GABAergic interneurons regulate cortical neural networks by providing inhibitory inputs, and their malfunction, resulting in failure to intricately regulate neural circuit balance, is implicated in brain diseases such as Schizophrenia, Autism and Epilepsy. During early development, GABAergic interneuron progenitors arise from the ventral telencephalic area such as Medial Ganglionic Eminence (MGE) and caudal ganglionic eminence (CGE) by the actions of secreted signaling molecules from nearby organizers, and migrate to their target sites where they form local synaptic connections. In this study, using combinatorial and temporal modulation of developmentally relevant dorsoventral and rostrocaudal signaling pathways (SHH, Wnt and FGF8), we efficiently generated MGE cells from multiple human pluripotent stem cells. Especially, modulation of FGF8/FGF19 signaling efficiently modultated MGE vs CGE differentiation. Human MGE cells spontaneously differentiated into Lhx6-expressing GABAergic interneurons and showed migratory properties. These human MGE-derived neurons generated GABA, fired action potential and displayed robust GABAergic postsynaptic activity. Transplantation into rodent brains results in well-contained neural grafts enriched with GABAergic interneurons that migrate in the host and mature to express somatostatin or parvalbumin. Thus, we propose that signaling modulation recapitulating normal developmental patterns efficiently generates human GABAergic interneurons. This strategy represents a novel tool in regenerative medicine, developmental studies, disease modeling, bioassay, and drug screening.

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Delayed cerebral ischemia (DCI) is a major determinant of patient outcome following aneurysmal subarachnoid hemorrhage. Although the exact mechanisms leading to DCI are not fully known, inflammation, cerebral vasospasm, and microthrombi may all function together to mediate the onset of DCI. Indeed, inflammation is tightly linked with activation of coagulation and microthrombi formation. Thromboinflammation is the intersection at which inflammation and thrombosis regulate one another in a feedforward manner, potentiating the formation of thrombi and pro-inflammatory signaling. In this review, we will explore the role(s) of inflammation and microthrombi in subarachnoid hemorrhage (SAH) pathophysiology and DCI, and discuss the potential of targeting thromboinflammation to prevent DCI after SAH.