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

Mol Neurobiol. 2017 Mar;54(2):1531-1540. doi: 10.1007/s12035-016-9748-y. Epub 2016 Feb 9.

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.

Keywords: Cerebral ischemia; Conditioned medium; Neural progenitor cells; Neuroregeneration; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Angiogenesis Inducing Agents / therapeutic use
  • Animals
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology*
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Neuroprotection / drug effects
  • Neuroprotection / physiology
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*
  • Time Factors

Substances

  • Angiogenesis Inducing Agents
  • Culture Media, Conditioned