Toll-Like Receptors on Human Mesenchymal Stem Cells Drive their Migration and Immunomodulating Responses

¹ Departments of Microbiology Immunology, Tulane University Health Sciences Center, New Orleans, LA 70112.
² Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112.

^* To whom correspondence should be addressed. E-mail: alibscan{at}tulane.edu.

	Abstract

Adult human bone marrow-derived mesenchymal stem cells (hMSCs) are under study as therapeutic delivery agents that assist in the repair of damaged tissues. To achieve the desired clinical outcomes for this strategy requires a better understanding of the mechanisms that drive the recruitment, migration and engraftment of hMSCs to the targeted tissues. It is known that hMSCs are recruited to sites of stress or inflammation to fulfill their repair function. It is recognized that toll-like receptors (TLRs) mediate stress responses of other bone marrow-derived cells. This study explored the role of TLRs in mediating stress responses of hMSCs. Accordingly, the presence of TLRs in hMSCs was established initially by RT-PCR assays. Flow cytometry and fluorescence immunocytochemical analyses confirmed these findings. The stimulation of hMSCs with TLR agonists led to the activation of downstream signaling pathways, including NF-B, AKT and MAPK. Consequently, activation of these pathways triggered the induction and secretion of cytokines, chemokines and related TLR gene products as established from cDNA array, immunoassay and cytokine antibody array analyses. Interestingly, the unique patterns of affected genes, cytokines and chemokines measured, identify these receptors as critical players in the clinically established immunomodulation, observed for hMSCs. Lastly, hMSCs migration was promoted by TLR ligand exposure as demonstrated by transwell migration assays. Conversely, disruption of TLRs by neutralizing TLR antibodies compromised hMSCs migration. This study defines a novel TLR-driven stress and immune modulating response for hMSCs that is critical to consider in the design of stem cell-based therapies.

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