Neural Stem Cells Alleviate Inflammation via Neutralization of IFN-γ Negative Effect in Ischemic Stroke Model

Abstract

Inflammatory response generated by ischemic stroke commonly affects functional or structural recovery. The aim of this study was to examine the IFN-γ caused inflammatory effects on NSCs in vitro and in vivo. We found that IFN-γ did not affect NSCs proliferation but increased the SOD2 level of inflammatory oxidative stress in NSCs culturing. High dose IFN-γ (500 ng) injection aggravated the level of inflammation in the cerebral ischemic model but did not alter the repairing functions of the NSCs in vivo. NSCs based treatment, including the NSCs-IFN-γ combined treatment, significantly improved the ischemic microenvironment by decreasing CD4+, CD8+ T cells and microglia infiltration. Furthermore, anti-inflammatory cytokines IL-10 and TGF-β1 expression were increased in the NSCs and combined treatment groups, but the level of pro-inflammatory cytokines (IL-1 β, IL-6, IFN-γ, and TNF-α) were decreased. The IFN-γ/Stat1 signaling pathway was also activated. NSCs transplantation therefore promoted the neurological recovery of ischemic stroke rats mainly by altering the inflammatory microenvironment, neutralizing the negative effect of IFN-γ. In conclusion, in addition to promoting cell replacement or engraftment, the NSCs-based transplantation also enhanced the therapeutic effects of transplantation by optimizing its immune microenvironment of ischemic areas.

Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders

“…Indeed, previous studies have shown that grafting of NSCs in prototypes of Alzheimer's disease, traumatic brain injury, hypoxic-ischemic injury, spinal cord injury and stroke resulted in reduced inflammation. [8,31,55,91,101,119,124] It has been shown that grafted NSCs ameliorate chronic CNS inflammation through several mechanisms. NSCs can reprogram the infiltrating inflammatory monocyte-derived cells into antiinflammatory myeloid cells via secretion of TGF-β2.…”

Neural stem cell small extracellular vesicle-based delivery of 14-3-3t reduces apoptosis and neuroinflammation following traumatic spinal cord injury by enhancing autophagy by targeting Beclin-1

“…Studies have shown that neural stem cells have a unique neuroprotective function that promotes functional recovery after acute SCI [10, 38]. In fact, previous studies have shown that neural stem cell transplantations can reduce inflammation in the prototype of traumatic brain injury, hypoxic ischemic injury, SCI, and stroke [39, 40]. However, it is difficult to assess the optimal NSC purification and transplantation times.…”

Therapeutic potential role of exosomes for ischemic stroke

“…Stem cells have become the primary choice for transplantation therapy because of their "infinite" proliferation and multi-prospective differentiation potential. Moreover, stem cell transplantation therapy has been shown to promote the recovery of damaged tissues [52,53], including spinal cord, heart, brain, and liver. Previous researches have shown that cell proliferation can be found in subventricular zone in rat model disposed by the middle cerebral artery occlusion (MCAO), suggesting that endogenous recovery process is started after stroke [54][55][56][57].…”

“…However, endogenous resilience may be limited due to hostile immune microenvironment over time [56,58]. In addition, the delayed inflammatory response to stroke leads to secondary neurological injury [52,58]. Insufficient endogenous stem cells after stroke can result in weak regeneration of nerve cells in the damaged area and slowdown in tissue function recovery.…”