Research Paper Volume 14, Issue 22 pp 8944—8969
JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
- 1 Medical Innovation Technology Inc. (MEDINNO Inc.), Seoul 08513, South Korea
- 2 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
- 3 Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, South Korea
- 4 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
- 5 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, South Korea
- 6 Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16149, South Korea
- 7 Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, South Korea
Received: September 9, 2022 Accepted: November 17, 2022 Published: November 29, 2022
https://doi.org/10.18632/aging.204410How to Cite
Copyright: © 2022 Ha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 105 ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.
Abbreviations
AhNSCs: adult human neural stem cells; MCAO: middle cerebral artery occlusion; HBSS: Hank’s balanced salt solution; TCC: 2,3,5-triphenyltetrazolium chloride; IF: Immunofluorescence; CC3: cleaved-caspase 3; NeuN: neuronal nuclear protein; GFAP: glial fibrillary acidic protein; Iba1: ionized calcium-binding adapter molecule 1; OGD: oxygen glucose deprivation; MTT: 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; ICC: Immunocytochemistry; qRT-PCR: quantitative real-time polymerase chain reaction.