JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models

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 proangiogenic 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.

A newly-synthesized compound CP-07 alleviates microglia-mediated neuroinflammation and ischemic brain injury via inhibiting STAT3 phosphorylation

“…Many studies have widely confirmed that inhibition of STAT3 phosphorylation using genetic or pharmacologic approaches could significantly improve neurological outcomes in cerebral ischemic models, [ 24 , 25 ] raising hopes for new therapeutic modalities of stroke. [ 26 , 27 ] Recent studies have also explored the therapeutic effects of several direct or indirect p-STAT3 inhibitors in rodent models of acute brain injury. [ 28 , 29 ] Zhu et al .…”

Neural Stem Cell-Derived Small Extracellular Vesicles: key Players in Ischemic Stroke Therapy – A Comprehensive Literature Review

“…Transplanting exogenous stem cells into the brain can fill the shortage of endogenous NSCs and stimulate nerve regeneration, rebuilding or repairing the brain-damaged area’s neural network. 52 Secondly, the paracrine effect can be observed in the context of stem cell transplantation in the brain.…”

Advances in neuroprotective therapy for acute ischemic stroke

“…Recent studies have focused on different types of stem cells including MSCs, neural stem cells (NSCs), and hair follicle stem cells. Among these, MSCs have been extensively investigated in preclinical and clinical research due to their capacity to mitigate oxidative stress, produce cytokines and extracellular vesicles that inhibit proinflammatory cytokines and inflammatory cell activation, suppress pyroptosis, as well as reduce BBB permeability [74]. Ha et al [75] verified that adult human NSCs can significantly reduce tissue and neural function loss, which is mediated through its paracrine neuroprotective and proangiogenic activities through the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.…”