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

Successful engraftment and early immune reconstitution of donor hematopoietic stem cells (HSCs) are crucial for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about how to promote implantation and early immune reconstitution of HSCs through regulating its own functions. Here, we identified very-late antigen (VLA-4) as a pivotal target in regulating HSC implantation. Critically, we screened out a VLA-4 agonist, which could promote the implantation and long-term hematopoietic reconstitution of donor HSCs in a mixed donor chimerism (MDC) mouse model and serial xenotransplantation model of human CD34+ cells from umbilical cord blood (UCB). Competitive transplantation mouse model and limited dilution assay for UCB CD34+ cells revealed that VLA-4 agonist could enhance the self-renewal capacity of HSCs and increase the number of severe combined immunodeficient (SCID)-repopulating cells (SRCs) to five-fold in vivo. Furthermore, the VLA-4 agonist could facilitate early post-transplant cell immune reconstitution by enhancing T cell output of HSCs. VLA-4 agonist regulates HSC functions and lymphoid progenitor differentiation through affecting the ERK1/2 phosphorylation pathway, whereas may not increase the risk of leukemia transformation. These findings indicate that the VLA-4 agonist holds a great clinical translational potential in enhancing engraftment of HSCs and early cellular immune reconstitution following allo-HSCT.