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Conditioned Medium Derived from Neural Progenitor Cells Induces Long-term Post-ischemic Neuroprotection, Sustained Neurological Recovery, Neurogenesis, and Angiogenesis

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Abstract

Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48 h when delivered up to 12 h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48 h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28 days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.

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Acknowledgments

The present study was supported by TUBITAK (#2221; to TRD) and the German Research Council (HE3173/2-2 and HE3173/3-1; to DMH).

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Authors and Affiliations

  1. Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany

    Thorsten R. Doeppner, Viktorija Traut, Alexander Heidenreich, Britta Kaltwasser, Bert Bosche & Dirk M. Hermann

  2. Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey

    Thorsten R. Doeppner

  3. Department of Neurology, University of Göttingen Medical School, Göttingen, Germany

    Thorsten R. Doeppner & Mathias Bähr

  4. Department of Surgery, Division of Neurosurgery, St Michael’s Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Bert Bosche

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  1. Thorsten R. Doeppner
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Correspondence to Thorsten R. Doeppner.

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Conflict of interest/disclosures

BB got a travel grant and a speaker honorary from CSL Behring (Germany) and material supports of CSL Behring (Germany and Canada). As a member of the scientific advisory board of Edge Therapeutics, Inc., BB received advisor honorary. The other authors declare no conflict of interest.

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Doeppner, T.R., Traut, V., Heidenreich, A. et al. Conditioned Medium Derived from Neural Progenitor Cells Induces Long-term Post-ischemic Neuroprotection, Sustained Neurological Recovery, Neurogenesis, and Angiogenesis. Mol Neurobiol 54, 1531–1540 (2017). https://doi.org/10.1007/s12035-016-9748-y

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