Bone-marrow mesenchymal stem cells (MSCs) are the origin of bone-forming cells with immunomodulation potential. HLA-G5 is among the generated immunosuppressive molecules. HLA-G proteins play a crucial role in the regulation of the immune response, particularly in the context of bone repair and regeneration. The function of HLA-G5 in MSCs is to modulate the immune response, thereby promoting a favorable environment for bone healing. This is achieved through the inhibition of pro-inflammatory cytokines and the promotion of anti-inflammatory cytokines. The regulation of HLA-G5 expression in MSCs is a complex process that involves multiple signaling pathways and transcription factors. Understanding the regulation and function of HLA-G5 in MSCs is essential for the development of novel therapeutic strategies for bone repair and regeneration.