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

  • Blood Adv. 2026 May 12;10(9):3103-3117. doi: 10.1182/bloodadvances.2025017456.
Qiaomei He  1 ,  Xi Sun  1 ,  Lin Veronica Chen  2 ,  Jun Yang  1 ,  Ying Gao  3 ,  Liping Wan  1 ,  Yu Cai  1 ,  Xiao Zhou  1 ,  Lianghua Shen  1 ,  Peiyao Jiang  1 ,  Jiayu Liu  1 ,  Xiaodan Ding  1 ,  Lu Li  1 ,  Yin Tong  1 ,  Huiying Qiu  1 ,  Chongmei Huang  1 ,  Baoxia Dong  1 ,  Kun Zhou  1 ,  Yuqin Yang  4 ,  Pengran Wang  1 ,  Xiaozhen Liang  3 ,  Yan Zhang  1 ,  Bo O Zhou  5 ,  Fang Zhang  1  6 ,  Xianmin Song  1
Affiliations
  • 1. Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Ear, Nose and Throat Institute, Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai, China.
  • 3. Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China.
  • 4. Department of Laboratory Animal Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 6. Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan Medical School, Sun Yat-sen University, Guangzhou, China.
PMID: 41758999 DOI: 10.1182/bloodadvances.2025017456
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.

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