Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases

Abstract

Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. STEM CELLS 2016;34:1474-1486 SIGNIFICANCE STATEMENTThe advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward in the treatment and, possibly, the cure of chronic inflammatory conditions, including immune-mediated enteropathies. By virtue of the ability to favor tissue regeneration and expansion of T cells with regulatory function, mesenchymal stem cells seem the best candidate. Moreover, the lack of immunogenicity makes them perfectly suitable in these nonlifethreatening conditions as their infusion may be performed across histocompatibility locus antigen barriers without the immunoablative regimen. However, further investigations are needed to discover the underlying mechanisms of action of these novel therapeutic strategies.

Autoimmunity of Gastrointestinal Tract

“…Another therapy proposed is mesenchymal cell application (MSC)-used intraperitoneally, intravenously. However, the results are not conclusive, although a decrease of pro-inflammatory cytokines in mucous biopsy was noted [51,52].…”

“…The use of monoclonal antibodies against TNF and/or IL-6, different combinations of immunosuppressive drugs result in partial and terminal remission in majority of patients. These patients are candidates for HSCT, even in poor clinical condition, because only this therapy offers possibility to cure the disease and save their life [51]. As alternative to HSCT from unrelated donor, autoHSCT was used for such patients with success in five out of eight patients with five-year survival in 66% [52].…”

Above the Epitranscriptome: RNA Modifications and Stem Cell Identity

“…The natural stem cell types (ESCs, EpiSCs, and adult stem cells, ASCs, [ 170 , 177 , 178 ]), and those generated in vitro (induced pluripotent stem cells, iPSCs [ 179 , 180 , 181 ]) have self-renewal properties but differ for the capability to generate differentiated cells (see Table 3 for details). Moreover, ASCs have the capability to replace damaged cells with new healthy substitutes within the adult tissues/organs where they reside or after therapeutic implantation, as this property is maintained in degenerated tissues/organs [ 17 , 181 , 182 , 183 , 184 , 185 , 186 ]. Furthermore, the regenerative potential may be enhanced by the combination of the stem cells with gene therapy technology [ 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 ] or by their association with selected biomaterials [ 174 , 196 , 197 , 198 , 199 , 200 ].…”

Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology

“…In particular, local MSC administration was particularly efficacious in the treatment of perianal fistula, a complication of Crohn’s disease (CD)[39]. In addition, inhibition of pro-inflammatory cytokines and patients activated T-cell apoptosis was described as a cell-to-cell mediated mechanism of MSCs[16].…”

“…The body of evidence on the potential of MSCs is remarkable, but with conflicting results in terms of efficacy, especially for systemic administration in luminal IBD[39]. In this context, there are some unresolved clinical issues.…”