Transdifferentiation-Induced Neural Stem Cells Promote Recovery of Middle Cerebral Artery Stroke Rats

PLoS One. 2015 Sep 9;10(9):e0137211. doi: 10.1371/journal.pone.0137211. eCollection 2015.

Abstract

Induced neural stem cells (iNSCs) can be directly transdifferentiated from somatic cells. One potential clinical application of the iNSCs is for nerve regeneration. However, it is unknown whether iNSCs function in disease models. We produced transdifferentiated iNSCs by conditional overexpressing Oct4, Sox2, Klf4, c-Mycin mouse embryonic fibroblasts. They expanded readily in vitro and expressed NSC mRNA profile and protein markers. These iNSCs differentiated into mature astrocytes, neurons and oligodendrocytes in vitro. Importantly, they reduced lesion size, promoted the recovery of motor and sensory function as well as metabolism status in middle cerebral artery stroke rats. These iNSCs secreted nerve growth factors, which was associated with observed protection of neurons from apoptosis. Furthermore, iNSCs migrated to and passed through the lesion in the cerebral cortex, where Tuj1+ neurons were detected. These findings have revealed the function of transdifferentiated iNSCs in vivo, and thus provide experimental evidence to support the development of personalized regenerative therapy for CNS diseases by using genetically engineered autologous somatic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / transplantation
  • Cell Differentiation / genetics
  • Cell Transdifferentiation*
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / pathology
  • Humans
  • Induced Pluripotent Stem Cells / transplantation
  • Infarction, Middle Cerebral Artery / therapy*
  • Kruppel-Like Factor 4
  • Mice
  • Nerve Regeneration*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / transplantation*
  • Neurons / transplantation
  • Oligodendroglia / transplantation
  • Rats

Grants and funding

This work was supported by the China Postdoctoral Science Foundation (2013M532138) and Military Twelfth Five-Year Key Sci-Tech Research Projects (Grant Nos. BWS11J002 and BWS12J010). This work was also supported in part by the Gillson Longenbaugh Foundation.