The aPKC-CBP Pathway Regulates Post-stroke Neurovascular Remodeling and Functional Recovery

Ayden Gouveia, Matthew Seegobin, Timal S. Kannangara, Ling He, Fredric Wondisford, Cesar H. Comin, Luciano da F. Costa, Jean Claude Béïque, Diane C. Lagace, Baptiste Lacoste, Jing Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Epigenetic modifications have emerged as attractive molecular substrates that integrate extrinsic changes into the determination of cell identity. Since stroke-related brain damage releases micro-environmental cues, we examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB-binding protein (CBP), in post-stroke neurovascular remodeling. Using a knockin mouse strain (CbpS436A) where the aPKC-CBP pathway was defective, we show that disruption of the aPKC-CBP pathway in a murine focal ischemic stroke model increases the reprogramming efficiency of ischemia-activated pericytes (i-pericytes) to neural precursors. As a consequence of enhanced cellular reprogramming, CbpS436A mice show an increased transient population of locally derived neural precursors after stroke, while displaying a reduced number of i-pericytes, impaired vascular remodeling, and perturbed motor recovery during the chronic phase of stroke. Together, this study elucidates the role of the aPKC-CBP pathway in modulating neurovascular remodeling and functional recovery following focal ischemic stroke. Wang and colleagues used a knockin mouse model CbpS436A to show that the disruption of the aPKC-CBP pathway increases the reprogramming efficiency of ischemia-activated pericytes to neural precursors (NPCs). As an outcome, CbpS436A mice show an increase in the transient population of locally derived NPCs shortly after stroke, while displaying a reduced number of pericytes and impaired vascular remodeling and motor recovery during the chronic phase of stroke.

Original languageEnglish (US)
Pages (from-to)1735-1744
Number of pages10
JournalStem Cell Reports
Volume9
Issue number6
DOIs
StatePublished - Dec 12 2017

Keywords

  • aPKC-CBP pathway
  • cellular reprogramming
  • ischemic stroke
  • neural precursors
  • pericyte
  • vascular remodeling

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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