Traumatic brain injury (TBI) is divided into primary injury and secondary injury based on its pathophysiological processes. Primary injury is often a kind of mechanical and irreversible damage. Uncontrolled primary injury can induce inflammatory response to cause secondary injury. Hypoxia and ischemia, oxidative stress, cerebral edema, inflammatory response, and apoptosis can aggravate nerve injury. Oxidative stress after cerebral hemorrhage can cause an imbalance in free radical release, thereby resulting in angiotensin catabolism, lipid peroxidation, and DNA/RNA damage (Yang et al., 2017). Neuro-inflammatory reaction is a crucial contributor to the early onset of brain injury. It involves activating astrocytes to release inflammatory cytokines, which in turn leads to neuronal damage after brain injury. Mesenchymal stem cells (MSCs) not only have the potential of proliferation and differentiation in the treatment of neurological diseases, but can also replace necrotic cells and replenish cell populations (Gao et al., 2019). In addition, stem cells can modulate inflammation-related cytokines, reduce inflammatory response, and exert anti-inflammatory effect (Yuan et al., 2023). In a specialized way, transplantation of MSCs derived from human umbilical cord can significantly interfere with inflammatory regulation in the body. This process not only intuitively and precisely decreases inflammatory response, but also effectively alleviates symptoms by improving anti-inflammatory drug activities (Wang et al., 2022). However, there are certain difficulties in the quantity, extraction, and MSCs application. For example, the iliac crest bone marrow is one of the most widely used MSC source, but it has a painful aspiration process and a small number of cells (Drela et al., 2020). Thus, looking for more practical stem cells will be beneficial for regenerative medicine development. Adipose-derived mesenchymal stem cells (ADSCs) are a kind of MSCs that can be obtained from human adipose tissues. ADSCs are easily expanded and differentiated in vitro (Zhang et al., 2022). Fortunately, ADSCs have the advantages of abundant sources, easy access, rapid reproduction pace, multi-lineage differentiation potential, and minimal immunogenicity (Mannino et al., 2021). Therefore, ADSCs transplantation is a potential therapy for brain injury.

Apelin, as a kind of adipocyte cytokine, is an endogenous ligand of G protein coupled receptors isolated from humans. The human apelin coding sequence is found on chromosome Xq25-q26.1 (Liu et al., 2021). Apelin is a regulatory peptide with protective effects on different cells and tissues. Serum apelin-13 has the potential to serve as a valuable predictive biomarker for TBI. It may be used in the treatment of cerebral ischemia by targeting on signaling pathways involving apelin-13 and apelin receptor (APJ) (Li et al., 2022; Zhuang et al., 2021). APJ belongs to the G protein-coupled receptor (GPCR) family and consists of seven-transmembrane receptors. The APJ gene maps to the q12 band of chromosome 11, and its amino acid sequence is 31 % similar to that of the human angiotensin II type 1 receptor (O'Dowd et al., 1993). A study shows that APJ has the GPCR structural characteristics and can regulate signaling pathways through oligomerization, which provides a new idea for brain injury and drug development (Yue et al., 2022). Besides, apelin can link to metabolic disorders through lipid and glucose metabolism (Bertrand et al., 2018). Investigations have demonstrated that apelin-loaded extracellular vesicles can significantly reduce plasma glucose levels (Cui et al., 2024). Apelin has a variety of biological effects, including the regulation of cardiovascular, immune function and angiogenesis (Masoud et al., 2020). Furthermore, apelin can enhance beneficial effects of stem cells. Apelin exerts direct stimulatory effects on the proliferation and differentiation of stem cells (Bernier-Latmani et al., 2022). Notably, new research has confirmed that apelin can slow down neuro-inflammatory reaction while increasing the number and types of endogenous NSCs (Liu et al., 2022).