Abstract
IntroductionOsteopontin (OPN) is a phosphoglycoprotein with important roles in tissue homeostasis, wound healing, immune regulation, and stress responses. It is expressed constitutively in the brain and upregulated during neuroinflammatory responses; for example, after focal cerebral ischemia. To date, its effects on neural stem cells (NSC) remain to be elucidated and are, accordingly, the subject of this study.MethodPrimary fetal rat NSC were cultured as homogenous monolayers and treated with different concentrations of OPN. Fundamental properties of NSC were assessed following OPN exposure, including proliferative activity, survival under oxidative stress, migration, and differentiation potential. To elucidate a putative action of OPN via the CXC chemokine receptor type 4 (CXCR4), the latter was blocked with AMD3100. To investigate effects of OPN on endogenous NSC in vivo, recombinant OPN was injected into the brain of healthy adult rats as well as rats subjected to focal cerebral ischemia. Effects of OPN on NSC proliferation and neurogenesis in the subventricular zone were studied immunohistochemically.ResultsOPN dose-dependently increased the number of NSC in vitro. As hypothesized, this effect was mediated through CXCR4. The increase in NSC number was due to both enhanced cell proliferation and increased survival, and was confirmed in vivo. Additionally, OPN dose-dependently stimulated the migration of NSC via CXCR4. Moreover, in the presence of OPN, differentiation of NSC led to a significant increase in neurogenesis both in vitro as well as in vivo after cerebral ischemia.ConclusionData show positive effects of OPN on survival, proliferation, migration, and neuronal differentiation of NSC. At least in part these effects were mediated via CXCR4. Results suggest that OPN is a promising substance for the targeted activation of NSC in future experimental therapies for neurological disorders such as stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0098-x) contains supplementary material, which is available to authorized users.
Highlights
Osteopontin (OPN) is a phosphoglycoprotein with important roles in tissue homeostasis, wound healing, immune regulation, and stress responses
In the presence of OPN, differentiation of neural stem cells (NSC) led to a significant increase in neurogenesis both in vitro as well as in vivo after cerebral ischemia
Immunocytochemical staining revealed that the cytokine receptor CXC chemokine receptor type 4 (CXCR4) was expressed on most primary NSC (Fig. 1b)
Summary
Osteopontin (OPN) is a phosphoglycoprotein with important roles in tissue homeostasis, wound healing, immune regulation, and stress responses It is expressed constitutively in the brain and upregulated during neuroinflammatory responses; for example, after focal cerebral ischemia. NSC mediate regeneration and functional recovery after stroke by way of neurogenesis and replacement of lost neurons, and via pleiotropic functions including neuroprotection, reduction of neuroinflammation, revascularization, and induction of plasticity (reviewed in [24]) Their ability to migrate to a site of injury, to survive in the local environment, and potentially form new neurons, is crucial for their function but is often impaired after stroke [25, 26], contributing to the insufficient capacity of the brain for self-repair and functional recovery. Supporting the proliferation, survival, and migration of endogenous NSC seems to be a promising therapeutic approach in stroke [22, 23, 27,28,29,30,31]
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