Combinatorial Modulation of Wnt, STAT3, TGF-β, and Tie2 Pathways Drives Brain Endothelial Cell-Like Differentiation from hiPSCs
During development, endothelial cells (ECs) migrate into the brain and acquire blood-brain barrier (BBB) properties such as tight junctions, limited transcellular transport, and high electrical resistance. Although key signaling pathways that are active in vivo have been identified, factors critical in inducing brain EC differentiation in vitro remain unclear. Here, we describe conditions that…
In a recent study, researchers have uncovered the key signaling pathways that drive human pluripotent stem cell (hiPSC)-derived endothelial cells to differentiate into brain endothelial cells with properties similar to those found in the brain. Key to this process, the study found, is the activation of Wnt/{beta}-catenin signaling, which upregulates the brain EC marker GLUT1 (SLC2A1) while suppressing the peripheral EC marker PLVAP.
At the same time, stimulation of STAT3 by CNTF together with TGF-{beta} inhibition leads to an increase in CLDN5 expression, another brain EC marker.
The researchers also discovered that hiPSC-derived ECs secrete high levels of angiopoietin-2 (ANGPT2). By inhibiting ANGPT2 with razumetib (AKB-9778), a PTPRB (VE-PTP) inhibitor, they were able to improve the integrity of the monolayer formed by the differentiated brain ECs. These findings suggest that by combinatorially modulating specific signaling pathways, researchers can stimulate the differentiation of hiPSCs into brain endothelial cells in vitro.
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