An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation

The use of allogeneic hematopoietic stem cell transplantation (HSCT) to cure multiple disorders is limited by deficiency and dysregulation of T-cells. Here we report a biomaterial-based scaffold that mimics features of T-cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells, and presents the Notch ligand Delta-like ligand-4 to facilitate T-cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T-cell progenitor seeding of the thymus, T-cell neogenesis and diversification of the T-cell receptor repertoire. Peripheral T-cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4(+) regulatory T-cell generation and improved survival after allogeneic HSCT. Compared with adoptive transfer of T-cell progenitors, BMCs increased donor chimerism, T-cell generation and antigen-specific T-cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T-cell regeneration and mitigating graft-versus-host disease in HSCT.