Induced pluripotent stem cells can improve thrombolytic effect of low-dose rt-PA after acute carotid thrombosis in rat

Abstract

Background Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is the standard treatment for acute ischemic stroke. Standard-dose rt-PA (0.9 mg/kg) is known to achieve good recanalization but carries a high bleeding risk. Lower dose of rt-PA has less bleeding risk but carries a high re-occlusion rate. We investigate if induced pluripotent stem cells (iPSCs) can improve the thrombolytic effect of low-dose rt-PA (0.45 mg/kg). Methods Single irradiation with 6 mW/cm2 light-emitting diode (LED) for 4 h at rat common carotid artery was used as thrombosis model according to our previous report. Endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and interleukin 1 beta (IL-1 beta) were used as the inflammatory markers for artery endothelial injury. Angiopoietin-2 (AP-2), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were examined in artery wall and iPSCs culture. Animal ultrasound was used to evaluate the stenosis degree of common carotid artery before and at 2 h, 24 h, 4 days and 7 days after LED irradiation. Results After LED irradiation alone, there was a persistent occlusion from 2 h to 7 days. Standard-dose rt-PA alone could recanalize the occluded artery from 24 h to 7 days to stenotic degree ≤ 50%. Low-dose rt-PA or 1 × 106 mouse iPSCs alone could not recanalize the occluded arteries from 2 h to 7 days. Combination use of low-dose rt-PA plus 1 × 106 mouse iPSCs caused better recanalization from 24 h to 7 days. ET-1, ICAM-1 and IL-1 beta were strongly expressed after LED irradiation but reduced after iPSCs treatment. AP-2, BDNF and VEGF were rarely induced after LED irradiation but strongly expressed after iPSCs treatment. In vitro study showed iPSCs could express AP-2, BDNF and VEGF. Conclusion The adjuvant use of iPSCs may help improving the thrombolytic effect of low-dose rt-PA by suppressing inflammatory factors and inducing angiogenic trophic factors. Stem cells could be a potential regimen in acute thrombolytic therapy to improve recanalization and reduce complications.

Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges

“…iPSCs exhibit multiple effects in treating IS, including migration to ischemic brain tissue, differentiation into neurons, pro-inflammatory factor down-regulation, and anti-inflammatory factor up-regulation, eventually improving motor function [86] . Meanwhile, iPSCs enhance the thrombolytic effect of low-dose tissue plasminogen activators [87] . A recent study found that small EVs derived from iPSCs can rejuvenate the blood-brain barrier of aged mice, preventing IS occurrence [88] .…”

Protective effects of CHIP overexpression and Wharton's jelly mesenchymal‐derived stem cell treatment against streptozotocin‐induced neurotoxicity in rats

“…Several studies have verified the protective effects of MSCs on the nervous system 31,32 . In particular, WJMSCs can attenuate neurodegeneration, and they are widely used as a therapeutic treatment for neurological diseases such as ischemic stroke, traumatic brain injury, neonatal hypoxia‐ischemia, and Alzheimer's disease because of their stimulatory effect on trophic and immunoregulatory factors 25,33–3536 …”