In vitro-differentiated T/natural killer-cell progenitors derived from human CD34+ cells mature in the thymus.
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a treatment option for patients with hematopoietic malignancies that is hampered by treatment-related morbidity and mortality, in part the result of opportunistic infections, a direct consequence of delayed T-cell recovery. Thymic output can be improved by facilitation of thymic immigration, known to require precommitment of CD34(+) cells. We demonstrate that Delta-like ligand-mediated predifferentiation of mobilized CD34(+) cells in vitro results in a population of thymocyte-like cells arrested at a T/natural killer (NK)-cell progenitor stage. On intrahepatic transfer to Rag2(-/-)gamma(c)(-/-) mice, these cells selectively home to the thymus and differentiate toward surface T-cell receptor-alphabeta(+) mature T cells considerably faster than animals transplanted with noncultured CD34(+) cells. This finding creates the opportunity to develop an early T-cell reconstitution therapy to combine with HSCT.
Meek
Bob
B
Department of Internal Medicine, Division of Haematology, Maastricht University Medical Center, Maastricht, The Netherlands;
Cloosen
Silvie
S
Borsotti
Chiara
C
Van Elssen
Catharina H M J
CH
Vanderlocht
Joris
J
Schnijderberg
Melanie C A
MC
van der Poel
Marjolein W M
MW
Leewis
Bas
B
Hesselink
Reinout
R
Manz
Markus G
MG
Katsura
Yoshimoto
Y
Kawamoto
Hiroshi
H
Germeraad
Wilfred T V
WT
Bos
Gerard M J
GM
D000818:Animals; D018952:Antigens, CD34; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse