Sodium tanshinone IIA sulfonate improves the ischemic microenvironment by inhibiting apoptosis and promotes the treatment of ischemic brain injury by iPSCs

Background Ischemic stroke is the second leading cause of disability and death worldwide. Sodium tanshinone IIA sulfonate (STS), a well-known Chinese medicine monomer, is commonly used to treat ischemic brain injury because of its anti-apoptotic, anti-oxidative and anti-inflammatory properties. The aim of this study was to clarify the mechanism of STS combined with induced pluripotent stem cells (iPSCs) in treating ischemic brain injury by investigating changes in the ischemic microenvironment in a rat model of cerebral ischemia-reperfusion injury. Methods This study employed magnetic resonance imaging (MRI) to examine functional recovery after a combined therapeutic approach involving STS and iPSCs in vivo. Cerebral ischemia was induced by the middle cerebral artery occlusion approach, and thirty male rats were randomly assigned to five groups: Sham, MCAO, MCAO + STS, MCAO + iPSCs, and MCAO + iPSCs + STS. MRI were conducted on Days 1 and 7, with neurofunctional tests performed every other day. Additionally, 1.0×10⁶GFP-Luc-iPSCs were transplanted on Day 3 and bioluminescence imaging in brains was performed on Days 1 and 5 after transplantation. Proteomic analysis and immunofluorescent analyses were performed on Day 7. Results STS reduced infarct size and enhanced neurological function scores after MCAO. Furthermore, proteomic analysis revealed extensive remodeling of the ischemic microenvironment, with 365 differentially expressed proteins between the Sham and MCAO groups. Proteomic analysis demonstrated that STS primarily improved the ischemic microenvironment by inhibiting apoptosis between the MCAO and STS groups, a finding that was further validated by Western blotting and TUNEL assays. We next assessed iPSCs survival after transplantation. Compared with the iPSCs group, the combined treatment with STS significantly improved iPSCs survival, reduced infarct size and enhanced neurological function scores. Immunofluorescence revealed an increased expression of NeuN and CD31, demonstrating that the combined therapy more effectively promoted neurovascular repair. Moreover, increased GFP co-localization with BDNF, VEGF, and DCX was observed in the combined treatment with STS, indicating STS enhanced iPSCs-mediated paracrine effects and neurogenic potential. Conclusions STS enhances the survival and proliferation of iPSCs by improving the ischemic microenvironment through the suppression of apoptosis and enhances iPSCs-mediated paracrine mechanisms and their potential for differentiation. In summary, STS combined with iPSCs could be a more effective therapeutic approach than using these stem cells individually.