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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 ¹

Sergio Rutella^2,*,, Giuseppina Bonanno, Maria Marone, Daniela de Ritis, Andrea Mariotti, Maria Teresa Voso^*, Giovanni Scambia, Salvatore Mancuso, Giuseppe Leone^* and Luca Pierelli^*,

^* Department of Hematology, Laboratory of Immunology, and Department of Gynecology, Catholic University Medical School, Rome, Italy

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^dimlineage (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^dimlin^- 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^dimlin^- HSCs maintained with IL-15, but not with IL-2 or IL-7, proliferated vigorously and differentiated into a homogeneous population of CD7⁺CD45^brightCD25⁺CD44⁺ lymphoid progenitors with high expression of the T cell-associated transcription factor GATA-3. Although they harbored nonclonally rearranged TCR genes, IL-15-primed CD34^-CD133^-CD7^-CD45^dimlin^- HSCs failed to achieve full maturation, as manifested in their CD3^-TCR^-- 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^dimlin^- 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.

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				S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, M. Corallo, M. G. Prisco, A. Eramo, C. Napoletano, D. Gallo, A. Perillo, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD133 Antigen in Human Endometrial Tumors Clin. Cancer Res., July 1, 2009; 15(13): 4299 - 4311. [Abstract] [Full Text] [PDF]