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Nat Methods. 2017 May;14(5):531-538. doi: 10.1038/nmeth.4258. Epub 2017 Apr 10.

Progenitor T-cell differentiation from hematopoietic stem cells using Delta-like-4 and VCAM-1.

Author information

1
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
2
Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
3
Medicine by Design, a Canada First Research Excellence Program at the University of Toronto, Toronto, Ontario, Canada.
4
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
5
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

Abstract

The molecular and cellular signals that guide T-cell development from hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. The thymic microenvironment integrates multiple niche molecules to potentiate T-cell development in vivo. Recapitulating these signals in vitro in a stromal cell-free system has been challenging and limits T-cell generation technologies. Here, we describe a fully defined engineered in vitro niche capable of guiding T-lineage development from HSPCs. Synergistic interactions between Notch ligand Delta-like 4 and vascular cell adhesion molecule 1 (VCAM-1) were leveraged to enhance Notch signaling and progenitor T-cell differentiation rates. The engineered thymus-like niche enables in vitro production of mouse Sca-1+cKit+ and human CD34+ HSPC-derived CD7+ progenitor T-cells capable of in vivo thymus colonization and maturation into cytokine-producing CD3+ T-cells. This engineered thymic-like niche provides a platform for in vitro analysis of human T-cell development as well as clinical-scale cell production for future development of immunotherapeutic applications.

PMID:
28394335
DOI:
10.1038/nmeth.4258
[Indexed for MEDLINE]

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