Furthermore, CoCl 2-induced microRNA- (miR-) 146a expression regulated the secretion of inflammatory cytokines, whereas anti-miR-146a abolished CoCl 2-induced anti-inflammatory properties of hUCB-MSCs. Treatment with CoCl 2 was found to increase the anti-inflammatory effects of hUCB-MSCs in a HIF-1 О±- and ERK-dependent manner. In the present study, the role of CoCl 2 in the immunomodulation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) was examined.

Also, CoCl 2 has been shown to confer a protective effect on TNF- О±/IFN- Оі-induced inflammation in vitro. Treatment with the hypoxia-mimetic CoCl 2 is used to evaluate the effect of immune responses and delineate the underlying signaling mechanisms. Cobalt chloride (CoCl 2) is a hypoxia-mimetic compound that induces biochemical and molecular responses similar to those observed under hypoxic conditions. Of these, HIF-1 О± plays a key role in the cellular response against hypoxia by activating the transcription of various genes involved in the differentiation, colony formation, proliferation, and paracrine action of hMSCs. Hypoxia plays pivotal roles in the maintenance of hMSCs and is regulated by several transcriptional factors, including various hypoxia-inducible factors (HIFs).

Hence, the aim of the present study was to develop a method to enhance the immunosuppression of hMSCs and clarify the therapeutic effects of modified hMSCs. Improvement of immunomodulating properties is expected to enhance the therapeutic effects of hMSCs. Many studies have demonstrated that transplanted MSCs help prepare the inflammatory microenvironment by producing immunomodulatory factors that modulate the progression of inflammation. The release of paracrine/autocrine factors is a key mechanism of action of hMSCs.

Human mesenchymal stem cells (hMSCs), also termed as stromal cells, are isolated from a variety of tissues, including bone marrow, adipose tissue, and umbilical cord blood and are recognized as a promising therapeutic agent for clinical application because of their high proliferative capacity, multilineage differentiation potential, and immunomodulatory properties. These findings suggest that CoCl 2 may improve the therapeutic effects of hUCB-MSCs for the treatment of inflammatory diseases. Furthermore, pretreatment of transplanted MSCs with CoCl 2 can suppress lung inflammation more than naГЇve MSCs can in a mouse model of asthma. These data suggest that treatment with CoCl 2 enhances the immunosuppressive capacity of hUCB-MSCs through the ERK-HIF-1 О±-miR-146a-mediated signaling pathway. Hypoxia-inducible factor- (HIF-) 1 О± silencing and ERK inhibition abolished CoCl 2-induced miR-146a expression, suggesting that ERK and HIF-1 О± signals are required for CoCl 2-induced miR-146a expression in hUCB-MSCs. Treatment of hUCB-MSCs with CoCl 2 leads to increased expression of microRNA- (miR-) 146a, which was reported to modulate anti-inflammatory responses. Furthermore, the effect of CoCl 2 is exerted by promoting the expression of anti-inflammatory mediators (e.g., PGE 2) and inhibiting that of inflammatory cytokines (e.g., TNF- О± and IFN- Оі). Here, treatment with cobalt chloride (CoCl 2) was more effective than naГЇve hUCB-MSCs in suppressing inflammatory responses in a coculture system with phytohemagglutinin- (PHA-) activated human peripheral blood mononuclear cells (hPBMCs). hMSCs show enhanced therapeutic effects via paracrine secretion or cell-to-cell contact that modulates inflammatory or immune reactions. Human mesenchymal stem cells (hMSCs), including human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), which have high proliferation capacity and immunomodulatory properties, are considered to be a good candidate for cell-based therapies.