Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke

Abstract

Background Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. Methods Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 μl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. Results SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). Conclusions This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer’s Disease

“…Recently, using a stroke animal model, a positive influence of voluntary exercise on mesenchymal stromal cell (MSC) transplantation therapy was demonstrated. Yabuno et al (2023) found that neurological deficits in rats inflicted with transient middle cerebral artery occlusion were significantly reversed after a combination of voluntary exercise (wheel running) and intracerebral transplantation of human modified bone marrow-derived MSCs [ 48 ]. Importantly, endogenous neurogenesis in the subventricular zone (SVZ) and DG, and mRNA levels of VEGF and BDNF, were also upregulated by mice undergoing the combination of exercise and MSC transplantation compared to those in single therapy or without therapy [ 48 ].…”

“…Yabuno et al (2023) found that neurological deficits in rats inflicted with transient middle cerebral artery occlusion were significantly reversed after a combination of voluntary exercise (wheel running) and intracerebral transplantation of human modified bone marrow-derived MSCs [ 48 ]. Importantly, endogenous neurogenesis in the subventricular zone (SVZ) and DG, and mRNA levels of VEGF and BDNF, were also upregulated by mice undergoing the combination of exercise and MSC transplantation compared to those in single therapy or without therapy [ 48 ]. In addition, using an animal model of Parkinson’s disease (PD), which is also one of the most common neurodegenerative diseases, the upregulation of BDNF and an increase in neurogenesis following exercise was demonstrated.…”

The potential of a combined cell‐based therapy and rehabilitation approach for stroke recovery

“…Indeed, voluntary exercise combined with the IC transplantation of human BMMSCs may improve gross neurological but not sensorimotor recovery at postoperative Day 14 in a rat transient MCAO model. 43 The underlying therapeutic mechanisms put forward include the synergistic effects on the attenuation of infarct size, angiogenesis, as well as BDNF-and VEGF-mediated neurogenesis. The low survival (<0.05%) of the transplanted cells at Day 3, however, likely as a result of technical issues, might partly explain the overlapping/limited combinatorial effect on the behavioral outcomes.…”

“…It is imperative that the increase in endogenous NSPCs after cell‐based therapy must be followed up with not only an increased training but also an appropriate rehabilitation modality that would allow the immature endogenous and exogenous cells to properly mature and effectively integrate with the host tissue. Voluntary exercise, forced physical training, and EE have all been shown to improve motor function by increasing BDNF and neurogenesis, which is one of the main driving forces underlying stroke recovery 24,25,43,61 . However, behavioral task specificity and integration need to be more widely incorporated in experimental rehabilitation strategies to achieve better functional outcomes in stroke animals 39 …”

“…53 Voluntary exercise induces an increased level of plasticity-related proteins in the stroke brain, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), which endogenous and transplanted cells also respond to. 20,43 BDNF and VEGF are neurotrophic factors whose levels are increased after stroke and are responsible for neural survival, neurovascular remodeling, and glial scar modulation. In fact, voluntary exercise and IC cell transplantation in stroke rats upregulate BDNF and VEGF levels and promote perilesional remodeling by boosting angiogenesis and neurogenesis.…”