Osteopontin mediates survival, proliferation and migration of neural stem cells through the chemokine receptor CXCR4

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.

Osteopontin directly modulates cytokine expression of primary microglia and increases their survival

“…OPN has previously been shown to promote survival of various cells including bone marrow cells (Lin et al , 2000), dendritic cells (Kawamura et al , 2005), cancer cells (Lee et al , 2007), and neural stem cells (Rabenstein, Hucklenbroich, 2015), and to protect neurons after experimental cerebral ischemia (Doyle, Yang, 2008, Meller, Stevens, 2005. We here show that OPN additionally promotes survival of microglia under stress conditions, namely the cultivation of microglia in serum-free medium.…”

“…The pleiotropic protein OPN exerts direct effects on microglia, but is also protective for neurons (Meller, Stevens, 2005), modulates astrocytic responses (Gliem et al , 2015), and affects neural stem cells (Rabenstein et al , 2015). A classification of differential M1-and M2-phenotyes has been established for (blood-derived) macrophages (Mantovani et al , 2004).…”

The Neural Cell Adhesion Molecule-Derived (NCAM)-Peptide FG Loop (FGL) Mobilizes Endogenous Neural Stem Cells and Promotes Endogenous Regenerative Capacity after Stroke

“…Therapeutic effects of systemic or intracerebroventricular drug injections i.e. of Aromatic-turmerone or Osteopontin on neural stem cell proliferation have been described before Rabenstein et al 2015). In addition to NSC modulation, the focus of interest is also on influencing neurogenic niches and secondary degeneration.…”

“…Besides transplanted cells, endogenous NSC can be mobilized from their neurogenic niches, namely the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus. However, the intrinsic potential of endogenous NSC is insufficient and external stimuli are necessary to fully exploit their therapeutic potential (Arvidsson et al 2002;Lee et al 2012;Rueger et al 2012;Hucklenbroich et al 2014;Lindvall and Kokaia 2015;Rabenstein et al 2015;Braun et al 2016). The small NCAM-derived peptide FGL crosses the blood-brainbarrier and constitutes an attractive candidate molecule for enhancing the therapeutic potential of endogenous NSC and may thus open a new therapeutic vista.…”

Research update for articles published in EJCI in 2015

“…Recently, the thrombin-cleaved OPN N-terminal was indicated as potential biomarker of acute atherothrombotic ischaemic stroke, without data on potential prognostic value [88]. Conversely, experimental evidence emphasized the role of OPN in promoting neural stem cells viability via CXCR4 signalling [89]. Further data also indicated OPN as a potential promoter of astrocyte polarization finally leading to re-establishment of the blood-brain barrier after acute ischaemic stroke [90].…”