Isogenic blood-brain barrier models based on patient-derived stem cells display inter-individual differences in cell...

Area of Science:

• Neuroscience
• Stem Cell Biology
• Vascular Biology

Background:

• The blood-brain barrier (BBB) is crucial for brain homeostasis, comprising brain microvascular endothelial cells (BMECs), astrocytes, pericytes, and neurons.
• Isogenic in vitro BBB models using human pluripotent stem cells are emerging, but the influence of individual genetic variations on model performance is not well understood.

Purpose of the Study:

• To investigate how inter-individual variability affects the yield and phenotype of isogenic BBB models derived from patient-specific induced pluripotent stem cells (iPSCs).
• To assess differences in cell differentiation efficiency and BBB functional properties among iPSC lines from different individuals.

Main Methods:

• Differentiated astrocytes, BMECs, and neurons from four asymptomatic patient-derived iPSC lines (two male, two female) using established protocols.
• Quantified cell lineage marker expression, BBB phenotype, barrier induction, and neurite process formation.
• Compared iPSC-derived BMEC barrier properties to the established hCMEC/D3 cell line.

Main Results:

• iPSC-derived BMECs exhibited superior barrier properties compared to hCMEC/D3 monolayers.
• Significant inter-individual differences were observed in cell lineage marker expression, differentiation efficiency, and BBB functional maturation among iPSC lines.
• These variations influenced the ability to induce barrier function and form neurite processes in the differentiated cells.

Conclusions:

• Isogenic BBB models can be successfully generated using patient-derived iPSCs, offering a valuable tool for studying neurovascular function.
• Inter-individual genetic polymorphisms subtly influence cell differentiation, maturation, and BBB properties, underscoring the importance of considering genetic variability in iPSC-based models.
• These findings suggest that patient-specific iPSC-derived BBB models may reflect underlying genetic differences impacting brain barrier development and function.