Schizophrenia-associated complement component C4 induces maturation and reactivity in human astrocytes

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• The complement system (CS), particularly C4, is linked to schizophrenia (SCZ) risk and brain development.
• Astrocytes, key brain cells, produce CS components and influence synaptic plasticity.

Purpose of the Study:

• To investigate the direct impact of exogenous C4 on human iPSC-derived astrocyte differentiation, maturation, and reactivity.
• To elucidate potential molecular mechanisms underlying C4-mediated astrocyte changes.

Main Methods:

• Human induced pluripotent stem cell (hiPSC)-derived astrocytes were treated with recombinant human C4 protein.
• Treatments included chronic exposure during differentiation and acute exposure post-maturation.
• Astrocyte differentiation, maturation markers (CD44, GFAP), morphology, NF-κB translocation, MAPK/ERK, and mTORC1 signaling were assessed.

Main Results:

• Chronic C4 exposure did not affect astrocyte differentiation.
• Both chronic and acute C4 treatments induced astrocyte maturation and reactivity phenotypes.
• Upregulation of reactive astrocyte markers, altered morphology, NF-κB nuclear translocation, MAPK/ERK activation, and mTORC1 suppression were observed.

Conclusions:

• Elevated C4 levels promote astrocyte maturation and reactivity.
• These findings offer insights into complement dysregulation's role in SCZ pathogenesis via astrocyte dysfunction.