Sema4d, also known as CD100, is a homodimeric protein belonging to the semaphorin family. It has diverse functions in the immune system, such as in T cell priming, antibody production, and cell-to-cell adhesion. Sema4d exerts its functions through interacting with receptors like PlexinB1, and is involved in multiple signaling pathways including Src-dependent VE-cadherin dysfunction, PI3K/Akt, and RhoA/ROCK pathways [3,4,6]. It plays important roles in various biological processes and diseases, influencing angiogenesis, cell proliferation, and differentiation [1,4,5]. Genetic models, such as gene knockout mouse models, are valuable for studying Sema4d's functions.

In diabetic retinopathy, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti-Sema4D antibody alleviated vascular dysfunction, including pericyte loss, vascular leakage, and neovascularization. Anti-Sema4D also had a therapeutic advantage over anti-VEGF on pericyte dysfunction and showed a synergistic effect with anti-VEGF [1]. In liver fibrosis, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism and regulating the balance of Th1, Th2, Th17, and T-bet + Treg cells [2]. In acute myeloid leukemia (AML), SEMA4D promoted the proliferation and inhibited apoptosis of AML cells by binding to PlexinB1, and anti-SEMA4D antibody could inhibit AML development in xenograft mouse models [4]. In osteosarcoma, knockdown of Sema4D suppressed cell proliferation, migration, and invasion, as Sema4D/Plexin-B1 promoted the development of osteosarcoma by activating the Pyk2-PI3K/AKT pathway [5]. In choroidal neovascularization, Sema4D knockout attenuated the disease by inhibiting M2 macrophage polarization via regulation of the RhoA/ROCK pathway [6].

In conclusion, Sema4d is involved in multiple biological functions such as immune regulation, cell-cell communication, and angiogenesis. The gene knockout models of Sema4d have revealed its roles in various disease conditions, including diabetic retinopathy, liver fibrosis, AML, osteosarcoma, and choroidal neovascularization. These findings suggest that Sema4d could be a potential therapeutic target for these diseases.

References:

1. Wu, Jie-Hong, Li, Ya-Nan, Chen, An-Qi, Yue, Zhen-Yu, Hu, Bo. 2020. Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy. In EMBO molecular medicine, 12, e10154. doi:10.15252/emmm.201810154. https://pubmed.ncbi.nlm.nih.gov/31943789/

2. Wang, Lifu, Li, Dinghao, Zhu, Zifeng, Wu, Zhongdao, Sun, Xi. 2023. Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression. In Pharmacological research, 195, 106886. doi:10.1016/j.phrs.2023.106886. https://pubmed.ncbi.nlm.nih.gov/37591326/

3. Maleki, Kimia T, Cornillet, Martin, Björkström, Niklas K. 2015. Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases. In Clinical immunology (Orlando, Fla.), 163, 52-9. doi:10.1016/j.clim.2015.12.012. https://pubmed.ncbi.nlm.nih.gov/26732857/

4. Liu, Lu, Yang, Lin, Liu, Xiaojun, Nie, Ziyuan, Luo, Jianmin. 2022. SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling. In Journal of translational medicine, 20, 304. doi:10.1186/s12967-022-03500-w. https://pubmed.ncbi.nlm.nih.gov/35794581/

5. Li, Changhui, Wan, Lei, Wang, Peng, Li, Congda, Wang, Xishan. . Sema4D/Plexin-B1 promotes the progression of osteosarcoma cells by activating Pyk2-PI3K-AKT pathway. In Journal of musculoskeletal & neuronal interactions, 21, 577-583. doi:. https://pubmed.ncbi.nlm.nih.gov/34854398/

6. Cui, Kaixuan, Tang, Xiaoyu, Yang, Boyu, Xu, Yue, Liang, Xiaoling. . Sema4D Knockout Attenuates Choroidal Neovascularization by Inhibiting M2 Macrophage Polarization Via Regulation of the RhoA/ROCK Pathway. In Investigative ophthalmology & visual science, 65, 34. doi:10.1167/iovs.65.6.34. https://pubmed.ncbi.nlm.nih.gov/38913005/