Human Embryonic Stem Cell-Derived NK Cells Acquire Functional Receptors and Cytolytic Activity

Stem Cell Institute and Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2005; 175(8):5095-103. DOI: 10.4049/jimmunol.175.8.5095
Source: PubMed


Human embryonic stem cells (hESCs) provide a unique resource to analyze early stages of human hematopoiesis. However, little is known about the ability to use hESCs to evaluate lymphocyte development. In the present study, we use a two-step culture method to demonstrate efficient generation of functional NK cells from hESCs. The CD56(+)CD45(+) hESC-derived lymphocytes express inhibitory and activating receptors typical of mature NK cells, including killer cell Ig-like receptors, natural cytotoxicity receptors, and CD16. Limiting dilution analysis suggests that these cells can be produced from hESC-derived hemopoietic progenitors at a clonal frequency similar to CD34(+) cells isolated from cord blood. The hESC-derived NK cells acquire the ability to lyse human tumor cells by both direct cell-mediated cytotoxicity and Ab-dependent cellular cytotoxicity. Additionally, activated hESC-derived NK cells up-regulate cytokine production. hESC-derived lymphoid progenitors provide a novel means to characterize specific cellular and molecular mechanisms that lead to development of specific human lymphocyte populations. These cells may also provide a source for innovative cellular immune therapies.

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    • "Since the derivation of hESCs, more than 20 years ago by Thomson et al., numerous groups have successfully differentiated these cells into fully mature and functional cells from each germ layer (105). Shortly, after the original derivation of hESCs, various groups demonstrated the hematopoietic development using an in vitro model and defined conditions (103, 104, 106–111). "
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    ABSTRACT: Natural killer (NK) cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK-cell biology field and in deciphering how NK-cell function is regulated, is driving efforts to utilize NK-cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK-cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, which adds another tool to the expanding NK-cell-based cancer immunotherapy arsenal.
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    • "Nevertheless, prolonged culture leads to NK cell exhaustion; that is, the resulting cells become ineffective in killing target cells and die within a few days after infusion into the recipient [2]. Therefore, in recent years there have been attempts to generate NK cells from more abundant cell sources, such as embryonic stem cell (ESC) and umbilical cord blood (UCB) [3]–[8]. "
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    • "In 2005, Woll and colleagues used a two-step process to differentiate human ES cells into NK cells in vitro. These cells had the ability to lyse human tumor cells deficient in MHC class I expression and up-regulate cytokine production (82). Subsequently, NK cells were successfully differentiated from human iPS cells, using a similar two-stage culture system (83), the cells obtained representing a pure population that did not require cell sorting or co-culture with xenogeneic stromal cells. "
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