The conditioned medium of human embryonic stem cell‐derived mesenchymal stem cells alleviates neurological deficits and improves synaptic recovery in experimental stroke

Abstract

The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell-conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO). CM was infused either one time (1 hr post-MCAO) or three times (1, 24, and 48 hr post-MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth-associated protein-43, synaptophysin, cAMP response element-binding protein, and phosphorylated-cAMP response elementbinding protein levels were also assessed in peri-ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells-MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity.

Current status of ischemic stroke treatment: From thrombolysis to potential regenerative medicine

“…This suggests that either autologous or allogeneic MSCs exhibit the desired paracrine effects. In another study by Asgari Taei et al., ESC-derived CM of MSCs (ESC-MSC-CM) led to increased functional recovery, reduced infarction volume, and reduced mortality [ 86 ]. They identified upregulation of GAP-43, SYP, and p-CREB in ischemic areas as possible mediators for recovery [ 86 ].…”

“…In another study by Asgari Taei et al., ESC-derived CM of MSCs (ESC-MSC-CM) led to increased functional recovery, reduced infarction volume, and reduced mortality [ 86 ]. They identified upregulation of GAP-43, SYP, and p-CREB in ischemic areas as possible mediators for recovery [ 86 ]. Other experiments have also attempted to isolate which cytokines are responsible for this recovery.…”

Induced Pluripotent Stem Cells for Ischemic Stroke Treatment

“…At the preclinical level, transplantation of MSCs, especially BMSCs, improved functional recovery in MCAO model rats. MSC transplantation was shown to reduce the lesion volume ( Koh et al, 2008 ; Li et al, 2010 ; Shen et al, 2011 ), enhance sensorimotor ( Huang et al, 2013 ) and cognitive functions ( Lowrance et al, 2015 ), promote angiogenesis and neurogenesis ( Bao et al, 2011 ), modulate inflammatory and immune responses ( Ohtaki et al, 2008 ), and improve synaptic recovery ( Asgari Taei et al, 2021 ). Although some studies have shown no significant reduction of ischemic lesion volumes, the functional outcome nevertheless improved after the administration of MSCs; these discrepancies were suggested to be due to not recanalizing the middle cerebral artery ( Zacharek et al, 2010 ; Gutiérrez-Fernández et al, 2013 ).…”

Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

“…However, this approach has not yet been tested in humans. Most of the current studies were conducted in animal models ( Table 1; Brenneman et al, 2010;Chang et al, 2013;Kawabori et al, 2013;Cheng et al, 2015;Webb et al, 2018;Tian et al, 2019;Tobin et al, 2020;Asgari Taei et al, 2021). Further studies are needed to determine the best route for stem cell transplantation in treating stroke patients.…”