Immunomodulatory Effect of Urine-derived Stem Cells on Inflammatory Bowel Diseases via Downregulating Th1/Th17 Immune Responses in a PGE2-dependent Manner

Abstract

Background and Aims Despite the therapeutic promise of stem cell therapy in the treatment of inflammatory bowel diseases [IBD], most donor cell populations have to be obtained via invasive approaches and often remain insufficiently validated. Urine-derived stem cells [USC] were recently shown to have regenerative properties and can be harvested in a safe, low-cost, and noninvasive way. This study aims to evaluate the immunomodulatory effect of USC and their efficacy in the management of IBD. Methods Human USC were isolated and expanded from the urine of healthy male adult volunteers [n = 3, age range 24–30 years]. USC were characterised by cell surface marker expression profile and multipotent differentiation. The in vitro immunomodulatory effect of USC was evaluated by co-culturing with human CD4+ T cells upon stimulation with phytohaemagglutinin [PHA]. The proliferation of CD4+ T was measured by fluorescence-activated cell sorting [FACS]. Cytokine array and quantitative real-time polymerase chain reaction [RT-PCR] were applied to examine cytokine levels. In vivo therapeutic value of USC was assessed using a murine colitis model induced by dextran sulphate sodium [DSS] or 2, 4, 6-trinitrobenzene sulphonic acid [TNBS]. The immunomodulatory effect of USC and bone marrow-derived mesenchymal stem cells [BMSC] was compared when co-cultured with CD4+ T cells. The therapeutic efficacy of USC and BMSC on IBD was compared when administered in an acute DSS model in vivo. Results USC were positive for mesenchymal stem cell markers but were negative for haematopoietic stem cell markers. These cells differentiated into osteo-, adipo-, and chondrogenic cell lineages. Similar to BMSC, the proliferation of CD4+ T cells was significantly inhibited when co-cultured with USC, as a consequence of Th1/Th17 immune response inhibition. Systemic administration of USC significantly ameliorated the clinical and histopathological severity of colitis and increased the survival rate in both acute and chronic murine colitis models. Moreover, implantation of USC led to downregulation of the Th1/Th17 immune responses in a PGE2-dependent manner. Conclusions This study demonstrated that implantation of USC reduces inflammation in an IBD rodent model via downregulation of Th1/Th17 immune responses, indicating that USC therapy serves as a potential cell-based therapeutic candidate treatment for IBD.

Cell Therapy With Mesenchymal Stem Cells Induces an Innate Immune Memory Response That Attenuates Experimental Colitis in the Long Term

“…Numerous immune responses have been implicated in the beneficial effect associated with cell therapy with MSCs. 6–10 In this study, we examined whether these beneficial effects are also maintained in the long term in a clinically relevant experimental model of colitis.…”

“…Regardless of the h-aMSC dose used and day of infusion of the h-aMSCs, a similar degree of colitis attenuation was observed in all instances, which accords with previous results published in the literature. 6 , 14 , 28 …”

“…Mesenchymal stem cells [MSCs] are used in a wide diversity of cell therapy protocols for treatment of inflammatory disorders, with very promising results. 2–5 Although an array of immune responses have been described with respect to the immunomodulatory action of MSCs, such as induction of cells with a regulatory phenotype, inhibition of inflammatory cells, and secretion of anti-inflammatory molecules, 6–12 among others, the precise mechanism of action of MSCs is not fully defined. The immune responses induced by MSCs can take place in a broad spectrum of in vivo conditions that include different sources of MSCs, cell doses, MHC context, and even the route of administration.…”

Urine-derived stem/progenitor cells: A focus on their characterization and potential

“…Stem cells, like USCs, could be beneficial based on their immunoregulatory effect controlling inflammation[ 86 ]. Indeed, Zhou et al[ 87 ] demonstrated that implantation of USCs in a rodent model reduced inflammatory bowel diseases. Systemic administration of USCs significantly ameliorated the clinical and histopathological severity of colitis and increased the survival rate in both acute and chronic murine colitis models.…”

Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications

“…MSCs can also inhibit monocyte differentiation into dendritic cells and skew them to a tolerogenic profile [ 19 ]. Moreover, effects of MSCs on suppression of T helper 1 (Th1) cells and Th17 proliferation [ 20 ] together with regulatory T cells (Tregs) expansion have also been documented in many inflammatory conditions [ 21 ].…”