Contributions
Abstract: P423
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Despite a past study describing adult neurogenesis in individuals with multiple sclerosis (MS), mounting evidence from mouse models of MS and human postmortem MS tissue indicates otherwise. Above settling this debate, understanding the mechanisms by which human neural progenitors respond to neuroinflammation remains a critical issue in MS and may shed light on these conflicting data. Pursuit of these questions, however, has been experimentally inaccessible until the recent development of human cerebral organoids, 3D cultures that model the spatiotemporal dynamics underlying human corticogenesis. By implementing cerebral organoids derived from healthy induced pluripotent stem cells (iPSCs), we investigated the effect of a single inflammatory cytokine, IFN-g, on the developmental dynamics of the human stem cell niche, which largely reflects the requisite events activated during repair. Continuous exposure of organoids to IFN-g for 42 days at 5, 10 and 100 ng/mL led to significantly less growth in organoid size starting at day 21. We observed increased apoptosis only in organoids exposed to IFN-g at 100 ng/mL while lower IFN-g doses showed similar levels of apoptosis and proliferation. Immunostaining revealed a premature displacement of stem cells from the subventricular-like zone, resulting in a smaller central progenitor pool and a reduction in mitotic outer radial glia, the cell type responsible for the dramatic expansion of the human cortex. In spite of a reduced progenitor pool, organoids exposed to IFN-g maintained the proper emergence of early born neurons. qPCR analyses suggest aberrant migration of progenitors, as indicated by increased DAB1 and CDH2 expression in IFN-g organoids. Our work provides insights into how neuroinflammation in MS disrupts the developmental processes enacted during repair and paves the way, as a novel paradigm, for future studies to interrogate human neurogenesis in the presence of inflammation from MS patient-derived cells.
Disclosure: Nothing to disclose.
Abstract: P423
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Despite a past study describing adult neurogenesis in individuals with multiple sclerosis (MS), mounting evidence from mouse models of MS and human postmortem MS tissue indicates otherwise. Above settling this debate, understanding the mechanisms by which human neural progenitors respond to neuroinflammation remains a critical issue in MS and may shed light on these conflicting data. Pursuit of these questions, however, has been experimentally inaccessible until the recent development of human cerebral organoids, 3D cultures that model the spatiotemporal dynamics underlying human corticogenesis. By implementing cerebral organoids derived from healthy induced pluripotent stem cells (iPSCs), we investigated the effect of a single inflammatory cytokine, IFN-g, on the developmental dynamics of the human stem cell niche, which largely reflects the requisite events activated during repair. Continuous exposure of organoids to IFN-g for 42 days at 5, 10 and 100 ng/mL led to significantly less growth in organoid size starting at day 21. We observed increased apoptosis only in organoids exposed to IFN-g at 100 ng/mL while lower IFN-g doses showed similar levels of apoptosis and proliferation. Immunostaining revealed a premature displacement of stem cells from the subventricular-like zone, resulting in a smaller central progenitor pool and a reduction in mitotic outer radial glia, the cell type responsible for the dramatic expansion of the human cortex. In spite of a reduced progenitor pool, organoids exposed to IFN-g maintained the proper emergence of early born neurons. qPCR analyses suggest aberrant migration of progenitors, as indicated by increased DAB1 and CDH2 expression in IFN-g organoids. Our work provides insights into how neuroinflammation in MS disrupts the developmental processes enacted during repair and paves the way, as a novel paradigm, for future studies to interrogate human neurogenesis in the presence of inflammation from MS patient-derived cells.
Disclosure: Nothing to disclose.