The Role of Astrocyte-Derived Factors in the Regulation of Multidrug Resistance at the Developing Blood-Brain Barrier

P-glycoprotein (P-gp; encoded by Abcb1) at the blood-brain barrier (BBB) plays an important role in regulating the movement of exogenous and endogenous substrates into the developing brain. P-gp levels in brain endothelial cells (BECs), which form the capillaries of the BBB, increase dramatically in late gestation and early post-natal life. During this period, glial precursors differentiate into astrocytes and begin to ensheathe brain microvessels. However, little is known regarding the effect of astrocytes on Abcb1/P-gp at the developing BBB. This thesis investigated the effects of astrocyte-derived factors on regulating Abcb1/P-gp at the developing BBB. In particular, the studies in this thesis demonstrated the upregulatory effect of transforming growth factor-beta1 (TGF-β1), a growth factor secreted by astrocytes in late gestation, on P-gp at the BBB. This effect was attenuated as gestation progressed. During this time in pregnancy, it is common for women to receive synthetic glucocorticoids (sGC). This thesis has demonstrated that sGC treatment matures the BBB as it increases P-gp and tight junction function. These BECs also display attenuated responsiveness to TGF-β1 stimulation, an effect similar to that seen in post-natal guinea pig BECs obtained following normal pregnancies. By utilizing a co-culture model using guinea pig BECs and astrocytes from two distinct time-points in gestation, the studies in this thesis have demonstrated that astrocytes enhance levels of Abcb1 mRNA and P-gp function in BECs via astrocyte-derived factors. However, post-natal astrocytes induce a more prominent increase in P-gp at the developing BBB compared to fetal astrocytes. This effect was correlated with higher levels of secreted proteins by post-natal astrocytes compared to fetal astrocytes. Thus, compromised astrocyte maturation may dysregulate P-gp function and expression at the BBB, which may contribute to the pathogenesis of neurodevelopmental disorders. This new knowledge will be critical in the development of future therapies to counteract these effects.

Department dc:contributor.department

Physiology

Year dc:date.issued

2016

Author dc:creator

• Baello, Stephanie

Advisor dc:contributor.advisor

• Matthews, Stephen G

• blood-brain barrier
• brain endothelium
• fetus
• neurovascular unit
• p-glycoprotein
• tgf-beta1

Handle dc:identifier.uri

http://hdl.handle.net/1807/89047

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/89047