VLA-4 agonist promotes engraftment and immune reconstitution of allogeneic hematopoietic stem cells

作者：Qiaomei He, Xi Sun, Hui Cheng, Jie Yang, Yipeng Gao, Liping Wan, Yu Cai, Xiao Zhou, Lianghua Shen, Peiyao Jiang, Jiayu Liu, Xiaodan Ding, Lu Li, Yin Tong, Huiying Qiu, Chongmei Huang, Baoxia Dong, Kun Zhou, Yuqin Yang, Pengran Wang, Xi Liang, Yan Zhang, Bo O. Zhou, Fang Zhang, Xianmin Song · 发表于：Blood Advances · 年份：2026 · DOI：10.1182/bloodadvances.2025017456 · 研究领域：Hematopoietic Stem Cell Transplantation、Cell Adhesion Molecules Research、Cell death mechanisms and regulation

ABSTRACT: 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-4 (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 extracellular signal-regulated kinase 1/2 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 after allo-HSCT.