VLA-4 Agonist Promotes Engraftment and Immune Reconstitution of Allogeneic Hematopoietic Stem Cells

Full engraftment and early immune reconstitution of donor hematopoietic stem cells (HSCs) after allogeneic HSC transplantation (allo-HSCT) are crucial. However, effective and safe clinical modality remains lacking. Here, very-late antigen (VLA-4) was identified as a pivotal target for HSC engraftment, and one of its agonists was identified, which significantly promotes donor HSC engraftment and long-term hematopoietic reconstitution by enhancing its self-renewal capacity in allogeneic transplantation and serial xenotransplantation mouse models. Furthermore, the VLA-4 agonist facilitated early immune reconstitution by augmenting T-cell differentiation from HSCs, with the reconstituted immune cells exhibiting potent antiviral effects without exacerbating acute graft-versus-host disease. Mechanistically, VLA-4 A2 activated ERK1/2 phosphorylation to regulate HSC function and lymphoid progenitor differentiation, without inducing leukemogenic gene expression. These findings underscore the significant clinical translational potential of the VLA-4 agonist in promoting HSC engraftment and early cellular immune reconstitution following allo-HSCT.