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Sci Adv. 2019 Oct 9;5(10):eaax2011. doi: 10.1126/sciadv.aax2011. eCollection 2019 Oct.

LPA1/3 overactivation induces neonatal posthemorrhagic hydrocephalus through ependymal loss and ciliary dysfunction.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
2
Biomedical Sciences Graduate Program, University of California San Diego School of Medicine, La Jolla, CA, USA.
3
Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Abstract

Posthemorrhagic hydrocephalus (PHH) in premature infants is a common neurological disorder treated with invasive neurosurgical interventions. Patients with PHH lack effective therapeutic interventions and suffer chronic comorbidities. Here, we report a murine lysophosphatidic acid (LPA)-induced postnatal PHH model that maps neurodevelopmentally to premature infants, a clinically accessible high-risk population, and demonstrates ventriculomegaly with increased intracranial pressure. Administration of LPA, a blood-borne signaling lipid, acutely disrupted the ependymal cells that generate CSF flow, which was followed by cell death, phagocytosis, and ventricular surface denudation. This mechanism is distinct from a previously reported fetal model that induces PHH through developmental alterations. Analyses of LPA receptor-null mice identified LPA1 and LPA3 as key mediators of PHH. Pharmacological blockade of LPA1 prevented PHH in LPA-injected animals, supporting the medical tractability of LPA receptor antagonists in preventing PHH and negative CNS sequelae in premature infants.

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