Abstract
Therapeutic treatment of various inflammation-related diseases using mesenchymal stem cells (MSCs) has increased in recent years because of the paracrine action of these cells but shows several limitations. First, MSC-based therapies exhibit varying efficacies; thus, biomarkers should be determined to identify who may benefit from these candidate therapeutic agents. Second, the mechanism underlying the therapeutic effects is poorly understood. To evaluate the effects of human umbilical cord blood-derived MSCs (UCB-MSCs) on macrophages, the macrophage cell line NR8383 stimulated with lipopolysaccharide (LPS) was cocultured by UCB-MSCs. We found that UCB-MSCs mediated changes in macrophage polarization towards M2 from M1 macrophages. To identify the paracrine action underlying the anti-inflammation effect of UCB-MSCs, the secretion of UCB-MSCs exposed to LPS-stimulated NR8383 cells was tested using a biotin label-based 507 antibody array. Among the secreted proteins, we selected pentraxin-related protein PTX3/tumor necrosis factor-inducible gene 14 protein (PTX3) to investigate its association with UCB-MSCs in macrophage polarization. We found that human PTX3 was secreted from UCB-MSCs under inflammation condition and reinforced the M2 macrophage marker via the Dectin-1 receptor by activating MSK1/2 phosphorylation signaling in NR8383 cells. Accordingly, knockdown of PTX3 in UCB-MSCs significantly attenuated their therapeutic effects in a neonatal hyperoxic lung injury resulting in reduced survival, lung alveolarization, M2 marker expression, Dectin-1 levels, anti-inflammatory cytokines, and improved M1 marker expression and inflammatory cytokines compared to control MSC-injected rats. UCB-MSCs show therapeutic potential by controlling macrophage polarization. Interestingly, higher PTX3 levels in UCB-MSCs induced greater improvement in the therapeutic effects than lower PTX3 levels. Collectively, PTX3 is a potential marker with critical paracrine effects for predicting the therapeutic potential of MSC therapy in inflammatory diseases; quality control assessments using PTX3 may be useful for improving the therapeutic effects of UCB-MSCs.
Highlights
Mesenchymal stem cells (MSCs) exhibit the capacity for continuous self-renewal and for differentiation into specific cells, as well as the ability to regenerate damaged tissues and regulate various immune cell functions [1,2,3,4]
To analyze the macrophage polarization effect of Umbilical cord blood (UCB)-MSCs, rat alveolar macrophages (NR8383 cells) stimulated by LPS were cocultured with UCB-MSCs
CD11b was activated in LPS-stimulated NR8383 cells; this was significantly blocked by coculture with UCBMSCs
Summary
Mesenchymal stem cells (MSCs) exhibit the capacity for continuous self-renewal and for differentiation into specific cells, as well as the ability to regenerate damaged tissues and regulate various immune cell functions [1,2,3,4]. Recent studies reported that during inflammation regulation in various diseases, MSCs can induce macrophage polarization, through which therapeutic effects were observed such as suppressed inflammation and enhanced anti-inflammation [10,11,12]. According to a previous study, MSCs exposed to an inflammatory condition secrete tumor necrosis factor-inducible gene 6 (TSG6) or prostaglandin E2 (PGE2), which are known to be involved in macrophage polarization [22,23,24]. It is necessary to identify additional proteins involved in macrophage polarization induced by MSCs and determine the signaling mechanism that enhances anti-inflammation. To select highly efficient stem cells effective for treating inflammatory conditions, proteins secreted from MSCs were subjected to mass identification, and PTX3 (PTX3/TSG14, pentraxin-related protein PTX3/tumor necrosis factor-inducible gene 14 protein) was verified as a potential marker. The anti-inflammatory therapeutic mechanism of MSCs in inflammatory diseases was established, and we found that the selection criteria for MSCs predicted to exhibit outstanding efficacy may enhance the therapeutic effects of these cells
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