Hematopoietic Origin of Human Natural Killer (NK) Cells: Generation from Immature Progenitors

Silva, Maria R.G.; Kessler, Steven W.; Ascensāo, Joāo L.

doi:10.1159/000163803

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…For these reasons, it is unlikely that they will be used for clinical applications. Interestingly, the system reported by Silva et al contained human serum without stroma cells and was therefore favored for clinical scaling-up (40). This NK cell expansion method was later abandoned, once stroma cells were recognized as a potential critical component for the enhancement of NK cell proliferation (40).…”

Section: Nk Cell Differentiation and Expansionmentioning

confidence: 99%

“…Interestingly, the system reported by Silva et al contained human serum without stroma cells and was therefore favored for clinical scaling-up (40). This NK cell expansion method was later abandoned, once stroma cells were recognized as a potential critical component for the enhancement of NK cell proliferation (40). In 2007, Kao et al showed that serum-free expanded CD34+ cells may be differentiated into a NK cell product with an average purity of 40–60% after 5–7 weeks of culture, with a mean expansion rate of 300-fold.…”

Section: Nk Cell Differentiation and Expansionmentioning

confidence: 99%

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Improving the Outcome of Leukemia by Natural Killer Cell-Based Immunotherapeutic Strategies

et al. 2014

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Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells are widely recognized as potent anti-leukemia mediators. Alloreactive donor NK cells have been shown to improve the outcome of allogeneic stem-cell transplantation for leukemia. In addition, in vivo transfer of NK cells may soon reveal an important therapeutic tool for leukemia, if tolerance to NK-mediated anti-leukemia effects is overcome. This will require, at a minimum, the ex vivo generation of a clinically safe NK cell product containing adequate numbers of NK cells with robust anti-leukemia potential. Ideally, ex vivo generated NK cells should also have similar anti-leukemia potential in different patients, and be easy to obtain for convenient clinical scale-up. Moreover, optimal clinical protocols for NK therapy in leukemia and other cancers are still lacking. These and other issues are being currently addressed by multiple research groups. This review will first describe current laboratory NK cell expansion and differentiation techniques by separately addressing different NK cell sources. Subsequently, it will address the mechanisms known to be responsible for NK cell alloreactivity, as well as their clinical impact in the hematopoietic stem cells transplantation setting. Finally, it will briefly provide insight on past NK-based clinical trials.

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Section: Nk Cell Differentiation and Expansionmentioning

confidence: 99%

Section: Nk Cell Differentiation and Expansionmentioning

confidence: 99%

Improving the Outcome of Leukemia by Natural Killer Cell-Based Immunotherapeutic Strategies

et al. 2014

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“…Initial studies showed that CD56ϩCD3-NK cell differentiation from CD34ϩ bone marrow cells required interleukin-2 (IL-2) and bone marrow stromal cells [2][3][4]. However, further studies showed that the stromal requirement for CD56ϩCD3-cell differentiation can be substituted with a combination of IL-2 and stem cell factor (SCF) [5][6][7][8]. Although IL-2 initiates CD56ϩCD3-cell differentiation from CD34ϩ, in vitro bone marrow stromal cells do not secrete this cytokine.…”

Section: Introductionmentioning

confidence: 99%

G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte

Sconocchia

Fujiwara

Rezvani

et al. 2004

Journal of Leukocyte Biology

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To study the early stages of development from stem cells of the CD56+ cell population [which includes natural killer (NK) cells], granulocyte-colony stimulating factor-mobilized peripheral blood CD34+ cells from healthy donors were sorted to >99% purity and cultured in the presence of stem cell factor and interleukin (IL)-2. After 3 weeks in culture, the majority of cells acquired CD33, with or without human leukocyte antigen-DR and CD14. In 20 stem cell donors tested, 8.7 +/- 8.8% of cells were CD56+. Two major CD56+ subsets were identified: CD56(bright), mainly CD33- cells (7+/-10%, n=11) with large, granular lymphocyte morphology, and CD56dim, mainly CD33+ (2.5+/-2, n=11) cells with macrophage morphology. The CD56bright population had cytoplasmic granzyme A but lacked killer inhibitory receptor, suggesting they were immature NK cells. The CD56dim, CD33+, population lacked NK markers. They may represent a minor subset of normal monocytes at a developmental stage comparable with the rare CD56+ CD33+ hybrid myeloid/NK cell leukemia. Consistent with a monocyte nature, CD56dimCD33+ proliferated and produced a variety of cytokines upon lipopolysaccharide stimulation, including IL-8, IL-6, monocyte chemoattractant protein-1, and macrophage-derived chemokine but not interferon-gamma. In a short-term cytotoxicity assay, they failed to kill but powerfully inhibited the proliferation of the NK-resistant cell line P815. The generation of CD56+ cells was negatively regulated by hyaluronic acid and IL-4, indicating that extracellular matrix may play an important role in the commitment of CD34+ cells into CD56 myeloid and lymphoid lineages.

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“…NK cell progenitors exist in human and rat bone marrow (BM) [5][6][7] and propagation of NK cells from normal human BM populations bearing the CD34 and other markers has been reported [8][9][10][11][12]. Still, their functional development is not well defined.…”

Section: Introductionmentioning

confidence: 99%

Definition of Early Progenitors and Functional Maturation of Human Natural Killer Cells: Requirements for Cytocidal Activity

Vaz

Hoffman²,

Almeida-Porada³

et al. 1998

Pathobiology

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We examined the in vitro development of human natural killer (NK) cells to define the earliest hematopoietic progenitors which could give rise to NK cells. Our data indicates that NK cells arise from the Thy 1+ subpopulations of CD34+ marrow cells. In cultures with IL2 we generated up to 96.5% NK cells from CD34+ Thy 1+ and in cultures with IL7, cells bearing NK cell surface markers were also observed but were devoid of functional activity. We also addressed the functional integrity of these cultured cells by examining the appearance of granzyme A, serine esterase, Met-ase and perforin and correlating these with lytic activity. Granzyme A mRNA could be detected in IL-2-cultured cells and serine esterase activity as well as perforin were also found at the single cell level. Human Met-ase (Hu-Met-1) was not detected at any time of analysis. Granzyme expression occurs early in cells cultured with IL2 but its presence did not correlate with lytic function; CD56+ cells grown in the presence of IL7 express these enzymes and perforin after longer periods of culture, but lack the ability to lyse NK targets.

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Hematopoietic Origin of Human Natural Killer (NK) Cells: Generation from Immature Progenitors

Cited by 8 publications

References 18 publications

Improving the Outcome of Leukemia by Natural Killer Cell-Based Immunotherapeutic Strategies

Improving the Outcome of Leukemia by Natural Killer Cell-Based Immunotherapeutic Strategies

G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte

Definition of Early Progenitors and Functional Maturation of Human Natural Killer Cells: Requirements for Cytocidal Activity

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