Bone marrow‐derived mesenchymal stem cells are capable of mediating hepatitis B virus infection in injured tissues

Rong, Qi-fei; Zhang, L.; Su, Enben; Li, J.; Liu, Z.; Huang, Zhong; Ma, Wanbiao; Cao, Kejiang; Huang, Jun

doi:10.1111/j.1365-2893.2008.00978.x

Cited by 12 publications

(11 citation statements)

References 36 publications

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“…Alternatively, BM-MSCs may secrete cytokines, including fibroblast growth factor (42,43), epidermal growth factor (EGF) (44), and hepatocyte growth factor (HGF) (43,45,46) to inhibit HBV replication (47). In addition, intracellular HBV cccDNA in BM-MSCs co-cultured with HepG2.2.15 cells was not detected, which supports the conclusion that HBV is unable to replicate in BM-MSCs (48,49). …”

Section: Discussionsupporting

confidence: 66%

Biological effects of bone marrow mesenchymal stem cells on hepatitis B virus in vitro

Zheng

Zhang

Shen

et al. 2017

Molecular Medicine Reports

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The aim of the present study was to explore the effects of co-culturing bone marrow-derived mesenchymal stem cells (BM-MSCs) cultured with hepatitis B virus (HBV)-infected lymphocytes in vitro. BM-MSCs and lymphocytes from Brown Norway rats were obtained from the bone marrow and spleen, respectively. Rats were divided into the following five experimental groups: Group 1, splenic lymphocytes (SLCs); group 2, HepG2.2.15 cells; group 3, BM-MSCs + HepG2.2.15 cells; group 4, SLCs + HepG2.2.15 cells; and group 5, SLCs + BM-MSCs + HepG2.2.15 cells. The viability of lymphocytes and HepG2.2.15 cells was assessed using the MTT assay at 24, 48 and 72 h, respectively. Levels of supernatant HBV DNA and intracellular HBV covalently closed circular DNA (cccDNA) were measured using quantitative polymerase chain reaction. Supernatant cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). T cell subsets were quantified by flow cytometry using fluorescence-labeled antibodies. In addition, the HBV genome sequence was analyzed by direct gene sequencing. Levels of HBV DNA and cccDNA in group 5 were lower when compared with those in group 3 or group 4, with a significant difference observed at 48 h. The secretion of interferon-γ was negatively correlated with the level of HBV DNA, whereas secretion of interleukin (IL)-10 and IL-22 were positively correlated with the level of HBV DNA. Flow cytometry demonstrated that the percentage of CD3+CD8+ T cells was positively correlated with the levels of HBV DNA, and the CD3+CD4+/CD3+CD8+ ratio was negatively correlated with the level of HBV DNA. Almost no mutations in the HBV DNA sequence were detected in HepG2.2.15 cells co-cultured with BM-MSCs, SLCs, or in the two types of cells combined. BM-MSCs inhibited the expression of HBV DNA and enhanced the clearance of HBV, which may have been mediated by the regulation of the Tc1/Tc2 cell balance and the mode of cytokine secretion to modulate cytokine expression.

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Section: Discussionsupporting

confidence: 66%

Biological effects of bone marrow mesenchymal stem cells on hepatitis B virus in vitro

Zheng

Zhang

Shen

et al. 2017

Molecular Medicine Reports

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“…We show that nonliver‐derived mesenchymal stem cells (UCMSCs) are turned permissive to the entire HBV life cycle upon in vitro hepatogenic differentiation. None of the few studies conducted on in vitro infection of other MSCs evaluated binding and uptake kinetics 28, 29. We set up infection conditions in order to analyze the different steps of the viral cycle and demonstrated that, although replication efficiency downstream of viral entry was quite low, HBV uptake was fully supported by D‐UCMSCs and comparable to PHHs.…”

Section: Discussionmentioning

confidence: 99%

Differentiated umbilical cord matrix stem cells as a newin vitromodel to study early events during hepatitis B virus infection

et al. 2013

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The role of cell differentiation state on hepatitis B virus (HBV) replication has been well demonstrated, whereas how it determines cell susceptibility to HBV entry is far less understood. We previously showed that umbilical cord matrix stem cells (UCMSC) can be differentiated towards hepatocyte-like cells in vitro. In this study we infected undifferentiated (UD-) and differentiated (D-) UCMSCs with HBV and studied the infection kinetics, comparing them to primary human hepatocytes (PHHs). UD-UCMSCs, although permissive to viral binding, had a very limited uptake capacity, whereas D-UCMSCs showed binding and uptake capabilities similar to PHHs. Likewise, asialoglycoprotein receptor (ASGPR) was up-regulated in UCMSCs upon differentiation. In D-UCMSCs, a dose-dependent inhibition of HBV binding and uptake was observed when ASGPR was saturated with known specific ligands. Subsequent viral replication was shown in D-UCMSCs but not in UD-UCMSCs. Susceptibility of UCMSCs to viral replication correlated with the degree of differentiation. Replication efficiency was low compared to PHHs, but was confirmed by (1) a dose-dependent inhibition by specific antiviral treatment using tenofovir; (2) the increase of viral RNAs along time; (3) de novo synthesis of viral proteins; and (4) secretion of infectious viral progeny. Conclusion: UCMSCs become supportive of the entire HBV life cycle upon in vitro hepatic differentiation. Despite low replication efficiency, D-UCMSCs proved to be fully capable of HBV uptake. Overall, UCMSCs are a unique human, easily available, nontransformed, in vitro model of HBV infection that could prove useful to study early infection events and the role of the cell differentiation state on such events. (HEPATOLOGY 2013;57:59-69)

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“…Conversely, BM-MSCs obtained from healthy donors fully supported HBV infection, replication, expression, and secretion, which could make the MSCs a reservoir of virus [ 42 ]. Furthermore, it has been reported that MSCs can serve as an extrahepatic virus reservoir by harboring and transporting HBV to the injured tissues after transplantation of HBV-exposed MSCs into myocardial infarction (MI) mouse model [ 47 ]. Although autologous BM-MSCs were resistant to HBV infection and were proven to be safe for transplantation, obtaining autologous BMSCs from chronic hepatitis B patients is too invasive and may cause distress to patients.…”

Section: Safety In Using Mscs As Cellular Therapy In Virus-relatedmentioning

confidence: 99%

Mesenchymal Stromal Cells and Viral Infection

Thanunchai

Hongeng

Thitithanyanont

2015

Stem Cells International

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Mesenchymal Stromal Cells (MSCs) are a subset of nonhematopoietic adult stem cells, readily isolated from various tissues and easily culture-expanded ex vivo. Intensive studies of the immune modulation and tissue regeneration over the past few years have demonstrated the great potential of MSCs for the prevention and treatment of steroid-resistant acute graft-versus-host disease (GvHD), immune-related disorders, and viral diseases. In immunocompromised individuals, the immunomodulatory activities of MSCs have raised safety concerns regarding the greater risk of primary viral infection and viral reactivation, which is a major cause of mortality after allogeneic transplantation. Moreover, high susceptibilities of MSCs to viral infections in vitro could reflect the destructive outcomes that might impair the clinical efficacy of MSCs infusion. However, the interplay between MSCs and virus is like a double-edge sword, and it also provides beneficial effects such as allowing the proliferation and function of antiviral specific effector cells instead of suppressing them, serving as an ideal tool for study of viral pathogenesis, and protecting hosts against viral challenge by using the antimicrobial activity. Here, we therefore review favorable and unfavorable consequences of MSCs and virus interaction with the highlight of safety and efficacy for applying MSCs as cell therapy.

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Bone marrow‐derived mesenchymal stem cells are capable of mediating hepatitis B virus infection in injured tissues

Abstract: These results indicate that MSCs could serve as an additional extrahepatic virus reservoir, which may play a role at least in part in mediating HBV trans-infection into the injured tissues through the process of MSCs recruitment.

Cited by 12 publications

References 36 publications

Biological effects of bone marrow mesenchymal stem cells on hepatitis B virus in vitro

Biological effects of bone marrow mesenchymal stem cells on hepatitis B virus in vitro

Differentiated umbilical cord matrix stem cells as a newin vitromodel to study early events during hepatitis B virus infection

Mesenchymal Stromal Cells and Viral Infection

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