Accumulating literature has showed MSCs and HSCs may be bene

Accumulating literature has showed MSCs and HSCs may be beneficial for CD patients. We searched all studies available to evaluate clinical efficacy and safety of stem gnrh agonists in severe refractory CD. Located in bone marrow, HSCs can give rise to all blood cells and transplanted HSCs can reconstitute the hematopoietic system of the hosts [5]. HSCs transplantation is widely considered to be a potential therapy for severe autoimmune diseases [6]. With the synergistic effect of adhesion molecules and platelets, HSCs are able to home to the injured tissues [7]. Originally isolated from bone marrow, MSCs can also be isolated from a variety of other sources such as placenta, umbilical cord, adipose tissue, teeth and menstrual fluid [8]. Bone marrow-derived MSCs are best characterized for their biological functions and most widely used for immunoregulation and regenerative cell therapy [9–11]. Like HSCs, they are also capable of migrating to injured tissues. In contrast to HSCs, MSCs transplantation do not induce graft-versus-host-disease (GVHD) and have even been used to treat GVHD [12].
Methods
Review of objectives
Discussion Inflammatory bowel diseases include UC and CD. Though they share similar pathologic and epidemiological features, the clinical manifestations differ from each other [34]. Unlike UC, CD causes intestinal transmural inflammation (ulceration) and fistulas may occur in up to 50% of the patients [2]. Moreover, the global incidence and prevalence of CD are increasing [35]. To date, much progress has been made in the pharmacological therapy for CD [36]. CD therapy is based on a so-called step-up approach. 5-Aminosalicylates remain a mainstay of treating first-episode CD. If it failed, patients would be given by glucocorticoids to achieve rapid symptom relief. For further therapy, glucocorticoids would be followed by methotrexate or acetazolamide or 6-MP or cyclosporine follow to gain long-term disease control [37]. For patients with severe CD who fail corticosteroids and immunosuppressor such as methotrexate, then biological agents are a viable alternative. They target specific molecules. Infliximab, one of anti-TNF agents, is a chimeric monoclonal antibody directed against the proinflammatory cytokine tumor necrosis factor-α, and has been approved by the US Food and Drug Administration for use in moderate to severe CD. Anti-adhesion molecules represent a new promising immunomodulatory therapy in CD. Vedolizumab is a monoclonal antibody, blocking the pathway of mucosal addressin cell adhesion molecule-1, was approved in May 2014 for treating CD [38]. The ultimate goal for CD therapy is to gain sustained clinical and endoscopic remission [39]. Nevertheless, there are still about half of CD patients who do not response to pharmacological therapy and have to receive intestinal resection in about 10 years after CD onset [40]. Stem cells can home to the damaged tissues and differentiate into specific cells to help restore tissue function or regulate host immune function through an army of cytokine and signaling molecules [41–43]. Before HSC transplantation, patients need to undergo a high-dose immune ablation regimen to eliminate T-lymphocytes and memory T cells. After retransfusion of HSCs, they generate naïve cells and restore the immune system [44]. In addition, HSCs may integrate into the existing tissues and differentiate into other types of cells [42]. MSCs may exert its action by immunoregulation [43]. To be more exciting, Sanchez et al. [45] have shown for the first time that specific inhibition of SMAD-2/3 signaling pathway in hESCs facilitates the conversion of hESCs into multipotent MSCs with fully immunosuppressive and anti-inflammatory properties in vivo, opening up new avenues for future clinical applications of MSCs. Information on homing and differentiation of transplanted stem cells in the injured intestines are rapidly accumulating. In indomethacin (IDM)-treated rats, Qu et al. [46] found that transplanted BM-MSCs labeled with PKH26 resided in the injured intestinal areas, mainly in the crypts and villi. Surprisingly, cotransplanted stem cells expressed Lgr-5, a marker of intestinal stem cells (ISCs) two weeks after cell transfusion [46,47], which indicated that transplanted stem cells are capable of migrating to the damaged tissue and further transdifferentiate into ISCs to restore epithelium function.