Qixian Tongluo Formula promotes the directional differentiation of neural stem cells into neurons via fibrinogen-mediated BMPRI/ID3 signal axis after ischemic stroke

TL;DR

This study shows that Qixian Tongluo Formula helps neural stem cells turn into neurons after stroke by using a specific signaling pathway involving fibrinogen.

Contribution

The study reveals a novel mechanism by which QXTLF promotes NSC differentiation into neurons via the fibrinogen-mediated BMPRI/ID3 axis after ischemic stroke.

Findings

QXTLF reduced cerebral infarction and improved neurological scores in MCAO rats.

QXTLF promoted NSC differentiation into neurons in the hippocampus after stroke.

Fibrinogen mediated QXTLF's effect through the BMPRI/ID3 signaling pathway.

Abstract

Promoting nerve regeneration is a crucial approach in treating ischemic stroke, with neural stem cells (NSCs) playing a vital role in this process. Qixian Tongluo Formula (QXTLF) has shown effectiveness in treating ischemic stroke, yet its impact on regulating the directional differentiation of NSCs during ischemic stroke remains unclear. A middle cerebral artery occlusion (MCAO) model was induced in Sprague-Dawley rats, and primary NSCs were isolated from these rats. By gavage QXTLF (7.83 g/kg/d or 31.32 g/kg/d) was administered intragastrically to the MCAO rats. In vitro experiments confirmed the successful isolation of NSCs from rats, capable of differentiating into immature neurons, mature neurons and astrocytes. In vitro, NSCs were exposed to fibrinogen (Fg) and induced by low glucose-oxygen (LGO) conditions to simulate the NSC niche in ischemic stroke. Various assessments were conducted, including neurological score evaluation in MCAO rats, analysis of infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining, and examination of the expression of markers like bromodeoxyuridine (BrdU), doublecortin (DCX), microtubule-associated protein 2 (MAP-2), glial fibrillary acidic protein (GFAP), and bone morphogenetic protein type I receptor (BMPRI)/inhibitor of DNA binding 3 (ID3) by immunofluorescence and western blot analysis. The Fg content was quantified by enzyme-linked immunosorbent assay. Results demonstrated that QXTLF reduced cerebral infarction and decreased the neurological score of MCAO rat in a dose-dependent manner. Additionally, QXTLF promoted the directional differentiation of NSCs into neurons within ipsilateral hippocampus following cerebral ischemia. Furthermore, the study revealed that QXTLF facilitated the directional differentiation of LGO-induced NSCs into neurons and implicated Fg in mediating this effect. QXTLF was found to regulate the directional differentiation of LGO-induced NSCs through the Fg-mediated BMPRI/ID3 signal axis, highlighting its role in promoting the differentiation of NSCs into neurons post-ischemic stroke.

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