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Publication — IRIC

DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells.

T cells show tremendous efficacy as cellular therapeutics. However, obtaining primary T cells from human donors is expensive and variable. Pluripotent stem cells (PSCs) have the potential to provide a renewable source of T cells, but differentiating PSCs into hematopoietic progenitors with T cell potential remains an important challenge. Here, we report an efficient serum- and feeder-free system for differentiating human PSCs into hematopoietic progenitors and T cells. This fully defined approach allowed us to study the impact of individual proteins on blood emergence and differentiation. Providing DLL4 and VCAM1 during the endothelial-to-hematopoietic transition enhanced downstream progenitor T cell output by ~80-fold. These two proteins synergized to activate notch signaling in nascent hematopoietic stem and progenitor cells, and VCAM1 additionally promoted an inflammatory transcriptional program. We also established optimized medium formulations that enabled efficient and chemically defined maturation of functional CD8αβ+, CD4, CD3+, TCRαβ+ T cells with a diverse TCR repertoire.

Publication date
August 26, 2022
Principal Investigators
Michaels YS, Edgar JM, Major MC, Castle EL, Zimmerman C, Yin T, Hagner A, Lau C, Hsu HH, Ibañez-Rios MI, Durland LJ, Knapp D, Zandstra PW
PubMed reference
Sci Adv 2022;8(34):eabn5522
PubMed ID
School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.