Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells
Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells
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DOI：
10.1158/2326-6066.cir-14-0117
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发表时间：
2015-02
影响因子：
10.1
通讯作者：
Rong Zhang;Tian-yi Liu;S. Senju;M. Haruta;N. Hirosawa;Motoharu Suzuki;Minako Tatsumi;Norihiro Ueda;Hiroyuki Maki;Ryusuke Nakatsuka;Yoshikazu Matsuoka;Yutaka Sasaki;S. Tsuzuki;H. Nakanishi;R. Araki;M. Abe;Y. Akatsuka;Y. Sakamoto;Y. Sonoda;Y. Nishimura;K. Kuzushima;Y. Uemura
中科院分区：
文献类型：
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作者：
Rong Zhang;Tian-yi Liu;S. Senju;M. Haruta;N. Hirosawa;Motoharu Suzuki;Minako Tatsumi;Norihiro Ueda;Hiroyuki Maki;Ryusuke Nakatsuka;Yoshikazu Matsuoka;Yutaka Sasaki;S. Tsuzuki;H. Nakanishi;R. Araki;M. Abe;Y. Akatsuka;Y. Sakamoto;Y. Sonoda;Y. Nishimura;K. Kuzushima;Y. Uemura
Zhang及其同事将c-Myc转导到小鼠iPSC（诱导多能干细胞）中，以产生增殖的骨髓细胞，这些细胞以依赖于精氨酸的方式增殖，同时保留其分化为刺激肿瘤抗原特异性T细胞反应的功能性抗原呈递细胞的潜力。使用树突状细胞（DC）来引发肿瘤相关抗原特异性T细胞应答，为癌症免疫治疗提供了一种有前途的方法。胚胎干细胞（ESC）和诱导多能干细胞（iPSC）可以分化为功能性DC，从而提供无限的DC来源。然而，先前建立的从多能干细胞（PSC）产生实际体积的DC的方法在分化培养开始时需要大量的PSC。在这项研究中，我们产生了小鼠增殖骨髓细胞（pMC）作为抗原呈递细胞（APC）的来源，使用慢病毒介导的c-Myc基因转导到小鼠PSC衍生的骨髓细胞。pMCs几乎可以无限期地以依赖于精氨酸的方式增殖，同时保留其分化为功能性APC的潜力。用IL 4加GM-CSF处理后，pMCs的增殖受损，并分化为表达低水平主要组织相容性复合体（MHC）-I、MHC-II、CD 40、CD 80和CD 86的未成熟DC样细胞（pMC-DC）。此外，暴露于成熟刺激物诱导TNFα和IL 12 p70的产生，并增强MHC-II、CD 40和CD 86的表达，这因此提示典型的DC成熟。与骨髓来源的DC类似，它们刺激初级混合淋巴细胞反应。此外，用H-2Kb限制性OVA 257 -264肽脉冲的pMC-DC的体内转移引发了OVA特异性细胞毒性T细胞，并在小鼠中引发了针对表达OVA的黑素瘤的攻击的保护。总之，表现出亮氨酸依赖性增殖和DC样分化的骨髓细胞可用于解决与DC制备相关的问题。Cancer Immunol Res; 3（6）; 668-77.©2015 AACR.
Zhang and colleagues transduced c-Myc into mouse iPSC (induced pluripotent stem cells) to generate proliferating myeloid cells that propagate in a cytokine-dependent manner while retaining their potential to differentiate into functional antigen-presenting cells that stimulate tumor antigen-specific T-cell responses. The use of dendritic cells (DC) to prime tumor-associated antigen-specific T-cell responses provides a promising approach to cancer immunotherapy. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can differentiate into functional DCs, thus providing an unlimited source of DCs. However, the previously established methods of generating practical volumes of DCs from pluripotent stem cells (PSC) require a large number of PSCs at the start of the differentiation culture. In this study, we generated mouse proliferating myeloid cells (pMC) as a source of antigen-presenting cells (APC) using lentivirus-mediated transduction of the c-Myc gene into mouse PSC-derived myeloid cells. The pMCs could propagate almost indefinitely in a cytokine-dependent manner, while retaining their potential to differentiate into functional APCs. After treatment with IL4 plus GM-CSF, the pMCs showed impaired proliferation and differentiated into immature DC-like cells (pMC-DC) expressing low levels of major histocompatibility complex (MHC)-I, MHC-II, CD40, CD80, and CD86. In addition, exposure to maturation stimuli induced the production of TNFα and IL12p70, and enhanced the expression of MHC-II, CD40, and CD86, which is thus suggestive of typical DC maturation. Similar to bone marrow–derived DCs, they stimulated a primary mixed lymphocyte reaction. Furthermore, the in vivo transfer of pMC-DCs pulsed with H-2Kb-restricted OVA257-264 peptide primed OVA-specific cytotoxic T cells and elicited protection in mice against challenge with OVA-expressing melanoma. Overall, myeloid cells exhibiting cytokine-dependent proliferation and DC-like differentiation may be used to address issues associated with the preparation of DCs. Cancer Immunol Res; 3(6); 668–77. ©2015 AACR.