Biology subjects

Mangiameli, E.

Publications and source records attributed to Mangiameli, E..

2 recordsLinked to original sources

bioRxiv2026

Glia-enriched human brain organoids for studying developmental alterations in leukodystrophies

Leukodystrophies (LKD) comprise mostly inherited white matter disorders whose developmental origins and underlying pathomechanisms remain poorly understood. Progress has been limited by restricted access to human primary tissue and by the inability of animal models to fully recapitulate human neurodevelopment. Human induced pluripotent stem cell-derived neural organoids provide an alternative approach, but most culture systems do not capture later, glia-rich developmental stages relevant to these diseases. Recent studies have shown that appropriate patterning cues and long in vitro differentiation can generate neuroglial spheroids comprising multiple neuronal and macroglial populations, including mature oligodendrocytes. Here, we adapt the human oligodendrocyte (hOLS) spheroid platform to establish 3D models of globoid cell leukodystrophy (GLD), 4H leukodystrophy (4H), and Canavan disease (CD). Here we adapt this organoid platform to establish 3D models of globoid cell leukodystrophy (GLD), 4H leukodystrophy (4H), and Canavan disease (CD). Across 150 days of differentiation, hOLS from different genetic backgrounds displayed largely comparable growth kinetics and developmental trajectories, comprising multiple neuroglial cell types with predominantly ventral forebrain and midbrain identities. Comparison of LKD and control hOLS revealed both shared and disease-specific alterations, with prominent transcriptional changes in lysosomal, metabolic, and stress-response pathways. Lineage-resolved pathway analysis further identified signatures across individual LKDs, including mitochondrial and translational stress in GLD glial lineages, disruption of RNA metabolic and cell-cycle pathways in 4H, and prominent astrocyte-centered metabolic dysregulation in CD. Our results establish hOLS as a human 3D in vitro platform for studying the impact of LKD-associated genetic variants on early neural development and for dissecting lineage-specific disease vulnerability.

neuroscience↗

bioRxiv2020

Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

Globoid Cell Leukodystrophy (GLD, or Krabbe disease) is a rare lysosomal storage disease caused by inherited deficiency of {beta}-galactocerebrosidase (GALC). The build-up of galactosylsphingosine (psychosine) and other undegraded galactosylsphingolipids in the nervous system causes severe demyelination and neurodegeneration. The molecular mechanisms of GLD are poorly elucidated in neural cells and whether murine systems recapitulate critical aspects of the human disease is still to be defined. Here, we established a collection of GLD patient-specific induced pluripotent stem cell (iPSC) lines. We differentiated iPSCs from two patients (bearing different disease-causing mutations) into neural progenitors cells (NPCs) and their neuronal/glial progeny, assessing the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression by means of phenotypic, biochemical, molecular, and lipidomic analysis. We show a progressive increase of psychosine during the differentiation of GLD NPCs to neurons and glia. We report an early and persistent impairment of oligodendroglial and neuronal differentiation in GLD cultures, with peculiar differences observed in the two GLD lines. GLD cells display a global unbalance of lipid composition during the iPSC to neural differentiation and early activation of cellular senescence, depending on the disease-causing mutation. Restoration of GALC activity normalizes the primary pathological hallmarks and partially rescues the differentiation program of GLD NPCs. Our results suggest that multiple mechanisms besides psychosine toxicity concur to CNS pathology in GLD and highlight the need of a timely regulated GALC expression for proper lineage commitment and differentiation of human NPCs. These findings have important implications for establishing tailored gene therapy strategies to enhance disease correction in GLD.

genetics↗