Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling.

Objective: Mesenchymal stem cells (MSCs) are multipotent cells that are capable of differentiating into multilineages of the mesenchyme. MSCs were shown to have immune-modulating properties in vitro and were successfully used in vivo for controlling graft-versus-host disease, skin rejection, and modulation of inflammation. Our previous study suggested that human MSCs (hMSCs) block antigen-presenting cell (APC) maturation in a contact-dependent manner as well as induce the expression of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the molecular mechanisms that block initiation of immune responses by MSCs remains to be investigated.

Methods: A coculture system of hMSCs and APCs was used to study Signal Transducer and Activators of Transcription-3 (STAT3) activation using nonradioactive STAT3 transcription factor assay, flow cytometric immunostaining, and Western blotting.

Results: We show that the transcription factor STAT3 is constitutively activated in hMSCs, and upon coculturing with APCs, there is a significant increase in its activity in both cell types. This increase in STAT3 activity is independent of soluble factor(s) and requires cell-cell contact. Importantly, blocking STAT3 signaling in the APCs by specific inhibitors resulted in reduced IL-10 expression and reversal of hMSC-mediated inhibition of proinflammatory cytokines.

Conclusion: These findings suggest that APC's STAT3 plays a key role in mediating the immunomodulatory effects of hMSCs. Moreover, the induction of STAT3 signaling by hMSCs is mediated by a novel mechanism involving cell-cell interaction rather than the classical mechanism of induction by cytokines.