Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Abstract

Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

Astrocytes in a dish: Using pluripotent stem cells to model neurodegenerative and neurodevelopmental disorders

“…Similarly in vitro this means that only a small starting number of hPSCs are required to generate large numbers of mature cells. However, addition of exogenous mitogens can enable hPSC derived neural progenitors to proliferate in vitro culture for longer periods (46,90,93,105) (Table 1). Therefore, the addition of these mitogens to hPSC derived neural progenitors to drive expansion has become commonplace (46,90,93,105).…”

“…However, there is a distinct temporal shift from neuronal to glial fate acquisition (120) (Figure 1); initially neural progenitors are monopotent, generating neurons and only later become bipotent, differentiating into both neurons and glial cells, including astrocytes ( Figure 1). In relation to hPSC differentiation, astrocytes will differentiate from hPSC derived neural progenitors by 'default' after elongated periods in culture (90,93,105). The identification of a single specific cue that induces the neuron-to-glial fate switch remains elusive, but research has uncovered a number of essential signaling pathways (120).…”

“…This temporal control is also recapitulated in vitro, in neural progenitor cultures ex vivo and in hPSC differentiation (93,105), suggesting that fundamental intrinsic mechanisms control the switch. For a cell population highly enriched for astrocyte culture periods of over 180 days are required (90,93). In relation to hPSC differentiation, astrocytes will differentiate from hPSC derived neural progenitors by 'default' after elongated periods in culture (90,93,105).…”

“…Studies that have achieved high astrocyte yields without the addition of extrinsic factors tend to require much longer time periods in culture (90,93) (Table 1). Studies that have achieved high astrocyte yields without the addition of extrinsic factors tend to require much longer time periods in culture (90,93) (Table 1).…”

“…In the developing embryonic CNS progenitor populations proliferate in response to first FGF and later to EGF signaling (29,60). Therefore, the addition of these mitogens to hPSC derived neural progenitors to drive expansion has become commonplace (46,90,93,105). However, some hPSC differentiation protocols do not require the addition of mitogens for proliferation of the neural progenitors, and it is presumed that in these systems the progenitors produce autocrine signals to induce proliferation (33,94).…”