Three-dimensional (3D) spheroids
composed of brain cells have shown
great potential to mimic the pathophysiology of the brain. However,
a 3D spheroidal brain-disease model for cerebral ischemia has not
been reported. This study investigated an ultralow attachment (ULA)
surface-mediated formation of 3D cortical spheroids using primary
rat cortical cells to recapitulate the cerebral ischemic responses
in stroke by oxygen-glucose deprivation-reoxygenation (OGD-R) treatment.
Comparison between two-dimensional (2D) and 3D cell culture models
confirmed the better performance of the 3D cortical spheroids as normal
brain models. The cortical cells cultured in 3D maintained their healthy
physiological morphology of a less activated state and suppressed
mRNA expressions of pathological stroke markers, S100B, IL-1β,
and MBP, selected based on in vivo stroke model.
Interestingly, the spheroids formed on the ULA surface exhibited striking
aggregation dynamics involving active cell–substrate interactions,
whereas those formed on the agarose surface aggregated passively by
the convective flow of the media. Accordingly, ULA spheroids manifested
a layered arrangement of neurons and astrocytes with higher expressions
of integrin β1, integrin α5, N-cadherin, and fibronectin
than the agarose spheroids. OGD-R-induced stroke model of the ULA
spheroids successfully mimicked the ischemic response as evidenced
by the upregulated mRNA expressions of the key markers for stroke,
S100B, IL-1β, and MBP. Our study suggested that structurally
and functionally distinct cortical spheroids could be generated by
simply tuning the cell–substrate binding activities during
dynamic spheroidal formation, which should be an essential factor
to consider in establishing a brain-disease model.
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