Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes.
Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes.
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DOI：
10.1128/mbio.02109-15
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发表时间：
2016-01-26
期刊：
影响因子：
6.4
通讯作者：
Gao SJ
中科院分区：
文献类型：
--
作者：
Lee MS;Yuan H;Jeon H;Zhu Y;Yoo S;Shi S;Krueger B;Renne R;Lu C;Jung JU;Gao SJ
卡波西肉瘤（KS）是一种高度血管生成和侵袭性肿瘤，通常累及包括口腔在内的不同器官部位，由卡波西肉瘤相关疱疹病毒（KSHV）感染引起。在KS肿瘤细胞上已经鉴定出多种细胞标志物，但它们的起源仍然是一个谜。我们以前的研究表明，KSHV可以有效地感染，转化和重编程大鼠原代间充质干细胞（MSC）到KS样肿瘤细胞。在这项研究中，我们发现，来自不同器官，包括骨髓（MSCbm），脂肪组织（MSCa），牙髓，牙龈组织（GMSC）和脱落的乳牙的人原代MSC，是允许KSHV感染。我们成功地建立了KSHV感染的MSCa、MSCbm和GMSC（LTC-KMSC）的长期培养物。虽然LTC-KMSCs的增殖率低于未感染的细胞，但它们表达KS标志物的混合物，并显示出不同的血管生成、侵袭性和转化表型。遗传分析鉴定了KSHV衍生的microRNA，其通过激活AKT途径介导KSHV诱导的血管生成活性。这些结果表明，人骨髓间充质干细胞可能是KSHV的体内靶细胞，并建立了有效的模型，描绘KSHV感染，复制和恶性转化的生物学相关的细胞类型的机制。卡波西肉瘤是艾滋病患者最常见的癌症。虽然KSHV感染是卡波西肉瘤发展所必需的，但KSHV靶细胞的起源仍不清楚。我们表明，KSHV可以有效地感染不同来源的人原代间充质干细胞，并重新编程它们，以获得不同程度的卡波西肉瘤样细胞标志物和血管生成，侵袭性和转化表型。这些结果表明，人骨髓间充质干细胞可能是KSHV的靶细胞，并建立了揭示KSHV诱发恶性转化机制的模型。
Kaposi’s sarcoma (KS), a highly angiogenic and invasive tumor often involving different organ sites, including the oral cavity, is caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV). Diverse cell markers have been identified on KS tumor cells, but their origin remains an enigma. We previously showed that KSHV could efficiently infect, transform, and reprogram rat primary mesenchymal stem cells (MSCs) into KS-like tumor cells. In this study, we showed that human primary MSCs derived from diverse organs, including bone marrow (MSCbm), adipose tissue (MSCa), dental pulp, gingiva tissue (GMSC), and exfoliated deciduous teeth, were permissive to KSHV infection. We successfully established long-term cultures of KSHV-infected MSCa, MSCbm, and GMSC (LTC-KMSCs). While LTC-KMSCs had lower proliferation rates than the uninfected cells, they expressed mixtures of KS markers and displayed differential angiogenic, invasive, and transforming phenotypes. Genetic analysis identified KSHV-derived microRNAs that mediated KSHV-induced angiogenic activity by activating the AKT pathway. These results indicated that human MSCs could be the KSHV target cells in vivo and established valid models for delineating the mechanism of KSHV infection, replication, and malignant transformation in biologically relevant cell types. Kaposi’s sarcoma is the most common cancer in AIDS patients. While KSHV infection is required for the development of Kaposi’s sarcoma, the origin of KSHV target cells remains unclear. We show that KSHV can efficiently infect human primary mesenchymal stem cells of diverse origins and reprogram them to acquire various degrees of Kaposi’s sarcoma-like cell makers and angiogenic, invasive, and transforming phenotypes. These results indicate that human mesenchymal stem cells might be the KSHV target cells and establish models for delineating the mechanism of KSHV-induced malignant transformation.