Journal
NATURE BIOTECHNOLOGY
Volume 37, Issue 3, Pages 293-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41587-019-0017-2
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Funding
- National Institutes of Health [UL1 TR002541, U19 HL129903, R01 EB023287]
- Cancer Research Institute Postdoctoral Fellowship
- Blavatnik Biomedical Accelerator Program at Harvard University
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Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. 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 similar to 6-fold in mouse HSCT and similar to 2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4(+) regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to 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.
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