Hydrogel-imposed boundary conditions guide single-lumen neuroepithelial morphogenesis.

Area of Science:

• Biomaterials Science
• Developmental Biology
• Stem Cell Biology

Background:

• Three-dimensional (3D) stem cell cultures are valuable for studying human neurodevelopment.
• Existing neural organoid methods lack defined extracellular matrix (ECM) signaling and exhibit variable morphologies, limiting reproducibility.
• This variability hinders their use for modeling early developmental processes and diseases.

Purpose of the Study:

• To engineer a biomaterial system that guides human induced pluripotent stem cells (iPSCs) into forming reproducible neuroepithelial tissues.
• To investigate the role of extracellular matrix (ECM) properties in directing self-organization and morphogenesis.
• To establish a platform for modeling neurodevelopmental disorders.

Main Methods:

• Development of hyaluronic acid-elastin-like protein (HELP) hydrogels with dynamic covalent bonds to mimic neural ECM.
• Utilizing these hydrogels to impose extrinsic boundary conditions on self-organizing iPSCs.
• Characterizing the self-organization process and identifying key regulators of tissue morphology.

Main Results:

• iPSCs robustly self-organized into single-lumen neuroepithelial tissues within HELP hydrogels.
• Matrix stress relaxation rate and tensional homeostasis were identified as critical for single-lumen rosette formation.
• Phenotypic abnormalities were observed in a 22q11.2 deletion syndrome model using this system.

Conclusions:

• Tunable engineered hydrogels can initiate single-cell derived 3D neuroepithelial tissues.
• This system allows investigation of how matrix boundary conditions influence developmental morphogenesis.
• The developed hydrogel platform provides a reproducible method for neurodevelopmental disease modeling.