Embryonic Stem Cells Promoting Macrophage Survival and Function are Crucial for Teratoma Development.
Embryonic Stem Cells Promoting Macrophage Survival and Function are Crucial for Teratoma Development.
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促进巨噬细胞存活和功能的胚胎干细胞对于畸胎瘤的发展至关重要
DOI：
10.3389/fimmu.2014.00275
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发表时间：
2014
影响因子：
7.3
通讯作者：
Ren Y
中科院分区：
文献类型：
--
作者：
Chen T;Wang X;Guo L;Wu M;Duan Z;Lv J;Tai W;Renganathan H;Didier R;Li J;Sun D;Chen X;He X;Fan J;Young W;Ren Y
近年来，干细胞疗法在许多疾病中具有巨大的潜在应用。然而，干细胞的致瘤特性限制了其潜在的临床应用;因此，在移植之前必须建立降低干细胞致瘤潜力的策略。我们已经证明，胚胎干细胞（ESC）的同基因移植引起炎症反应，涉及骨髓源性巨噬细胞（BMDM）的快速招募。ESCs能够阻止成熟巨噬细胞由巨噬细胞集落刺激因子（M-CSF）撤药诱导的凋亡，从而通过以M-CSF非依赖性方式阻断各种凋亡途径而显著延长巨噬细胞寿命。ESC表达并分泌IL-34，其可能负责ESC促进的巨噬细胞存活。ESC的这种抗凋亡作用涉及细胞外信号调节激酶（ERK）1/2和PI 3 K/Akt通路的激活，因此，ERK 1/2和PI 3 K/AKT激活的抑制降低了ESC诱导的巨噬细胞存活。在功能上，ESC处理的巨噬细胞也显示出更高水平的吞噬活性。ESC还用于将BMDM分化为M2样巨噬细胞，其表现出大多数肿瘤相关巨噬细胞表型和功能特征。ESC培养的巨噬细胞产生高水平的TNF-α、Tie-2和TNF-α，它们参与血管生成并促进畸胎瘤进展。我们的研究表明，诱导M2样巨噬细胞活化是畸胎瘤发展的重要机制。靶向巨噬细胞以抑制畸胎瘤发展的策略将增加基于ESC的疗法的安全性，因为巨噬细胞的消耗完全抑制ESC诱导的血管生成和畸胎瘤发展。
Stem cell therapies have had tremendous potential application for many diseases in recent years. However, the tumorigenic properties of stem cells restrict their potential clinical application; therefore, strategies for reducing the tumorigenic potential of stem cells must be established prior to transplantation. We have demonstrated that syngeneic transplantation of embryonic stem cells (ESCs) provokes an inflammatory response that involves the rapid recruitment of bone marrow-derived macrophages (BMDMs). ESCs are able to prevent mature macrophages from macrophage colony-stimulating factor (M-CSF) withdrawal-induced apoptosis, and thus prolong macrophage lifespan significantly by blocking various apoptotic pathways in an M-CSF-independent manner. ESCs express and secrete IL-34, which may be responsible for ESC-promoted macrophage survival. This anti-apoptotic effect of ESCs involves activation of extracellular signal-regulated kinase (ERK)1/2 and PI3K/Akt pathways and thus, inhibition of ERK1/2 and PI3K/AKT activation decreases ESC-induced macrophage survival. Functionally, ESC-treated macrophages also showed a higher level of phagocytic activity. ESCs further serve to polarize BMDMs into M2-like macrophages that exhibit most tumor-associated macrophage phenotypic and functional features. ESC-educated macrophages produce high levels of arginase-1, Tie-2, and TNF-α, which participate in angiogenesis and contribute to teratoma progression. Our study suggests that induction of M2-like macrophage activation is an important mechanism for teratoma development. Strategies targeting macrophages to inhibit teratoma development would increase the safety of ESC-based therapies, inasmuch as the depletion of macrophages completely inhibits ESC-induced angiogenesis and teratoma development.
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影响因子：
3.7
作者：
Haagensen EJ;Thomas HD;Wilson I;Harnor SJ;Payne SL;Rennison T;Smith KM;Maxwell RJ;Newell DR
通讯作者：
Newell DR
影响因子：
14.8
作者：
Ben-David, Uri;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
82.9
作者：
Donnelly, SC;Haslett, C;Bucala, R
通讯作者：
Bucala, R
DOI：
10.1073/pnas.1312197110
发表时间：
2013-10-01
影响因子：
11.1
作者：
Cieslewicz, Maryelise;Tang, Jingjing;Pun, Suzie H.
通讯作者：
Pun, Suzie H.
影响因子：
20.3
作者：
Biswas, SK;Gangi, L;Sica, A
通讯作者：
Sica, A