Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy?

Abstract

Core tip: Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract. A limited experience is available with hematopoietic and mesenchymal stem cell transplantation for the treatment of these conditions. Research is ongoing with other cell lines which have been used in conditions alike to inflammatory bowel disease and which will possibly have a therapeutic role in this condition.

INTRODUCTION

Inflammatory bowel disease (IBD) mainly consists of two clinical conditions, Crohn’s disease (CD) and ulcerative colitis (UC). It is mainly characterized by chronic, destructive inflammation of the gastrointestinal tract for which no curative treatment is currently available.

Its etiology is unknown, but it is accepted that it could be the result of loss of tolerance to intraluminal bowel antigens[1]. Genetic, environmental, and microbiological factors are involved in its development, together with morphological and functional changes in the intestinal barrier associated to an impaired immune response[2]. Early data supporting genetic involvement in the pathogenesis of IBD come from familial clinical studies showing a greater incidence in twins[3,4], first-degree relatives[5,6] and given ethnic groups[7,8]. Genome-wide association scan studies have allowed for identification of more than 163 loci associated to IBD[9], 73 genes associated to CD and 47 to UC[10], and overlapping genes for both conditions have also been found[11]. Genetic factors would however account for less than 25% of cases[12]. The exception is represented by a monogenic disorder referred to as IBD-like diseases, which are associated with severe colitis in childhood and have at most three loci alternatives[13]. On the other hand the increase of the incidence of IBD suggests that environmental factors are more important than genetic factors in the development of IBD[14].

Since IBD etiology is currently unknown, current treatment is intended to control the inflammatory intestinal process, thus avoiding irreversible structural damage. However, current therapeutic results are discouraging. Thirty-three percent of patients with CD do not respond to anti-TNF alfa therapy[15-18], and one third of responders loss the response[19]. Based on all the foregoing and on advances in understanding of the pathophysiological mechanisms involved in IBD development, new biological drugs and cell therapies are being investigated.

ADULT STEM CELLS

At present, HSCs and MSCs have been used in several clinical trials. However, up to now, the results are unpredictable. For additional information, the reader is referred to the recent review published by our group in 2014[20].

AMNIOTIC FLUID STEM CELLS

Amniotic fluid stem cells (AFSCs) are isolated from the excess of second-trimester amniotic fluid obtained during routine amniocentesis for prenatal diagnosis. Recently, AFSCs were used in a neonatal rat model of necrotizing enterocolitis, one of the primary causes of morbidity and mortality in neonates, showed a decrease in intestinal damage, an increase in gut tissue repair and a higher survival[59,60]. A better understanding of the AFSCs biology and mechanisms of action may help to develop strategies for their use in other IBD.

INDUCED PLURIPOTENT STEM CELLS

These are pluripotent cells derived from somatic cells by the introduction of reprogramming factors (Oct-4, Sox2, Kfl4, c-Myc, Nanog and Lin28). These pluripotent cells can be differentiated to any tissue specific cells to generate autologous cells for cell-replacement therapy[61]. Human intestinal organoids have recently been generated from these cell lines[62]. This will allow in the future for studying the pathophysiology of the disease and for testing new therapies, including generation of potentially viable tissues. Induced pluripotent stem cells (iPSCs) have been derived from somatic cells obtained from patients suffering a variety of diseases and important progress has been made in establishing preclinical iPSC-based disease models including IBD[63]. Although iPSCs do not have the ethical problems of embryonic stem cells, there are many similarities between them and, as a consequence, iPSCs could develop teratomas following transplantation, hindering their use in clinical trials.

INTESTINAL STEM CELLS

Intestinal stem cells (ISCs) are a rare population of fast-cycling Lgr5⁺ cells and slow-cycling Tert⁺/Bmi1⁺ cells situated above them at the crypt base. ISCs are in charge of the renewal of the intestinal epithelium which is changed every 4-5 d and in the regeneration of the intestinal epithelium after injury or inflammation[64]. It has been suggested that Lgr5⁺ cells and Tert⁺/Bmi1⁺ cells are two functionally different populations of ISCs[65]. Lgr5⁺ cells are responsible for the maintenance of the normal homeostatis conditions, whereas Tert⁺/Bmi1⁺ cells are more quiescent cells responsible for the intestinal epithelium regeneration under injury or inflammation conditions[66,67]. ISCs have proliferation and mutipotency capabilities, i.e., they are able to divide and later differentiate into all intestinal subtypes (enterocytes, globet cells, Paneth cells and neuroendocrine cells). Recently, research in the ISCs field has advanced greatly and many ISCs markers have been identified[68]. However, an exhaustive characterization of ISCs as well as the identification of specific markers still remains elusive[64].

Transplantation of fetal and adult ISCs expanded in vitro presented a strong engraftment and healing potential in a colonic injury model in mice[69,70]. However, ISCs in culture maintained as single cells have a very limited use in the study of the development of IBD and as a method for drug screening. Recently, intestinal organoids have been obtained from adult mouse and human ISCs[66,71,72]. These organoids were able to engraft and repair murine and human epithelium and represent an important step forward in the treatment of IBD[73]. Human organoids will be a very useful tool to study the pathological mechanisms of the disease from a specific patient and to test which is the best treatment to repair the intestinal epithelium for that patient. These organoids will be an important way to reach a more personalized medicine for IBD. These results highlight that those intestinal stem cells are a very promising source of stem cells for future patient-specific regeneration of the digestive tract[68].

ENDOTHELIAL PROGENITOR CELLS

Besides local inflammation, IBD is characterized by anomalous angiogenesis/vasculogenesis and severe damage in epithelial cells[74]. Important results have been obtained using endothelial progenitor cells (EPCs) for the treatment of hindlimb ischemia and myocardial ischemia. Recently, EPCs transplantation into fetal sheep showed an efficient migration and homing within the mucosal layer and a contribution to the vasculogenesis of the intestine[75]. These results suggest that EPCs could represent an additional source of cells for IBD cellular therapy, on their own or in combination with other stem cells such as MSCs.

TOLEROGENIC IMMUNE CELL THERAPIES

In inflammatory disorders, special interest has been given to therapeutic strategies that could enhance the patient´s tolerance response to intraluminal antigens. T-regulatory cells (Tregs) suppress immune responses of other cells and maintain tolerance to self-antigens. Tregs can be generated ex vivo by activation of both, murine and human CD4 T cells, suggesting that they could be an extra source of cells for cellular therapies in IBD. Intraperitoneal injection of induced Tregs in a mouse model of chronic colitis showed an attenuation of the preexisting gut inflammation response[76,77].

Dendritic cells (DCs) are antigen-presenting cells involved in immunity and tolerance. DCs seem to be the most important regulators of immune tolerance in the gastrointestinal system, however, extensive studies are necessary to understand their role in this tissue and their mechanisms of action[78]. Like MSCs, tolerogenic-DCs (tol-DCs) do not express neither MHCII nor the T-cell co-stimulatory molecules, and will not activate an immune response in the host. Ex vivo generated tolerogenic-DCS are available as a clinical grade product and used as therapeutic vaccines to restore antigen-specific tolerance in autoimmune diseases[78]. Tol-DCs have been used in very few recent clinical studies such as rheumatoid arthritis and other not inflammatory diseases, and as a result conclusions about their clinical efficiency are still elusive. Several mouse models of colitis showed an important effect of tol-DCs in the prevention and reduction of symptoms of IBD[79-83]. However, several questions must be resolved before tol-DCs can be used in IBD cellular therapy in humans, mostly due to the differences in IBD and tol-DCs between mice and humans[84].

CONCLUSION

The goal for stem cell-based therapy is to provide a permanent cure for IBD. To achieve this, it will be necessary to obtain a cellular product (original or genetically modified) that has a high migration and homes into the intestine, has high survival after transplantation, regulates the immune reaction which is not detectable to the patient’s immune system, and will repair the injured tissue. Intestinal tissue is composed of several cell types and IBD are characterized by widespread damage. Cell-based therapies will probably be designed as a combination of several cell types that will produce a synergic therapeutic response.

ACKNOWLEDGMENTS

The authors thank Mr. Ian Ure for the English grammar revision of this manuscript.

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