Bidirectional cell-matrix interaction dictates neuronal network formation in a brain-mimetic 3D scaffold

Area of Science:

• Biomaterials Science
• Neuroscience
• Stem Cell Biology

Background:

• Human pluripotent stem cells (hPSCs) are crucial for studying neurobiology and disease, but lack suitable 3D platforms for neuronal culture.
• Existing biomimetic scaffolds struggle to fully replicate the brain's complex microenvironment for optimal neuronal network formation.

Purpose of the Study:

• To engineer a physiologically relevant 3D scaffold that mimics brain tissue composition and promotes neuronal network formation.
• To identify key chemical cues and matrix properties essential for supporting hPSC-derived neurons.

Main Methods:

• Bioengineered a 3D scaffold using hyaluronic acid (HA) and chondroitin sulfate (CS) composite gels.
• Covalently grafted dopamine (DA) moieties onto the HA-CS gel (HADA-CS) to enhance stability and remodeling properties.
• Cultured hPSC-derived neurons within the HA-CS and HADA-CS scaffolds, assessing neuronal growth and network formation.

Main Results:

• The chondroitin sulfate (CS) component in HA-CS gels modestly supported neuronal growth.
• The HADA-CS scaffold demonstrated enhanced stability, entrapped cell-secreted laminin, and bound brain-derived neurotrophic factor (BDNF).
• Neurons cultured in the HADA-CS scaffold expressed genes crucial for cell adhesion and cell-ECM signaling, supporting neurite outgrowth and network formation.

Conclusions:

• The developed HADA-CS scaffold effectively supports neuronal growth and network formation, offering a valuable tool for tissue engineering and disease modeling.
• This brain-mimetic scaffold bridges the gap between animal models and human diseases by providing biomimetic neurophysiology.
• The scaffold's injectable and self-healing properties are promising for regenerative medicine applications.