Diverse T-cell differentiation potentials of human fetal thymus, fetal liver, cord blood and adult bone marrow CD34 cells on lentiviral Delta-like-1-modified mouse stromal cells

Immunology. 2009 Sep;128(1 Suppl):e497-505. doi: 10.1111/j.1365-2567.2008.03013.x. Epub 2008 Nov 20.

Abstract

Human haematopoietic progenitor/stem cells (HPCs) differentiate into functional T cells in the thymus through a series of checkpoints. A convenient in vitro system will greatly facilitate the understanding of T-cell development and future engineering of therapeutic T cells. In this report, we established a lentiviral vector-engineered stromal cell line (LSC) expressing the key lymphopoiesis regulator Notch ligand, Delta-like 1 (DL1), as feeder cells (LSC-mDL1) supplemented with Flt3 ligand (fms-like tyrosine kinase 3, Flt3L or FL) and interleukin-7 for the development of T cells from CD34(+) HPCs. We demonstrated T-cell development from human HPCs with various origins including fetal thymus (FT), fetal liver (FL), cord blood (CB) and adult bone marrow (BM). The CD34(+) HPCs from FT, FL and adult BM expanded more than 100-fold before reaching the beta-selection and CD4/CD8 double-positive T-cell stage. The CB HPCs, on the other hand, expanded more than 1000-fold before beta-selection. Furthermore, the time required to reach beta-selection differed for the various HPCs, 7 days for FT, 14 days for FL and CB, and 35 days for adult BM. Nevertheless, all of the T cells developed in vitro were stalled at the double-positive or immature single-positive stage with the exception that some CB-derived T cells arrived at a positive selection stage. Consequently, the LSC-mDL1 culture system illustrated diverse T-cell development potentials of pre- and post-natal and adult human BM HPCs. However, further modification of this in vitro T-cell development system is necessary to attain fully functional T cells.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / physiology
  • Calcium-Binding Proteins
  • Cell Differentiation*
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Fetal Blood / cytology
  • Fetal Blood / drug effects
  • Fetal Blood / physiology
  • Fetus / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin-7 / pharmacology
  • Lentivirus
  • Liver / cytology
  • Liver / embryology
  • Membrane Proteins / pharmacology
  • Mice
  • Stromal Cells / drug effects
  • Stromal Cells / physiology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / embryology
  • Thymus Gland / immunology*
  • Transduction, Genetic

Substances

  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-7
  • Membrane Proteins
  • flt3 ligand protein