title: Increased lysis of stem cells but not their differentiated cells by natural killer cells; de-differentiation or reprogramming activates NK cells.
abstract: The aims of this study are to demonstrate the increased lysis of stem cells but not their differentiated counterparts by the NK cells and to determine whether disturbance in cell differentiation is a cause for increased sensitivity to NK cell mediated cytotoxicity. Increased cytotoxicity and augmented secretion of IFN-gamma were both observed when PBMCs or NK cells were co-incubated with primary UCLA oral squamous carcinoma stem cells (UCLA-OSCSCs) when compared to differentiated UCLA oral squamous carcinoma cells (UCLA-OSCCs). In addition, human embryonic stem cells (hESCs) were also lysed greatly by the NK cells. Moreover, NK cells were found to lyse human Mesenchymal Stem Cells (hMSCs), human dental pulp stem cells (hDPSCs) and human induced pluripotent stem cells (hiPSCs) significantly more than their differentiated counterparts or parental lines from which they were derived. It was also found that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFkappaB or targeted knock down of COX2 in monocytes significantly augmented NK cell cytotoxicity and secretion of IFN-gamma. Taken together, these results suggest that stem cells are significant targets of the NK cell cytotoxicity. However, to support differentiation of a subset of tumor or healthy untransformed primary stem cells, NK cells may be required to lyse a number of stem cells and/or those which are either defective or incapable of full differentiation in order to lose their cytotoxic function and gain the ability to secrete cytokines (split anergy). Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation for specific elimination of cancer stem cells.
authors.affiliation: Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Han-Ching
authors.initials: HC
authors.lastname: Tseng
authors.forename: Aida
authors.initials: A
authors.lastname: Arasteh
authors.forename: Avina
authors.initials: A
authors.lastname: Paranjpe
authors.forename: Antonia
authors.initials: A
authors.lastname: Teruel
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.forename: Armin
authors.initials: A
authors.lastname: Behel
authors.forename: Jackelyn A
authors.initials: JA
authors.lastname: Alva
authors.forename: Gina
authors.initials: G
authors.lastname: Walter
authors.forename: Christian
authors.initials: C
authors.lastname: Head
authors.forename: Tomo-o
authors.initials: TO
authors.lastname: Ishikawa
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cacalano
authors.forename: April D
authors.initials: AD
authors.lastname: Pyle
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.forename: Anahid
authors.initials: A
authors.lastname: Jewett
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D009062:Mouth Neoplasms / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D015850:Interleukin-6; D016209:Interleukin-8; D007371:Interferon-gamma