Regeneration-associated cell transplantation contributes to tissue recovery in mice with acute ischemic stroke

PLoS One. 2019 Jan 25;14(1):e0210198. doi: 10.1371/journal.pone.0210198. eCollection 2019.

Abstract

Various cell-based therapeutic strategies have been investigated for vascular and tissue regeneration after ischemic stroke. We have developed a novel cell population, called regeneration-associated cells (RACs), by quality- and quantity-controlled culture of unfractionated mononuclear cells. RACs were trans-arterially injected into 10-week-old syngeneic male mice at 1, 3, 5 or 7 days after permanent middle cerebral artery occlusion (MCAO) to determine the optimal timing for administration in terms of outcome at day 21. Next, we examined the effects of RACs injection at day 1 after MCAO on neurological deficits, infarct volume, and mediators of vascular regeneration and anti-inflammation at days 7 and 21. Infarct volume at day 21 was significantly reduced by transplantation of RACs at day 1 or 3. RACs injected at day 1 reduced the infarct volume at day 7 and 21. Angiogenesis and anti-inflammatory mediators, VEGF and IL-10, were increased at day 7, and VEGF was still upregulated at day 21. We also observed significantly enhanced ink perfusion in vivo, tube formation in vitro, and definitive endothelial progenitor cell colonies in colony assay. These results suggest that RAC transplantation in MCAO models promoted significant recovery of neural tissues through intensified anti-inflammatory and angiogenic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents
  • Angiogenic Proteins / metabolism
  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Cerebrum / blood supply*
  • Cerebrum / pathology
  • Culture Media / metabolism
  • Disease Models, Animal
  • Endothelial Progenitor Cells / physiology
  • Endothelial Progenitor Cells / transplantation*
  • Humans
  • Infarction, Middle Cerebral Artery / etiology
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / therapy*
  • Leukocytes, Mononuclear / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Cerebral Artery / surgery
  • Neovascularization, Physiologic / physiology*
  • Primary Cell Culture / methods
  • Regeneration*
  • Treatment Outcome

Substances

  • Angiogenesis Inducing Agents
  • Angiogenic Proteins
  • Culture Media

Grants and funding

This work was supported by the Japan Society for the Promotion of Science and SENSHIN Medical Research Foundation, http://www.jsps.go.jp/english/index.html, Scientific Research (C) 26461320, S.T. received the funding; Japan Agency for Medical Research and Development, https://www.amed.go.jp/en/index.html, Grant 15bk0104012h003, T.A. received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.