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Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review
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Journal of Cellular Immunotherapy xx (2016) 1e7 http://www.elsevier.com/locate/jocit
Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review Lei Ye a, Xiao-Wei Wu a, Na Yu a, Jing-Xin Pan b, Lian-Ming Liao c, Fang-Yu Wang a,*
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a
Department of Gastroenterology and Hepatology, Jinling Hospital, Medicine School of Nanjing University, Nanjing 210002, China b Medicine School of Nanjing University, Nanjing 210009, China c Central Laboratory, Union Hospital of Fujian Medical University, Fuzhou 350000, China Received 15 September 2015; revised 15 January 2016; accepted 15 January 2016 Available online ▪ ▪ ▪
Abstract Background: Refractory Crohn's disease, especially when complicated by complex perianal fistula, seriously reduces the patients' quality of life. Preclinical and clinical studies indicate stem cells may be a promising therapy for refractory Crohn's disease. Objective: To systematically review evidence on clinical efficacy and safety of stem cells in refractory Crohn's disease. Methods: A detailed search was performed to identify randomized controlled trials (RCT), systematic reviews of RCTs or high-quality nonRCTs published before September 2015 in the Cochrane Library, PubMed, Medline, EMBASE, and the ISI Web of Knowledge databases. Search terms included: MSC (mesenchymal stem cell), stem cells, HSC (hematopoietic stem cell), IBD (inflammatory bowel disease), CD (Crohn's disease), UC (ulcerative colitis). Two authors independently extracted data for analysis using predefined selection criteria and quality indicators. Trials were also retrieved from the website of www.Clinicaltrials.gov. Results: 18 of the 225 articles identified met the inclusion criteria. However, there were only two studies that had control groups. Therefore, a brief qualitative analysis of the evidence was considered to be more adequate. It seems stem cells can reduce Crohn's Disease Activity Index (CDAI) and help alleviate CD symptoms. Moreover, the incidence of serious adverse events caused by stem cell transplantation was very low (1.75%, 7/400). Conclusions: Stem cell therapy for CD is very promising, but large, multicenter and randomized clinical trials are needed to further support their therapeutic benefits. Copyright © 2016, Shanghai Hengrun Biomedical Technology Research Institute. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Stem cells; Crohn's disease; Clinical efficacy; Mesenchymal stem cell; Hematopoietic stem cell
ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Research question and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Eligibility criteria for the review (PICOS elements) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Critical evaluation and quality assessment . . . . . . . . 1.6. Results and data synthesis . . . . . . . . . . . . . . . . . . . . . . . . * Corresponding author. Department of Gastroenterology and Hepatology, 2. Review of objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jinling Hospital, Medicine School of Nanjing University, 305 Zhongshan East 2.1. Do patients response to the stem cell-based therapies? Road, Nanjing 210002, Jiangsu Province, China. E-mail address: [email protected] (F.-Y. Wang). Peer review under responsibility of Shanghai Hengrun Biomedical Technology Research Institute.
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Is there any remission in signs or symptoms of Crohn’s
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http://dx.doi.org/10.1016/j.jocit.2016.01.001 2352-1775/Copyright © 2016, Shanghai Hengrun Biomedical Technology Research Institute. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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2.3. Whether adverse events are acceptable? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The etiology of Crohn's disease (CD) is still not well understood. Interaction among the gut microbiota, the intestinal mucosa and the host immune system has been implicated in the pathogenesis of CD [1]. Perianal fistula is the most notorious complication of CD, which is formidable for both patients and clinicians, as there are around 25e30% patients having no other alternative choices but accepting surgery [2]. The past two decades have seen an explosion of scientific and clinical interest in stem cell transplantation for a variety of diseases including CD. There are several kinds of candidate stem cells with potential application for CD, such as hematopoietic stem cells (HSCs), amniotic fluid stem cells (AFSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) [3]. Among them, HSCs and MSCs have been evaluated in clinical trials [4]. Thus, the present review will focus on published clinical trials using HSCs and MSCs. 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 cells 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 [9e11]. Like HSCs, they are also capable of migrating to injured tissues. In contrast to HSCs, MSCs transplantation do not induce graft-versus-hostdisease (GVHD) and have even been used to treat GVHD [12]. 2. Methods 2.1. Research question and objectives This review aimed to answer the following question: Is autologous/allogeneic stem cell transplantation a safe and effective treatment for refractory CD? The primary objectives were to assess whether patients receiving stem cells transplantation achieved:
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1. any response to the stem cell-based therapies; 2. any alleviation in both clinical symptoms and endoscopic findings of CD; The secondary objectives were to assess whether the frequency and nature of adverse events was acceptable. 2.2. Data sources The search strategy was developed in accordance with the Center for Reviews and Dissemination's Guidance for Systematic Reviews in Health Care [13] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. The Cochrane Library, PubMed, Medline, EMBASE, and the ISI Web of Knowledge databases were searched for papers published from the data of the database set-up to September 2015 using the following key words: MSC (mesenchymal stem cell), stem cells, IBD (inflammatory bowel disease), CD (Crohn's disease), UC (ulcerative colitis), and combined words using Boolean logic (AND, OR). We also searched ClinicalTrials.gov for relevant clinical studies. To increase sensitivity, no restrictions were placed on study/trial/review type. 2.3. Eligibility criteria for the review (PICOS elements) Detailed information on the participants, interventions, comparisons, and outcomes to be included was provided in Table 1, as advocated by the 2009 Centre for Reviews and Dissemination handbook. 2.4. Study selection Two investigators (LY and NY) undertook the initial screen of titles and abstracts. Any disagreement about selection decisions was then discussed until concordance was reached. Full manuscripts of papers identified as potentially relevant were reviewed independently by the same two authors according to the pre-specified eligibility criteria showed in Table 1. Duplicate articles and those published in a language other than English were excluded. The selection process was showed in Fig. 1. 2.5. Critical evaluation and quality assessment Researches may vary considerably in methodology in the design or conduct of a study, obscuring the benefit/harm of an
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Table 1 Pre-specified eligibility criteria. Participants
Interventions
Comparison
Outcomes
Study types
CD patients, age 18yr Refractory to or unsuitable for current available therapies
Autologous/Allogeneic MSCs Autologous/Allogeneic HSCs
Self-control or placebo controls using fibrin glue or routine therapies
Clinical/Endoscopic remission/response (defined by CADI) perianal fistulas healing/closure SAEs should be included
RCTs/Systematic reviews of RCTs/high-quality Non-RCTs
CD: Crohn's disease; yr: year; MSCs: mesenchymal stem cells; HSCs: hematopoietic stem cells; CDAI: Crohn's Disease Activity Index; SAEs: serious adverse events; RCT: randomized controlled trials.
intervention. Each study included in a review must therefore undergo a quality assessment process. In accordance with the Cochrane Reviewers' Handbook and the Newcastle-Ottawa [15], each literature was assessed by the same investigators. Disagreement was resolved according to the pre-defined criteria. 2.6. Results and data synthesis Data extraction sheets were completed for each study. Quantitative data analyses were performed for eligible studies with adequate data; due to study heterogeneity and the small number of incorporated studies, meta-analysis was considered inappropriate for this review. Therefore, a brief qualitative analysis of the evidence was presented in narrative form shown in Tables 2e4. 3. Review of objectives 3.1. Do patients response to the stem cell-based therapies? As shown in Tables 2e4, a total of 18 articles were eligible for the qualitative analyses. To be more specific, there were 6 clinical trials using HSCs and 12 using MSCs respectively. Clinical response was defined as a decrease in Crohn's Disease Activity Index (CDAI) >100. Endoscopic improvement referred to a decrease of Crohn's disease endoscopic index of severity greater than 5, or a Crohn's disease endoscopic index of severity of less than 3. Considering some patients have developed perianal fistulas, the combined measurement of clinical response was defined as fistula closure. Totally there were 483 patients (Tables 2e4) with 400 evaluable CD patients. The data concerning luminal CD was limited. Five available studies had 45 CD patients, with improvement in clinical signs in 42. The results indicated a promising role of MSCs in CD therapy. As regarding the local treatment of perianal CD, similar satisfactory results have been published. Tow recently published studies [31,32], one study showed that a complete closure was achieved in 27 out of 33 patients after the final injection of ASCs [32]. However, a study conducted by Herreros et al. [33] including 200 participants stated that ASCs alone or in combination with fibrin glue was equivalent to fibrin glue alone.
3.2. Is there any remission in signs or symptoms of Crohn's disease? Of the six studies examining the efficacy of HSCs, the results were encouraging. Among 66 patients, 57 CD patients achieved complete remission as indicated by physical examination, CDAI level (CDAI < 150), bowel ultrasound sonography and/or radiological exam [16e21]. HSCs transplantation seemed to be superior to MSCs transplantation in terms of remission rate (86.36% (57/66) vs 44.90% (154/ 343)). However, due to the heterogeneity of the studies, caution should be took when HSCs and MSCs are compared with. What's more, there were few patients receiving HSCs transplantation. On the contract, there were 2 multicenter, randomized and double-blinded trials that evaluated the efficacy of MSCs [28,33]. Preparation of MSCs is more easy and cheaper than that of HSCs, which needs leukapheresis. In addition, no donorrecipient matching is required for on-the-shelf MSCs from donors (such as Prochymal™) [22], which is in contract to HSCs, for it may cause GVHD after transplantation. 3.3. Whether adverse events are acceptable? Each study evaluated the safety of the treatment and found that the incidence of serious adverse events (SAEs) was low. Only 3 studies reported several cases of SAEs (Tables 2e4). Hasselblatt et al. [19] reported 4 individuals who developed SAEs during stem cell mobilization. Of which, one patient suffered prolonged neutropenic fever and reversible acute renal failure as well as vaginal bleeding. Lopez-cubero et al. [20] recorded 1 case of SAEs. During the long-term follow-up period (4.5e15.3 yr), 1 patient developed septicemia which was considered to be not related to stem cell therapy. In another study reported by De la Portilla et al. [30], there were 2 cases of SAEs, which were “pyrexia” and “perianal abscess”respectively. Overall, the incidence of SAEs was low. 4. Discussion Up to now, mechanisms for stem cells in treating CD are still not well understood. Stem cells may suppress the immune reaction in injured tissues and differentiate into epithelia cells to promote tissue healing. However, what happens during the differentiation process remains mysterious. In the present review, we included 6 and 12 trials using HSCs and MSCs respectively. Despite variations in dosage, timing, and
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Fig. 1. A PRISMA diagram outlining the search strategy and study selection.
frequency of administration, stem cells seemed to significantly benefit the patients with refractory CD in terms of both
primary and secondary endpoints. These results were very encouraging.
Table 2 Hemapoietic stem cells transplantation studies in Crohn's disease. Study ID
Participants
Procedure
Remission (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Oyama et al. [16] Burt et al. [17]
12 24
Autologous HSCs Autologous HSCs
Clinical:11 (12 m) Clinical:24 (6e12 m)
None 1SAEs not related
Cassionotti et al. [18]
10
Autologous HSCs
Clinical:10 (3 m) Endoscopic:5 (3 m)
None
Hasselblatt et al. [19]
12
Autologous HSCs
Lopez-cubero et al. [20] Hommes et al. [21]
6 (5 evaluable) 3
Allogeneic HSCs Autologous HSCs
Clinical:5 (6 m) Endoscopic:5 (6 m) Clinical:4 (4.5e15.3 yr) Clinical:3 (5e6 yr)
4SAES related (fever, renal failure) 1SAEs related septicemia None
1 (15 m) 9% (12 m) 37% (24 m) 43% (36 m) 61% (48 m) 81% (60 m) 20% (12 m) 50% (24 m) 60% (36 m) 70% (48 m) 70% (60 m) 7 (37.2 m) 1 (1.5 yr) 1 (2 yr)
HSCs: hematopoietic stem cells; m: month; yr: year; SAEs: serious adverse events. Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Table 3 Mesenchymal stem cell transplantation studies in luminal Crohn's diseases. Study ID
Participants
Procedure
Response/Remission (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Onken et al. [22] Duijvestein et al. [23]
10 (9 evaluable) 10 (6 evaluable)
Prochymal™ Autologous BMMSCs
1SAES unrelated None
NA NA
Liang et al. [24]
7 (4CD/3UC)
None
2 (6e7 m)
Forbes et al. [25]
16 (15 evaluable)
Allogeneic BMMSCs/UC-MSCs Allogeneic BMMSCs
1SAES unrelated
NA
Lazebnik et al. [26]
50 (11CD/39UC)
Allogeneic BMMSCs
Clinical:9/3 (14 d) Clinical:3/0 (6 w) Endoscopic:2/0 (6 w) Clinical:7/3 (3 m) Endoscopic:3/0 (3e5 m) Clinical:12/8 (42 d) Endoscopic:7/0 (42 d) Clinical:11/0 (4e8 m, CD) 39/0 (4e8 m, UC)
NA
NA
CD: Crohn's disease; UC: ulcerative colitis; BMMSCs: Bone marrow-derived MSCs; UC-MSCs: umbilical cord-derived MSCs; Prochymal™: Ex vivo cultured mesenchymal stem cells from marrow of screened, healthy volunteers; SAES: serious adverse events; NA: Not available. d: day; w: week; m: month.
Table 4 Mesenchymal stem cell transplantation studies in perianal Crohn's diseases. Study ID
Participants
Procedure
Response/Closure (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Garcia-Olmo et al [27] Garcia-Olmo et al [28]
5 (4 evaluable) 49 (14CD)
8 Fistulas in 4:2/6 (8 w) Group A:NA/1 (7CD, 8 w) Group B:2/5 (7CD, 8 w)
None None
NA Group B:3 (12 m) Data for CD:NA
Ciccocioppo et al. [29] De la Portilla et al. [30]
12 (10 evaluable) 24 (22 evaluable)
Autologous ASCs Autologous Group A:25 (7CD) ASCs þ Fg Group B:24 (7CD) Fg Autologous BMMSCs Allogeneic ASCs
3/7 (12 m) 23 Fistulas in 22:5/18 (6 m)
None (12 m) NA
Cho et al. [31] Lee et al. [32] Herreros et al. [33]
10 33 200
Autologous ASCs Autologous ASCs Autologous Group A: ASCs Group B: ASCs þ Fg Group C: Fg
1/3 (2 m) 5/27 (2 m) Group A: NA/25 (12 w) Group B: NA/26 (12 w) Group C: NA/22 (12 w)
None 2SAES Pyrexia Perianal abscess None None None
3 (8 m) 3 (12 m) NA
CD: Crohn's disease; ASCs: Adipose-derived MSCs; Fg: Fibrin glue; SAES: serious adverse events; NA: Not available; w: week; m: month.
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 stepup 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 longterm 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-a, 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 [41e43]. 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
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Table 5 Large ongoing Phase III trials using stem cells for perianal Crohn's diseases. Trial code
Condition
Sponsor
Status
Intervention
Enrollment
NCT0154157 NCT00482092
Perianal fistula Perianal fistula
Tigenix Osiris Therapeutics
Active, not recruiting Active, not recruiting
Two groups: ASCs, placebo Three groups: Placebo High-dose ASCs Low-dose ASCs
208 270
ASCs: Adipose-derived MSCs; Source: Clinicaltrials.gov.
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. While a large number of clinical trials have been completed or underway, there is a lack of strong evidence of their effectiveness and safety. Some experts pointed out that autologous transplantation may put patients at a risk of receiving the genetically defective immune cells, while allogeneic transplantation has a potential to cause myeloablation [35]. Moreover, recent studies stated that cultured MSC may undergo transdifferentiation into proinflammatory cells in the chronic inflammatory environment. Yasuhiro et al. [48] first demonstrated that MSCs secreted IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in bone marrow. More researches are needed to further understand the mechanisms of stem cells before they enter clinical application. We still do not know what kind of stem cells is best for CD. In addition to HSCs and MSCs, amniotic fluid stem cells have been used and the results were encouraging [49]. IFN-g-treated human amniotic fluid stem cells could inhibit T-cell proliferation and increase CD4(þ) CD25(þ) FOXP3(þ) regulatory T cells. In vivo, IFN-g-treated human amniotic fluid stem cells were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. Thus, amniotic fluid stem cells may be a new source of stem cells for immunotherapy. There exit several limitations of the review. First, the number of included studies was small and none of these trials were RCT. Second, most of the trials enrolled a few patients. In one trial with 200 patients enrolled, there was no greater improvement in patients receiving ASCs and fibrin glue compared to that receiving fibrin glue alone. Third, quantitative data analyses could not be performed due to heterogeneity in designing, classifications of fistulas, treatment and the duration of follow-up.
5. Conclusion Stem cell therapy is a field that has developed considerably in the past decade. Currently available clinical data indicates that stem cell therapy for CD is very promising. In spite of the huge accomplishments, stem cell-based therapy is still in its infancy. There are only 2 ongoing Phase III trials using stem cells for the treatment of CD (Table 5). However, there is a long way to go before they are officially approved to be used for CD. Further large randomized trials are warranted. Enormous advances are needed to bridge the translational gap between the benchtop researches and clinical applications of stem cells for CD. Author contributions Ye L and Wang FY designed the study; Ye L, Pan JX and Yu N searched all articles; Ye Land Wu XW developed the methodology; Ye L, Wu XW, Yu N, Liao LM and Wang FY wrote the manuscript. Conflict of interest
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None. References [1] Fofanova TY, Petrosino JF, Kelermayer R. Microbiome-epigenome interactions and the environmental origins of inflammatory bowel diseases. J Peiatr Gastroenterol Nutr 2015 Aug 21 [Epub ahead of Q3 print]. [2] Nielsen OH, Rogler G, Hahnloser D, Thomsen OO. Diagnosis and management of fistulizing Crohn's disease. Nat Clin Pract Gastroenterol Hepatol 2009;6(2):92e106. [3] Flores AI, Gomez-Gomez GJ, Masedo-Gonzaiez A, MartinezMontiel MP. Stem cell therapy in inflammatory bowel disease: a promising therapeutic strategy? World J Stem Cells 2015;7(2):343e51. [4] Gazouli M, Roubelakis MG, Theodoropoulos GE. Stem cells as potential targeted therapy for inflammatory bowel disease. Inflamm Bowel Dis 2014;20(5):952e5. [5] Hongbao Ma, Young Margaret, Yan Yang, Huaijie Zhu, Yucui Zhu. Hematopoietic stem cells. Stem Cell 2015;6(1). [6] Muraro PA, Uccelli A. Immuno-therapeutic potential of haematopoietic and mesenchymal stem cell transplantation in MS. Results Probl Cell Differ 2010;51:237e57. [7] Kavanagh DP, Kalia N. Hematopoietic stem cell homing to injured tissues. Stem Cell Rev 2011;7:672e82. [8] Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 2011;14(9):12.
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Journal of Cellular Immunotherapy xx (2016) 1e7 http://www.elsevier.com/locate/jocit
Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review Lei Ye a, Xiao-Wei Wu a, Na Yu a, Jing-Xin Pan b, Lian-Ming Liao c, Fang-Yu Wang a,*
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a
Department of Gastroenterology and Hepatology, Jinling Hospital, Medicine School of Nanjing University, Nanjing 210002, China b Medicine School of Nanjing University, Nanjing 210009, China c Central Laboratory, Union Hospital of Fujian Medical University, Fuzhou 350000, China Received 15 September 2015; revised 15 January 2016; accepted 15 January 2016 Available online ▪ ▪ ▪
Abstract Background: Refractory Crohn's disease, especially when complicated by complex perianal fistula, seriously reduces the patients' quality of life. Preclinical and clinical studies indicate stem cells may be a promising therapy for refractory Crohn's disease. Objective: To systematically review evidence on clinical efficacy and safety of stem cells in refractory Crohn's disease. Methods: A detailed search was performed to identify randomized controlled trials (RCT), systematic reviews of RCTs or high-quality nonRCTs published before September 2015 in the Cochrane Library, PubMed, Medline, EMBASE, and the ISI Web of Knowledge databases. Search terms included: MSC (mesenchymal stem cell), stem cells, HSC (hematopoietic stem cell), IBD (inflammatory bowel disease), CD (Crohn's disease), UC (ulcerative colitis). Two authors independently extracted data for analysis using predefined selection criteria and quality indicators. Trials were also retrieved from the website of www.Clinicaltrials.gov. Results: 18 of the 225 articles identified met the inclusion criteria. However, there were only two studies that had control groups. Therefore, a brief qualitative analysis of the evidence was considered to be more adequate. It seems stem cells can reduce Crohn's Disease Activity Index (CDAI) and help alleviate CD symptoms. Moreover, the incidence of serious adverse events caused by stem cell transplantation was very low (1.75%, 7/400). Conclusions: Stem cell therapy for CD is very promising, but large, multicenter and randomized clinical trials are needed to further support their therapeutic benefits. Copyright © 2016, Shanghai Hengrun Biomedical Technology Research Institute. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Stem cells; Crohn's disease; Clinical efficacy; Mesenchymal stem cell; Hematopoietic stem cell
ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Research question and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Eligibility criteria for the review (PICOS elements) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Critical evaluation and quality assessment . . . . . . . . 1.6. Results and data synthesis . . . . . . . . . . . . . . . . . . . . . . . . * Corresponding author. Department of Gastroenterology and Hepatology, 2. Review of objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jinling Hospital, Medicine School of Nanjing University, 305 Zhongshan East 2.1. Do patients response to the stem cell-based therapies? Road, Nanjing 210002, Jiangsu Province, China. E-mail address: [email protected] (F.-Y. Wang). Peer review under responsibility of Shanghai Hengrun Biomedical Technology Research Institute.
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Is there any remission in signs or symptoms of Crohn’s
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http://dx.doi.org/10.1016/j.jocit.2016.01.001 2352-1775/Copyright © 2016, Shanghai Hengrun Biomedical Technology Research Institute. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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2.3. Whether adverse events are acceptable? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The etiology of Crohn's disease (CD) is still not well understood. Interaction among the gut microbiota, the intestinal mucosa and the host immune system has been implicated in the pathogenesis of CD [1]. Perianal fistula is the most notorious complication of CD, which is formidable for both patients and clinicians, as there are around 25e30% patients having no other alternative choices but accepting surgery [2]. The past two decades have seen an explosion of scientific and clinical interest in stem cell transplantation for a variety of diseases including CD. There are several kinds of candidate stem cells with potential application for CD, such as hematopoietic stem cells (HSCs), amniotic fluid stem cells (AFSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) [3]. Among them, HSCs and MSCs have been evaluated in clinical trials [4]. Thus, the present review will focus on published clinical trials using HSCs and MSCs. 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 cells 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 [9e11]. Like HSCs, they are also capable of migrating to injured tissues. In contrast to HSCs, MSCs transplantation do not induce graft-versus-hostdisease (GVHD) and have even been used to treat GVHD [12]. 2. Methods 2.1. Research question and objectives This review aimed to answer the following question: Is autologous/allogeneic stem cell transplantation a safe and effective treatment for refractory CD? The primary objectives were to assess whether patients receiving stem cells transplantation achieved:
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1. any response to the stem cell-based therapies; 2. any alleviation in both clinical symptoms and endoscopic findings of CD; The secondary objectives were to assess whether the frequency and nature of adverse events was acceptable. 2.2. Data sources The search strategy was developed in accordance with the Center for Reviews and Dissemination's Guidance for Systematic Reviews in Health Care [13] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. The Cochrane Library, PubMed, Medline, EMBASE, and the ISI Web of Knowledge databases were searched for papers published from the data of the database set-up to September 2015 using the following key words: MSC (mesenchymal stem cell), stem cells, IBD (inflammatory bowel disease), CD (Crohn's disease), UC (ulcerative colitis), and combined words using Boolean logic (AND, OR). We also searched ClinicalTrials.gov for relevant clinical studies. To increase sensitivity, no restrictions were placed on study/trial/review type. 2.3. Eligibility criteria for the review (PICOS elements) Detailed information on the participants, interventions, comparisons, and outcomes to be included was provided in Table 1, as advocated by the 2009 Centre for Reviews and Dissemination handbook. 2.4. Study selection Two investigators (LY and NY) undertook the initial screen of titles and abstracts. Any disagreement about selection decisions was then discussed until concordance was reached. Full manuscripts of papers identified as potentially relevant were reviewed independently by the same two authors according to the pre-specified eligibility criteria showed in Table 1. Duplicate articles and those published in a language other than English were excluded. The selection process was showed in Fig. 1. 2.5. Critical evaluation and quality assessment Researches may vary considerably in methodology in the design or conduct of a study, obscuring the benefit/harm of an
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Table 1 Pre-specified eligibility criteria. Participants
Interventions
Comparison
Outcomes
Study types
CD patients, age 18yr Refractory to or unsuitable for current available therapies
Autologous/Allogeneic MSCs Autologous/Allogeneic HSCs
Self-control or placebo controls using fibrin glue or routine therapies
Clinical/Endoscopic remission/response (defined by CADI) perianal fistulas healing/closure SAEs should be included
RCTs/Systematic reviews of RCTs/high-quality Non-RCTs
CD: Crohn's disease; yr: year; MSCs: mesenchymal stem cells; HSCs: hematopoietic stem cells; CDAI: Crohn's Disease Activity Index; SAEs: serious adverse events; RCT: randomized controlled trials.
intervention. Each study included in a review must therefore undergo a quality assessment process. In accordance with the Cochrane Reviewers' Handbook and the Newcastle-Ottawa [15], each literature was assessed by the same investigators. Disagreement was resolved according to the pre-defined criteria. 2.6. Results and data synthesis Data extraction sheets were completed for each study. Quantitative data analyses were performed for eligible studies with adequate data; due to study heterogeneity and the small number of incorporated studies, meta-analysis was considered inappropriate for this review. Therefore, a brief qualitative analysis of the evidence was presented in narrative form shown in Tables 2e4. 3. Review of objectives 3.1. Do patients response to the stem cell-based therapies? As shown in Tables 2e4, a total of 18 articles were eligible for the qualitative analyses. To be more specific, there were 6 clinical trials using HSCs and 12 using MSCs respectively. Clinical response was defined as a decrease in Crohn's Disease Activity Index (CDAI) >100. Endoscopic improvement referred to a decrease of Crohn's disease endoscopic index of severity greater than 5, or a Crohn's disease endoscopic index of severity of less than 3. Considering some patients have developed perianal fistulas, the combined measurement of clinical response was defined as fistula closure. Totally there were 483 patients (Tables 2e4) with 400 evaluable CD patients. The data concerning luminal CD was limited. Five available studies had 45 CD patients, with improvement in clinical signs in 42. The results indicated a promising role of MSCs in CD therapy. As regarding the local treatment of perianal CD, similar satisfactory results have been published. Tow recently published studies [31,32], one study showed that a complete closure was achieved in 27 out of 33 patients after the final injection of ASCs [32]. However, a study conducted by Herreros et al. [33] including 200 participants stated that ASCs alone or in combination with fibrin glue was equivalent to fibrin glue alone.
3.2. Is there any remission in signs or symptoms of Crohn's disease? Of the six studies examining the efficacy of HSCs, the results were encouraging. Among 66 patients, 57 CD patients achieved complete remission as indicated by physical examination, CDAI level (CDAI < 150), bowel ultrasound sonography and/or radiological exam [16e21]. HSCs transplantation seemed to be superior to MSCs transplantation in terms of remission rate (86.36% (57/66) vs 44.90% (154/ 343)). However, due to the heterogeneity of the studies, caution should be took when HSCs and MSCs are compared with. What's more, there were few patients receiving HSCs transplantation. On the contract, there were 2 multicenter, randomized and double-blinded trials that evaluated the efficacy of MSCs [28,33]. Preparation of MSCs is more easy and cheaper than that of HSCs, which needs leukapheresis. In addition, no donorrecipient matching is required for on-the-shelf MSCs from donors (such as Prochymal™) [22], which is in contract to HSCs, for it may cause GVHD after transplantation. 3.3. Whether adverse events are acceptable? Each study evaluated the safety of the treatment and found that the incidence of serious adverse events (SAEs) was low. Only 3 studies reported several cases of SAEs (Tables 2e4). Hasselblatt et al. [19] reported 4 individuals who developed SAEs during stem cell mobilization. Of which, one patient suffered prolonged neutropenic fever and reversible acute renal failure as well as vaginal bleeding. Lopez-cubero et al. [20] recorded 1 case of SAEs. During the long-term follow-up period (4.5e15.3 yr), 1 patient developed septicemia which was considered to be not related to stem cell therapy. In another study reported by De la Portilla et al. [30], there were 2 cases of SAEs, which were “pyrexia” and “perianal abscess”respectively. Overall, the incidence of SAEs was low. 4. Discussion Up to now, mechanisms for stem cells in treating CD are still not well understood. Stem cells may suppress the immune reaction in injured tissues and differentiate into epithelia cells to promote tissue healing. However, what happens during the differentiation process remains mysterious. In the present review, we included 6 and 12 trials using HSCs and MSCs respectively. Despite variations in dosage, timing, and
Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Fig. 1. A PRISMA diagram outlining the search strategy and study selection.
frequency of administration, stem cells seemed to significantly benefit the patients with refractory CD in terms of both
primary and secondary endpoints. These results were very encouraging.
Table 2 Hemapoietic stem cells transplantation studies in Crohn's disease. Study ID
Participants
Procedure
Remission (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Oyama et al. [16] Burt et al. [17]
12 24
Autologous HSCs Autologous HSCs
Clinical:11 (12 m) Clinical:24 (6e12 m)
None 1SAEs not related
Cassionotti et al. [18]
10
Autologous HSCs
Clinical:10 (3 m) Endoscopic:5 (3 m)
None
Hasselblatt et al. [19]
12
Autologous HSCs
Lopez-cubero et al. [20] Hommes et al. [21]
6 (5 evaluable) 3
Allogeneic HSCs Autologous HSCs
Clinical:5 (6 m) Endoscopic:5 (6 m) Clinical:4 (4.5e15.3 yr) Clinical:3 (5e6 yr)
4SAES related (fever, renal failure) 1SAEs related septicemia None
1 (15 m) 9% (12 m) 37% (24 m) 43% (36 m) 61% (48 m) 81% (60 m) 20% (12 m) 50% (24 m) 60% (36 m) 70% (48 m) 70% (60 m) 7 (37.2 m) 1 (1.5 yr) 1 (2 yr)
HSCs: hematopoietic stem cells; m: month; yr: year; SAEs: serious adverse events. Please cite this article in press as: Ye L, et al., Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review, Journal of Cellular Immunotherapy (2016), http://dx.doi.org/10.1016/j.jocit.2016.01.001
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Table 3 Mesenchymal stem cell transplantation studies in luminal Crohn's diseases. Study ID
Participants
Procedure
Response/Remission (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Onken et al. [22] Duijvestein et al. [23]
10 (9 evaluable) 10 (6 evaluable)
Prochymal™ Autologous BMMSCs
1SAES unrelated None
NA NA
Liang et al. [24]
7 (4CD/3UC)
None
2 (6e7 m)
Forbes et al. [25]
16 (15 evaluable)
Allogeneic BMMSCs/UC-MSCs Allogeneic BMMSCs
1SAES unrelated
NA
Lazebnik et al. [26]
50 (11CD/39UC)
Allogeneic BMMSCs
Clinical:9/3 (14 d) Clinical:3/0 (6 w) Endoscopic:2/0 (6 w) Clinical:7/3 (3 m) Endoscopic:3/0 (3e5 m) Clinical:12/8 (42 d) Endoscopic:7/0 (42 d) Clinical:11/0 (4e8 m, CD) 39/0 (4e8 m, UC)
NA
NA
CD: Crohn's disease; UC: ulcerative colitis; BMMSCs: Bone marrow-derived MSCs; UC-MSCs: umbilical cord-derived MSCs; Prochymal™: Ex vivo cultured mesenchymal stem cells from marrow of screened, healthy volunteers; SAES: serious adverse events; NA: Not available. d: day; w: week; m: month.
Table 4 Mesenchymal stem cell transplantation studies in perianal Crohn's diseases. Study ID
Participants
Procedure
Response/Closure (number of patients, time of evaluation)
SAEs
Recurrence (number of patients, time of evaluation)
Garcia-Olmo et al [27] Garcia-Olmo et al [28]
5 (4 evaluable) 49 (14CD)
8 Fistulas in 4:2/6 (8 w) Group A:NA/1 (7CD, 8 w) Group B:2/5 (7CD, 8 w)
None None
NA Group B:3 (12 m) Data for CD:NA
Ciccocioppo et al. [29] De la Portilla et al. [30]
12 (10 evaluable) 24 (22 evaluable)
Autologous ASCs Autologous Group A:25 (7CD) ASCs þ Fg Group B:24 (7CD) Fg Autologous BMMSCs Allogeneic ASCs
3/7 (12 m) 23 Fistulas in 22:5/18 (6 m)
None (12 m) NA
Cho et al. [31] Lee et al. [32] Herreros et al. [33]
10 33 200
Autologous ASCs Autologous ASCs Autologous Group A: ASCs Group B: ASCs þ Fg Group C: Fg
1/3 (2 m) 5/27 (2 m) Group A: NA/25 (12 w) Group B: NA/26 (12 w) Group C: NA/22 (12 w)
None 2SAES Pyrexia Perianal abscess None None None
3 (8 m) 3 (12 m) NA
CD: Crohn's disease; ASCs: Adipose-derived MSCs; Fg: Fibrin glue; SAES: serious adverse events; NA: Not available; w: week; m: month.
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 stepup 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 longterm 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-a, 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 [41e43]. 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
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Table 5 Large ongoing Phase III trials using stem cells for perianal Crohn's diseases. Trial code
Condition
Sponsor
Status
Intervention
Enrollment
NCT0154157 NCT00482092
Perianal fistula Perianal fistula
Tigenix Osiris Therapeutics
Active, not recruiting Active, not recruiting
Two groups: ASCs, placebo Three groups: Placebo High-dose ASCs Low-dose ASCs
208 270
ASCs: Adipose-derived MSCs; Source: Clinicaltrials.gov.
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. While a large number of clinical trials have been completed or underway, there is a lack of strong evidence of their effectiveness and safety. Some experts pointed out that autologous transplantation may put patients at a risk of receiving the genetically defective immune cells, while allogeneic transplantation has a potential to cause myeloablation [35]. Moreover, recent studies stated that cultured MSC may undergo transdifferentiation into proinflammatory cells in the chronic inflammatory environment. Yasuhiro et al. [48] first demonstrated that MSCs secreted IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in bone marrow. More researches are needed to further understand the mechanisms of stem cells before they enter clinical application. We still do not know what kind of stem cells is best for CD. In addition to HSCs and MSCs, amniotic fluid stem cells have been used and the results were encouraging [49]. IFN-g-treated human amniotic fluid stem cells could inhibit T-cell proliferation and increase CD4(þ) CD25(þ) FOXP3(þ) regulatory T cells. In vivo, IFN-g-treated human amniotic fluid stem cells were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. Thus, amniotic fluid stem cells may be a new source of stem cells for immunotherapy. There exit several limitations of the review. First, the number of included studies was small and none of these trials were RCT. Second, most of the trials enrolled a few patients. In one trial with 200 patients enrolled, there was no greater improvement in patients receiving ASCs and fibrin glue compared to that receiving fibrin glue alone. Third, quantitative data analyses could not be performed due to heterogeneity in designing, classifications of fistulas, treatment and the duration of follow-up.
5. Conclusion Stem cell therapy is a field that has developed considerably in the past decade. Currently available clinical data indicates that stem cell therapy for CD is very promising. In spite of the huge accomplishments, stem cell-based therapy is still in its infancy. There are only 2 ongoing Phase III trials using stem cells for the treatment of CD (Table 5). However, there is a long way to go before they are officially approved to be used for CD. Further large randomized trials are warranted. Enormous advances are needed to bridge the translational gap between the benchtop researches and clinical applications of stem cells for CD. Author contributions Ye L and Wang FY designed the study; Ye L, Pan JX and Yu N searched all articles; Ye Land Wu XW developed the methodology; Ye L, Wu XW, Yu N, Liao LM and Wang FY wrote the manuscript. Conflict of interest
Q2
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