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Therapeutic effects of combined cell transplantation and locomotor training in rats with brain injury.

ABSTRACT: Cell-based therapies are attracting attention as alternative therapeutic options for brain damage. In this study, we investigated the therapeutic effect of a combined therapy of cell transplantation and locomotor training by evaluating the neuronal connectivity. We transplanted neural cells derived from the frontal cortex of E14.5 GFP-expressing mice into the frontal lobe of 3-week-old rats with brain injury, followed by treadmill training (TMT) for 14 days. In the TMT(-) group, graft-derived neurites were observed only in the striatum and internal capsule. In contrast, in the TMT(+) group, they were observed in the striatum, internal capsule, and the cerebral peduncle and spinal cord. The length of the longest neurite was significantly longer in the TMT(+) group than in the TMT(-) group. In the TMT(+) group, Synaptophysin⁺ vesicles on the neuronal fibers around the ipsilateral red nucleus were found, suggesting that neuronal fibers from the grafted cells formed synapses with the host neurons. A functional analysis of motor recovery using the foot fault test showed that, 1 week after the transplantation, the recovery was significantly better in the cell transplantation and TMT group than the cell transplantation only group. The percentage of cells expressing C-FOS was increased in the grafts in the TMT(+) group. In conclusion, TMT promoted neurite extensions from the grafted neural cells, and the combined therapy of cell transplantation and locomotor training might have the potential to promote the functional recovery of rats with brain injury compared to cell transplantation alone.

SUBMITTER: Shimogawa T

PROVIDER: S-EPMC6549150 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Therapeutic effects of combined cell transplantation and locomotor training in rats with brain injury.

Shimogawa Takafumi T Sakaguchi Hideya H Kikuchi Tetsuhiro T Tsuchimochi Ryosuke R Sano Noritaka N Torikoshi Sadaharu S Ito Akira A Aoyama Tomoki T Iihara Koji K Takahashi Jun J

NPJ Regenerative medicine 20190605

Cell-based therapies are attracting attention as alternative therapeutic options for brain damage. In this study, we investigated the therapeutic effect of a combined therapy of cell transplantation and locomotor training by evaluating the neuronal connectivity. We transplanted neural cells derived from the frontal cortex of E14.5 GFP-expressing mice into the frontal lobe of 3-week-old rats with brain injury, followed by treadmill training (TMT) for 14 days. In the TMT(-) group, graft-derived ne ...[more]

PMID: 31231547

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Project description:Traumatic brain injury (TBI) may cause neurological damage, but an effective therapy and the associated mechanisms of action have not yet been elucidated. A TBI model was established using the modified Feeney method. A2B5+ cells, an oligodendroglial progenitor, were acquired from induced pluripotent stem cells (iPSCs) by mouse embryonic fibroblasts and were transplanted into the injured site. The neurological severity score (NSS) was recorded on 3 d, 7 d, 11 d, 15 d, and 19 d. Seven days after transplantation, oligodendrocytes 2 (Olig2) and myelin basic protein (MBP) were detected by immunohistochemistry (IHC) and Western blot (WB), and long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) were screened by microarray technology. Moreover, we took an intersection of the differentially expressed lncRNAs or mRNAs and scanned 10 kb upstream and downstream of the common lncRNAs. Meanwhile, Gene Ontology (GO) and pathway analysis on mRNAs was performed in the A2B5+ iPSC group. A2B5+ iPSCs survived and migrated around the injury site and differentiated into oligodendrocytes. Meanwhile, the increase in Olig2 and MBP were higher in A2B5+ cell-engrafted rats than that in TBI rats. However, the NSSs in the A2B5+ iPSC group were lower than that in the TBI group. Between the TBI and sham groups, 270 lncRNAs and 1,052 mRNAs were differently expressed ( P < 0.05, fold change (FC) > 2), while between the A2B5+ iPSC and TBI groups, 83 lncRNAs and 360 mRNAs were differently expressed ( P < 0.05, FC > 2). Meanwhile, 37 lncRNAs and 195 mRNAs were simultaneously changed in the 2 parts. Using bioinformatic analysis, we found the crucial lncRNA and mRNA were ENSRNOT00000052577 and Kif2c in the TBI brain with cell transplantation. This study demonstrated that A2B5+ iPSC grafts effectively improved neurological function, and the mechanism of action was associated with lncRNA and mRNA expression. Therefore, A2B5+ iPSC transplantation could be considered as a new method for the treatment of TBI, and ENSRNOT00000052577 and Kif2c may be new molecular targets or markers for functional improvement.

Dataset Information

Therapeutic effects of combined cell transplantation and locomotor training in rats with brain injury.

Publications

Therapeutic effects of combined cell transplantation and locomotor training in rats with brain injury.

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