disease has become a central tenet in strategies aiming at the development of novel therapeutic...
Article
The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated...
Article
Full-text available
Aquaporins (AQP) are water channel proteins that play important roles in the regulation of water homeostasis in physiological and pathological conditions. AQP4 and AQP9, the main aquaporin subtypes in the brain, are expressed in the adult forebrain subventricular zone (SVZ), where neural stem cells (NSCs) reside, but little is known about their exp...