Dual functions of natural killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues.
Dual functions of natural killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues.
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DOI：
10.7150/jca.5519
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发表时间：
2013
影响因子：
3.9
通讯作者：
Tseng HC
中科院分区：
文献类型：
--
作者：
Jewett A;Man YG;Tseng HC
来自我们实验室的累积证据表明，条件或无能量NK细胞具有通过分泌因子和通过诱导分化的直接细胞-细胞接触诱导健康干细胞和转化的癌症干细胞的抗性的能力。NK细胞的细胞毒性功能在肿瘤微环境中被许多不同的效应物及其分泌因子抑制。此外，在许多癌症患者中已经记录了外周血NK细胞功能降低。我们以前已经表明，NK细胞介导的显着的细胞毒性对原发性口腔鳞状细胞癌干细胞（OSCSC）相比，其更分化的口腔鳞状细胞癌细胞（OSCC）。此外，人胚胎干细胞（hESC）、人间充质干细胞（hMSC）、人牙髓干细胞（hDPSC）和诱导的人多能干细胞（hiPSC）都比其分化的对应物或其衍生的亲本细胞对NK细胞介导的细胞毒性显著更敏感。我们还报道了通过阻断NFκB或COX 2基因缺失来抑制细胞分化或使细胞逆转为分化程度较低的表型，从而显著增强了NK细胞的功能。此外，当在单核细胞存在下培养干细胞或NK细胞时，干细胞对NK细胞介导的细胞毒性的抗性的诱导及其随后的分化被放大。因此，我们提出NK细胞成熟的两个阶段，即CD 16 + CD 56 dim/+ CD 69- NK细胞对于干细胞或低分化细胞的裂解是重要的，而CD 16 dim/-CD 56 dim/+ CD 69 +NK细胞对于组织的分化和最终再生以及炎症的消退是重要的，因此在功能上充当调节性NK细胞（NKreg）。发现NK细胞上的CD 16受体是具有显著诱导NK细胞无反应性潜力的受体，然而，我们最近的数据表明NKp 46而不是NKp 30或NKp 44也能够诱导NK细胞中的显著无反应性，尽管与CD 16受体触发相比，其水平较低。本文就NK细胞分裂无能的概念、NKreg的产生及其在细胞分化、组织修复和再生以及抗肿瘤中的作用作一综述。
Accumulated evidence from our laboratory indicates that conditioned or anergized NK cells have the ability to induce resistance of healthy stem cells and transformed cancer stem cells through both secreted factors and direct cell-cell contact by inducing differentiation. Cytotoxic function of NK cells is suppressed in the tumor microenvironment by a number of distinct effectors and their secreted factors. Furthermore, decreased peripheral blood NK cell function has been documented in many cancer patients. We have previously shown that NK cells mediate significant cytotoxicity against primary oral squamous carcinoma stem cells (OSCSCs) as compared to their more differentiated oral squamous carcinoma cells (OSCCs). In addition, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs), human dental pulp stem cells (hDPSCs) and induced human pluripotent stem cells (hiPSCs) were all significantly more susceptible to NK cell mediated cytotoxicity than their differentiated counterparts or parental cells from which they were derived. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or gene deletion of COX2 significantly augmented NK cell function. Furthermore, the induction of resistance of the stem cells to NK cell mediated cytotoxicity and their subsequent differentiation is amplified when either the stem cells or the NK cells were cultured in the presence of monocytes. Therefore, we propose that the two stages of NK cell maturation namely CD16+CD56dimCD69- NK cells are important for the lysis of stem cells or poorly differentiated cells whereas the CD16dim/-CD56dim/+CD69+NK cells are important for differentiation and eventual regeneration of the tissues and the resolution of inflammation, thus functionally serving as regulatory NK cells (NKreg). CD16 receptor on the NK cells were found to be the receptor with significant potential to induce NK cell anergy, however, our recent data indicated that NKp46 but not NKp30 or NKp44 were also able to induce significant anergy in NK cells, although the levels were less when compared to CD16 receptor triggering. The concept of split anergy in NK cells and generation of NKreg and its contribution to cell differentiation, tissue repair and regeneration and in tumor resistance will be discussed in this review.
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影响因子：
5.6
作者：
Greten TF;Manns MP;Korangy F
通讯作者：
Korangy F
影响因子：
3.7
作者：
Camp, BJ;Dyhrman, ST;Barth, RJ
通讯作者：
Barth, RJ
影响因子：
11.5
作者：
Jewett, A;Cacalano, NA;Teruel, A
通讯作者：
Teruel, A
影响因子：
2.7
作者：
Jewett, A;Wang, MY;Park, NH
通讯作者：
Park, NH
影响因子：
9.1
作者：
Jewett, A;Gan, XH;Bonavida, B
通讯作者：
Bonavida, B