Acute ischemic stroke (AIS) is a prevalent disease with high morbidity, disability, and recurrence rate (Feigin et al., 2021). However, currently, available treatments are limited. Tissue fibrinogen activator remains the US Food and Drug Administration (FDA) recommended first-line agent, with a narrow treatment window of only 4.5 h (Powers et al., 2019). Mechanical thrombectomy is another standard therapy that may benefit carefully selected patients with large vessel occlusions within 24 h of stroke onset (Berge et al., 2021). However, not all mechanical thrombectomies yield successful results. Poor reperfusion after endovascular thrombectomy is strongly associated with worse outcomes compared to the best medical management (Rex et al., 2023). Additionally, the success of endovascular thrombectomy and the subsequent clinical outcome of patients are influenced by various factors, such as comorbidities and other physiological changes (Chen et al., 2023; Wu et al., 2023; Yang et al., 2022). Therefore, there is an urgent need to develop novel therapies applicable to obtain optimal patient outcomes.

Stem cell-based therapies have emerged as a promising therapy for addressing a variety of intractable diseases, encompassing cancer, neurodegenerative diseases, and tissue-damaging disorders such as ischemic stroke (Rahbaran et al., 2022; Szydlak, 2023; Taeb et al., 2022). With the advantages of low immunogenicity, multidirectional differentiation potential, and relative ease to obtain and culture in vitro, mesenchymal stem cells (MSCs) have attracted continuous attention and become one of the most widely studied stem cells (Andrzejewska et al., 2021; Honmou et al., 2012). Numerous preclinical studies support the therapeutic effects of MSCs in stroke, including reducing lesion volume, decreasing neurological deficits, and promoting neurobehavioural outcomes (Sarmah et al., 2017; Vu et al., 2014). Multiple mechanisms contribute to the therapeutic benefit of MSCs, such as neuroprotection, immunomodulation, angiogenesis, and neural circuit reconstruction (Chen et al., 2003a; Chen et al., 2003b; Gutiérrez-Fernández et al., 2013; Lin et al., 2011; Song et al., 2013; Yoo et al., 2013). In addition to direct differentiation and paracrine effects, recent studies have revealed that MSCs also treat ischemic stroke through mitochondrial transfer and extracellular vesicles (EVs) transfer mechanisms. MSCs can transfer their active mitochondria to injured brain microvascular endothelial cells, astrocytes, and neurons, promoting the survival and proliferation of these cells (Chen et al., 2020; Gomzikova et al., 2021; Liu et al., 2019; Xu et al., 2023). MSCs-derived EVs contain various soluble components, such as lipids, proteins, and microRNAs, and as messengers for communication between MSCs and damaged cells, and MSCs-derived EVs transfer their contents to target cells to regulate their function and activity (Dumbrava et al., 2021; Gregorius et al., 2021; Guo et al., 2021; Li et al., 2021b). Nevertheless, the underlying mechanisms of MSCs transplantation for stroke have not been fully elucidated, and more investigations are needed to facilitate subsequent clinical translation.

Metabolomics is a comprehensive technique for profiling entire endogenous metabolites in a biological system. As a powerful phenotyping technique, metabolomic analysis promotes discovering biomarkers and understanding the underlying pathological mechanisms of complex diseases, such as stroke (Nicholson and Lindon, 2008; Wishart, 2016). As an additional benefit, using metabolomics can detect metabolites small enough to cross the blood-brain barrier and therefore has the potential to capture changes within the brain more sensitively than proteomics and transcriptomics (Ke et al., 2019; Qureshi et al., 2017). Recently, several studies have utilized metabolic profiles to explain the protective effects of pharmacological agents on ischemic brain injury (Gupta et al., 2020; Li et al., 2022; Ma et al., 2022), but there are still few reports explaining the therapeutic effects of stem cell treatment. Tanaka et al. (Tanaka et al., 2020) aimed to investigate the impact of two cell treatments (human umbilical cord derived CD34+ cells and MSCs) on brain metabolism in neonatal mice 72 h after MCAO. The researchers discovered that while the effect of cell therapy was not particularly significant in the metabolomic analysis, the involvement of tricarboxylic acid cycle, glycolysis/gluconeogenesis, and ketone body production was more pronounced following MSCs treatment compared to CD34+ cell treatment. In Lan et al.'s study (Lan et al., 2022), metabolomic screening was conducted on the brains of naïve rat, rather than stroke model rats, after intravenous injection of bone marrow mesenchymal stem cells (BMSCs), and 65 altered metabolites were identified. However, there is a knowledge gap in understanding the mechanisms of BMSCs therapy from the metabolic level, and more work needs to be done.

In the present study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). After evaluating the effect of BMSCs treatment on neurological functional outcomes and long-term neuronal survival, we focused on studying its impact on neuronal dendritic plasticity. Subsequently, we performed a non-targeted metabolomic analysis to observe changes in the metabolic profile of MCAO rats induced by BMSCs treatment and identified relevant metabolic pathways to investigate the potential mechanisms of BMSCs therapy.