3D Cell Structures via Epigenetic Remodeling for Neural Tissue Formation
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Solution Overview
Problem
Current methods for in vitro recapitulation of early mammalian embryogenesis often lack a significant portion of the central nervous system, particularly brain derivatives, in the generated embryo-like structures.
Innovation Solution
The use of epigenetic remodeling factors, specifically modulating the small ubiquitin-like modifier (SUMO) signaling pathway through hypoSUMOylation, to form organized 3D cell structures that include head-to-tail body axis and mid-hindbrain neuronal cell types, enabling the recapitulation of early developmental stages without the need for embryonic stem cells to form brain derivatives.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If embryonic stem cells are combined with extraembryonic stem cells to form embryo-like structures, then the structures can self-organize to mimic post-implantation embryos, but a large portion of the central nervous system is missing, particularly brain derivatives
Solution Approach 1:
The patent applies parameter changes by modifying the culture conditions and signaling pathway activation states. Specifically, it uses activated WNT signaling (through CHIR99021 treatment) and altered epigenetic states (through hypoSUMOylation) to transform the developmental trajectory of embryonic stem cells, enabling them to form neural tissues that were previously absent in standard embryo-like structures
Solution Approach 2:
The patent implements preliminary action by pre-treating embryonic stem cells with WNT agonists and SUMO inhibitors before combining them with extraembryonic cells. This preliminary modification of the embryonic stem cell state ensures they are primed to form neural tissues, thereby ensuring complete neural representation in the final embryo-like structure
2Productivity
If Wingless-type integration site protein (WNT) agonist pulse is applied to embryonic stem cells to recapitulate early organogenesis, then organogenesis can be initiated, but brain derivatives and central nervous system structures remain absent
Solution Approach 1:
The patent uses composite materials by combining multiple signaling modulators (WNT agonists and SUMO inhibitors) to create a复合 treatment regimen. This composite approach activates both WNT signaling and epigenetic remodeling simultaneously, producing embryo-like structures with complete neural representation that neither treatment could achieve alone
Solution Approach 2:
The patent introduces epigenetic remodeling factors as intermediaries between the WNT signaling pathway and neural differentiation. These factors (SUMO inhibitors) mediate the transition from general organogenesis to specific neural tissue formation, enabling the WNT-treated embryonic stem cells to properly develop brain derivatives
Data Source
AI summary
The invention relates to in vitro generation of organized 3D cell structures recapitulating various degrees of early organogenesis, including head-trunk embryo-like structures, using epigenetic remodeling factors. The invention relates in particular to methods of obtaining such organized 3D cell structures from mammalian cells, and to devices, in particular microfluidic platform, to perform such methods. The invention also concerns the use of the thus obtained 3D cell structures in applications of molecule screening, developmental testing, production of physiologically active substances and models for therapeutic investigation or use.