Identification of a novel subpopulation of human cord blood CD34-CD133-CD7-CD45+lineage- cells capable of lymphoid/NK cell differentiation after in vitro exposure to IL-15.
The hemopoietic stem cell (HSC) compartment encompasses cell subsets with heterogeneous proliferative and developmental potential. Numerous CD34(-) cell subsets that might reside at an earlier stage of differentiation than CD34(+) HSCs have been described and characterized within human umbilical cord blood (UCB). We identified a novel subpopulation of CD34(-)CD133(-)CD7(-)CD45(dim)lineage (lin)(-) HSCs contained within human UCB that were endowed with low but measurable extended long-term culture-initiating cell activity. Exposure of CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs to stem cell factor preserved cell viability and was associated with the following: 1) concordant expression of the stem cell-associated Ags CD34 and CD133, 2) generation of CFU-granulocyte-macrophage, burst-forming unit erythroid, and megakaryocytic aggregates, 3) significant extended long-term culture-initiating cell activity, and 4) up-regulation of mRNA signals for myeloperoxidase. At variance with CD34(+)lin(-) cells, CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs maintained with IL-15, but not with IL-2 or IL-7, proliferated vigorously and differentiated into a homogeneous population of CD7(+)CD45(bright)CD25(+)CD44(+) lymphoid progenitors with high expression of the T cell-associated transcription factor GATA-3. Although they harbored nonclonally rearranged TCRgamma genes, IL-15-primed CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs failed to achieve full maturation, as manifested in their CD3(-)TCRalphabeta(-)gammadelta(-) phenotype. Conversely, culture on stromal cells supplemented with IL-15 was associated with the acquisition of phenotypic and functional features of NK cells. Collectively, CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs from human UCB displayed an exquisite sensitivity to IL-15 and differentiated into lymphoid/NK cells. Whether the transplantation of CD34(-)lin(-) HSCs possessing T/NK cell differentiation potential may impact on immunological reconstitution and control of minimal residual disease after HSC transplantation for autoimmune or malignant diseases remains to be determined.
Rutella
Sergio
S
Department of Hematology, Laboratory of Immunology, Catholic University Medical School, Rome, Italy. sergiorutella@tin.it
Bonanno
Giuseppina
G
Marone
Maria
M
De Ritis
Daniela
D
Mariotti
Andrea
A
Voso
Maria Teresa
MT
Scambia
Giovanni
G
Mancuso
Salvatore
S
Leone
Giuseppe
G
Pierelli
Luca
L
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000378:metabolism; D019011:Antigens, CD7 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology; D017154:Stromal Cells / Q000276:immunology
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D019011:Antigens, CD7; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D006133:Growth Substances; D019409:Interleukin-15; C000606023:PROM1 protein, human; D010455:Peptides; D019089:Stem Cell Factor; D017493:Leukocyte Common Antigens