Six3 promoting the migration and neural differentiation of BMSCs via Btg2-mediated Akt signaling pathway activation: A therapeutic strategy for stroke
- 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- 2Department of Neurointervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Abstract
Bone marrow-derived mesenchymal stem cell (BMSC) transplantation holds therapeutic potential for stroke; however, but its effectiveness requires optimization. The transcription factor Sine Oculis Homeobox Homolog 3 (Six3) regulates processes crucial for BMSC therapy, such as neural cell proliferation and differentiation. However, whether Six3-modified BMSCs exert enhanced therapeutic effects on stroke remains unknown. In the present study, mouse BMSCs were isolated and identified using surface markers. Six3-overexpressing BMSCs exhibited enhanced proliferative, migratory and neural differentiation capacities. RNA-sequencing analysis comparing the gene expression profiles of BMSCs with and without Six3 overexpression identified BTG Anti-Proliferation Factor 2 (Btg2) as an upregulated gene (log2FC=1.45, P<0.05) in Six3-overexpressing cells. Further investigations revealed that Six3 directly binds to the TGATACTGTCT sequence within the Btg2 promoter and activates its transcription. Btg2 knockdown abolished the effects of Six3 overexpression. Mechanistically, Six3 promoted Akt phosphorylation via Btg2, enhancing BMSC viability and neural differentiation. A mouse model of stroke was established using transient middle cerebral artery occlusion (MCAO, 1.5-h occlusion and 24-h reperfusion). BMSCs were administered via tail vein injection at the onset of reperfusion. GFP expression detected in brain tissue at 24 h post-reperfusion confirmed successful the homing of BMSCs to the brain. The transplantation of Six3-overexpressing BMSCs ameliorated brain pathology, reducing apoptosis and cerebral infarct volume. Notably, Six3-modified BMSCs demonstrated a significantly greater therapeutic efficacy than unmodified BMSCs. Collectively, these findings demonstrate that Six3 enhances the therapeutic properties of BMSCs by transcriptionally activating Btg2, which promotes Akt phosphorylation. These findings provide novel mechanistic insight into the optimization of stem cell therapy in stroke.
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BibTeX
@article{fu2026six3,
title = {{Six3 promoting the migration and neural differentiation of BMSCs via Btg2-mediated Akt signaling pathway activation: A therapeutic strategy for stroke}},
author = {Zhenqiang Fu and Zhixin Li and Limin Zhang and Wentao Hu and Hecheng Yang and Jingtao Wang},
journal = {International Journal of Molecular Medicine},
year = {2026},
month = oct,
doi = {10.3892/ijmm.2026.6013},
url = {https://doi.org/10.3892/ijmm.2026.6013},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Six3 promoting the migration and neural differentiation of BMSCs via Btg2-mediated Akt signaling pathway activation: A therapeutic strategy for stroke
AU - Zhenqiang Fu
AU - Zhixin Li
AU - Limin Zhang
AU - Wentao Hu
AU - Hecheng Yang
AU - Jingtao Wang
PY - 2026
DA - 2026/10/12
JO - International Journal of Molecular Medicine
DO - 10.3892/ijmm.2026.6013
UR - https://doi.org/10.3892/ijmm.2026.6013
AB - Bone marrow-derived mesenchymal stem cell (BMSC) transplantation holds therapeutic potential for stroke; however, but its effectiveness requires optimization. The transcription factor Sine Oculis Homeobox Homolog 3 (Six3) regulates processes crucial for BMSC therapy, such as neural cell proliferation and differentiation. However, whether Six3-modified BMSCs exert enhanced therapeutic effects on stroke remains unknown. In the present study, mouse BMSCs were isolated and identified using surface markers. Six3-overexpressing BMSCs exhibited enhanced proliferative, migratory and neural differentiation capacities. RNA-sequencing analysis comparing the gene expression profiles of BMSCs with and without Six3 overexpression identified BTG Anti-Proliferation Factor 2 (Btg2) as an upregulated gene (log2FC=1.45, P<0.05) in Six3-overexpressing cells. Further investigations revealed that Six3 directly binds to the TGATACTGTCT sequence within the Btg2 promoter and activates its transcription. Btg2 knockdown abolished the effects of Six3 overexpression. Mechanistically, Six3 promoted Akt phosphorylation via Btg2, enhancing BMSC viability and neural differentiation. A mouse model of stroke was established using transient middle cerebral artery occlusion (MCAO, 1.5-h occlusion and 24-h reperfusion). BMSCs were administered via tail vein injection at the onset of reperfusion. GFP expression detected in brain tissue at 24 h post-reperfusion confirmed successful the homing of BMSCs to the brain. The transplantation of Six3-overexpressing BMSCs ameliorated brain pathology, reducing apoptosis and cerebral infarct volume. Notably, Six3-modified BMSCs demonstrated a significantly greater therapeutic efficacy than unmodified BMSCs. Collectively, these findings demonstrate that Six3 enhances the therapeutic properties of BMSCs by transcriptionally activating Btg2, which promotes Akt phosphorylation. These findings provide novel mechanistic insight into the optimization of stem cell therapy in stroke.
SN - 1107-3756
SN - 1791-244X
ER -