Adenoviral Transduction of Mesenchymal Stem Cells: In Vitro Responses and In Vivo Immune Responses after Cell Transplantation

Abstract

Adult mesenchymal stem cells (MSCs) are non-hematopoietic cells with multi-lineage potential which makes them attractive targets for regenerative medicine applications. However, to date, therapeutic success of MSC-therapy is limited and the genetic modification of MSCs using viral vectors is one option to improve their therapeutic potential. Ex-vivo genetic modification of MSCs using recombinant adenovirus (Ad) could be promising to reduce undesired immune responses as Ad will be removed before cell/tissue transplantation. In this regard, we investigated whether Ad-modification of MSCs alters their immunological properties in vitro and in vivo. We found that Ad-transduction of MSCs does not lead to up-regulation of major histocompatibility complex class I and II and co-stimulatory molecules CD80 and CD86. Moreover, Ad-transduction caused no significant changes in terms of pro-inflammatory cytokine expression, chemokine and chemokine receptor and Toll-like receptor expression. In addition, Ad-modification of MSCs had no affect on their ability to suppress T cell proliferation in vitro. In vivo injection of Ad-transduced MSCs did not change the frequency of various immune cell populations (antigen presenting cells, T helper and cytotoxic T cells, natural killer and natural killer T cells) neither in the blood nor in tissues. Our results indicate that Ad-modification has no major influence on the immunological properties of MSCs and therefore can be considered as a suitable gene vector for therapeutic applications of MSCs.

Genetically Modified Human Bone Marrow Derived Mesenchymal Stem Cells for Improving the Outcome of Human Islet Transplantation

“…These results are different from previously published reports that genetic modification of MSCs did not affect their differentiation potential [37], [38] and requires consideration of the effect of accumulated paracrine factors on the differentiation of genetically modified hBMSCs. Tracy et al have also shown that adenovirus transduction of BMSCs did not adversely affect their immunological properties as well as expression of chemokines and chemokine receptors [39]. However, they did not determine the effect of genetic modification on stemness as measured by expression of Nanog and Oct4 genes which are the key transcription factors for maintaining pluripotency and self-renewal potential of undifferentiated embryonic stem cells [40], [41].…”

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…While retrovirus and lentivirus vectors integrate their genetic material into the host cell genome [135], recombinant adenoviruses would not raise such safety concern; nevertheless, their direct systemic use can trigger potent immune responses against their own proteins instead [72,136]. Interestingly, Treacy et al [137] showed that adenoviral transduction of MSCs did not induce immune responses in vitro or after a single application in vivo. Furthermore, the expression levels of markers related to immune responses were not greatly modified when compared to using naïve cells.…”

The Biological Functions, Structure and Sources of CXCL10 and Its Outstanding Part in the Pathophysiology of Multiple Sclerosis

“…Chemokines are further subdivided into C, CC, CX3C and CXC subgroups according to the position of conserved cysteine motifs in their structure [14]. CXCL10 (interferon-γ-inducible protein 10, previously called IP-10) was initially discovered as a chemokine which is induced by interferon (IFN)-γ and is produced by a wide range of cell types including monocytes [15], neutrophils [16], endothelial cells [17], keratinocytes [18], fibroblasts [19], mesenchymal cells [20], dendritic cells [21], hepatocytes [22] and astrocytes [23]. CXCL10 binds to CXCR3, which is discussed in the next section.…”