Three-dimensional-engineered bioprinted in vitro human neural stem cell self-assembling culture model constructs of Alzheimer's disease

Abstract

The pathogenic cascade of Alzheimer's disease (AD) characterized by amyloid-β protein accumulation is still poorly understood, partially owing to the limitations of relevant models without in vivo neural tissue microenvironment to recapitulate cell–cell interactions. To better mimic neural tissue microenvironment, three-dimensional (3D) core-shell AD model constructs containing human neural progenitor cells (NSCs) with 2% matrigel as core bioink and 2% alginate as shell bioink have been bioprinted by a co-axial bioprinter, with a suitable shell thickness for nutrient exchange and barrier-free cell interaction cores. These constructs exhibit cell self-clustering and -assembling properties and engineered reproducibility with long-term cell viability and self-renewal, and a higher differentiation level compared to 2D and 3D MIX models. The different effects of 3D bioprinted, 2D, and MIX microenvironments on the growth of NSCs are mainly related to biosynthesis of amino acids and glyoxylate and dicarboxylate metabolism on day 2 and ribosome, biosynthesis of amino acids and proteasome on day 14. Particularly, the model constructs demonstrated Aβ aggregation and higher expression of Aβ and tau isoform genes compared to 2D and MIX controls. AD model constructs will provide a promising strategy to facilitate the development of a 3D in vitro AD model for neurodegeneration research.

Graphical abstract

Highlights

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  3D bioprinted co-axial core-shell  in vitro Alzheimer’s disease (AD) model constructs.

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  Co-axial constructs provide neural fiber-shaped microenvironment, a suitable shell thickness and a barrier-free core.

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  AD models show cell self-clustering and -assembling features and engineered reproducibility with long-term cell viability.

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  NSCs with FAD mutations show a higher level of self-renewal and differentiation in AD model than that in 2D and MIX models.

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  In vitro AD models present Aβ aggregation and higher expression of Aβ and tau isoform genes compared to 2D and MIX models.