Abstract
BackgroundThe use of bone marrow-derived human multipotent stromal cells (hMSC) in cell-based therapies has dramatically increased in recent years, as researchers have exploited the ability of these cells to migrate to sites of tissue injury, inflammation, and tumors. Our group established that hMSC respond to “danger” signals – by-products of damaged, infected or inflamed tissues – via activation of Toll-like receptors (TLRs). However, little is known regarding downstream signaling mediated by TLRs in hMSC.Methodology/Principal FindingsWe demonstrate that TLR3 stimulation activates a Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 1 pathway, and increases expression of suppressor of cytokine signaling (SOCS) 1 and SOCS3 in hMSC. Our studies suggest that each of these SOCS plays a distinct role in negatively regulating TLR3 and JAK/STAT signaling. TLR3-mediated interferon regulatory factor 1 (IRF1) expression was inhibited by SOCS3 overexpression in hMSC while SOCS1 overexpression reduced STAT1 activation. Furthermore, our study is the first to demonstrate that when TLR3 is activated in hMSC, expression of CXCR4 and CXCR7 is downregulated. SOCS3 overexpression inhibited internalization of both CXCR4 and CXCR7 following TLR3 stimulation. In contrast, SOCS1 overexpression only inhibited CXCR7 internalization.Conclusion/SignificanceThese results demonstrate that SOCS1 and SOCS3 each play a functionally distinct role in modulating TLR3, JAK/STAT, and CXCR4/CXCR7 signaling in hMSC and shed further light on the way hMSC respond to danger signals.
Highlights
Human MSC are excellent vehicles for cell-based therapeutics because they are isolated and can be exponentially expanded ex vivo
Conclusion/Significance: These results demonstrate that SOCS1 and SOCS3 each play a functionally distinct role in modulating TLR3, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and CXCR4/CXCR7 signaling in human multipotent stromal cells (hMSC) and shed further light on the way hMSC respond to danger signals
Among the 84 different JAK/STAT-related genes, we found that JAK2 was elevated 9.85-fold, the transcription factor interferon regulatory factor 1 (IRF1) was upregulated 16-fold, and SOCS1 was upregulated 21.11fold; several other genes were induced or inhibited at least 2fold following TLR3 stimulation (Table 1)
Summary
Human MSC are excellent vehicles for cell-based therapeutics because they are isolated and can be exponentially expanded ex vivo. The use of hMSC in cell-based therapies has dramatically increased in recent years, as researchers have exploited the ability of these cells to migrate to sites of tissue injury, inflammation, and tumors. Exposure of hMSC to TLR3 ligands may represent a distinct mechanism through which these cells sense danger signals and preferentially migrate to the target tissue in order to perform their reparative function. The use of bone marrow-derived human multipotent stromal cells (hMSC) in cell-based therapies has dramatically increased in recent years, as researchers have exploited the ability of these cells to migrate to sites of tissue injury, inflammation, and tumors. Our group established that hMSC respond to ‘‘danger’’ signals – by-products of damaged, infected or inflamed tissues – via activation of Toll-like receptors (TLRs). Little is known regarding downstream signaling mediated by TLRs in hMSC
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