Metcalf Lecture Award: Applying niche biology to engineer T-cell regenerative therapies

Abstract

The processes generating cells of adaptive immunity render them less amenable to the single cytokine signals used so effectively to regenerate myeloid cells. T-cell neogenesis begins in the bone marrow, where specific sets of late osteolineage cells govern the specification of hematopoietic cells capable of migrating to the thymus where differentiation is completed. Osteocalcin-expressing bone marrow stromal cells producing Dll4 serve as a progenitor niche enabling this T-competent cell production. Biocompatible alginate-based cryogels containing bone morphogenetic proteins (BMP-2) and the Notch ligand Dll4 were engineered to recapitulate the endogenous niche. These cryogels are highly pliable and can be injected under the skin of animals undergoing bone marrow transplantation. The result in mice is an ectopic niche fostering T-competent progenitor generation that results in improved T-cell numbers and receptor diversity. The recipients can generate neoantigen vaccine responses while having improved tolerance manifest by reduced graft-versus-host disease upon allogeneic transplant. Through emerging details of niches in the bone marrow, therapeutics more complex than those necessary for myeloid reconstitution are possible. Niche biology-guided bioengineered design offers the possibility of regenerative therapies for T lymphoid cells.