Recovery from ischemic tissue injury can be promoted by cell proliferation and neovascularization. Transient expression of four pluripotency factors (Pou5f1, Sox2, Myc, and Klf4) has been used to convert cell types but never been tested as a means to promote functional recovery from ischemic injury. Here we aimed to determine whether transient in situ pluripotency factor expression can improve neurobehavioral function. Cerebral ischemia was induced by transient bilateral common carotid artery occlusion, after which the four pluripotency factors were expressed through either doxycycline administration into the lateral ventricle in transgenic mice in which the four factors are expressed in a doxycycline-inducible manner. Histologic evaluation showed that this transient expression induced the proliferative generation of astrocytes and/or neural progenitors, but not neurons or glial scar, and increased neovascularization with upregulation of angiogenic factors. Furthermore, in vivo pluripotency factor expression caused neuroprotective effects such as increased numbers of mature neurons and levels of synaptic markers in the striatum. Dysplasia or tumor development was not observed. Importantly, neurobehavioral evaluations such as rotarod and ladder walking tests showed that the expression of the four factors dramatically promoted functional restoration from ischemic injury. These results provide a basis for novel therapeutic modality development for cerebral ischemia.
Bibliographical noteFunding Information:
This study was supported by grants from the National Research Foundation (S.-R.C., NRF-2014R1A2A1A11052042; 2015M3A9B4067068; H.K., 2015R1A2A1A15052668), the Ministry of Science and Technology, Republic of Korea, the Korean Health Technology R&D Project (H.K., HI14C2019; S.-R.C., HI16C1013; HI16C1012), Ministry of Health & Welfare, Republic of Korea, and the Yonsei University College of Medicine (6-2016-0126). We thank to Ahreum Baek for qRT-PCR and MinGi Kim for English editing. The authors indicate no potential conflicts of interest. J.H.S. performed most of the experiments, wrote the manuscript, and contributed to the study concept and design; M.-Y.L. and M.-S.K. performed in vitro experiments; J.H.Y. and M.S. performed animal experiments; C.H.S. contributed to the study concept and design; H.K. and S.-R.C. analyzed data, wrote the manuscript, developed the study concept, and supervised the project. All authors read and approved the manuscript.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Drug Discovery