Osteopontin Enhances Endogenous Repair After Neonatal Hypoxic–Ischemic Brain Injury
Background and Purpose—Hypoxic–ischemic (HI) brain injury is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. To identify molecules important for cerebral damage and repair, we investigated the growth factor-related gene expression profile after neonatal cerebral HI. We identified osteopontin (OPN) as the most highly upregulated factor early after HI. We therefore explored the role of endogenous OPN in brain damage and repair.
Methods—Nine-day-old wild-type mice were exposed to cerebral HI; growth factor-related gene expression profiles were analyzed 1 to 7 days later by reverse transcriptase–polymerase chain reaction arrays. To determine the contribution of OPN to brain damage, we used p9 OPN−/− and wild-type mice. HI brain damage, sensorimotor function, and cell proliferation and differentiation were compared.
Results—Gene expression profiling of 150 genes related to growth factors and neurotrophins showed that expression of 52 genes changed during the first 7 days after HI. OPN was the gene with the strongest increase expression at all time points measured. We show here for the first time that in response to neonatal HI, OPN-deficient mice developed increased gray and white matter loss and more pronounced sensorimotor deficits as compared with wild-type littermates. Furthermore, OPN deficiency decreases HI-induced cell proliferation/survival and oligodendrogenesis without affecting neuronal differentiation.
Conclusions—OPN plays an important role in repairing brain injury after neonatal HI by regulating cerebral cell proliferation/survival and oligodendrocyte differentiation after injury. The observed promyelinative effect of OPN may offer novel possibilities for a therapy targeting white matter injury.
- Received November 10, 2010.
- Revision received February 28, 2011.
- Accepted March 1, 2011.
- © 2011 American Heart Association, Inc.