Astrocyte-mediated regulation of multidrug resistance p-glycoprotein in fetal and neonatal brain endothelial cells: age-dependent effects.

Abstract

Brain endothelial cells (BECs) form a major component of the blood–brain barrier (BBB). In late gestation, these cells express high levels of the multidrug transporter p‐glycoprotein (P‐gp; encoded by Abcb1), which prevents the passage of an array of endogenous factors and xenobiotics into the fetal brain. P‐gp levels in the BECs increase dramatically in late gestation, coincident with astrocyte differentiation. However, the role of astrocytes in modulating P‐gp in the developing BBB is unknown. We hypothesized that factors produced by astrocytes positively regulate P‐gp in BECs. Astrocytes and BECs were isolated from fetal and postnatal guinea pigs. Levels of Abcb1 mRNA and P‐gp were increased in BECs co‐cultured with astrocytes compared to BECs in monoculture. Moreover, postnatal astrocytes enhanced P‐gp function in fetal BECs but fetal astrocytes had no effect on postnatal BECs. These effects were dependent on secreted proteins with a molecular weight in the range of 3–100 kDa. LC/MS‐MS revealed significant differences in proteins secreted by fetal and postnatal astrocytes. We propose that astrocytes are critical modulators of P‐gp at the developing BBB. As such, aberrations in astrocyte maturation, observed in neurodevelopmental disorders, will likely decrease P‐gp at the BBB. This would allow increased transfer of P‐gp endogenous and exogenous substrates into the brain, many of which have neurodevelopmental consequences.