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MBio. 2016 Jan 26;7(1):e02109-15. doi: 10.1128/mBio.02109-15.

Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes.

Author information

1
Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
3
Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea.
4
Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
6
Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
7
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA shoujiag@usc.edu.

Abstract

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.

IMPORTANCE:

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.

PMID:
26814175
PMCID:
PMC4742711
DOI:
10.1128/mBio.02109-15
[Indexed for MEDLINE]
Free PMC Article

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