Clinical Trials Using Mesenchymal Stem Cells In Liver Diseases And .

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Tsuchiya et al. Inflammation and Regeneration (2017) 37:16DOI 10.1186/s41232-017-0045-6Inflammation and RegenerationREVIEWOpen AccessClinical trials using mesenchymal stem cellsin liver diseases and inflammatory boweldiseasesAtsunori Tsuchiya*, Yuichi Kojima, Shunzo Ikarashi, Satoshi Seino, Yusuke Watanabe, Yuzo Kawata and Shuji TeraiAbstractMesenchymal stem cell (MSC) therapies have been used in clinical trials in various fields. These cells are easily expanded,show low immunogenicity, can be acquired from medical waste, and have multiple functions, suggesting their potentialapplications in a variety of diseases, including liver disease and inflammatory bowel disease. MSCs help prepare themicroenvironment, in response to inflammatory cytokines, by producing immunoregulatory factors that modulate theprogression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a largeamount of cytokines, chemokines, and growth factors, including exosomes that stimulate angiogenesis, preventapoptosis, block oxidation reactions, promote remodeling of the extracellular matrix, and induce differentiation oftissue stem cells. According to ClinicalTrials.gov, more than 680 clinical trials using MSCs are registered for cell therapyof many fields including liver diseases (more than 40 trials) and inflammatory bowel diseases (more than 20 trials). Inthis report, we introduce background and clinical studies of MSCs in liver disease and inflammatory bowel diseases.Keywords: Mesenchymal stem cell, Liver disease, Inflammatory bowel disease, Cell therapyBackgroundThe digestive system, which consists of the gastrointestinal tract, liver, pancreas, and biliary tree, functions in digestion, absorption, and metabolism and affects the basisof life. Various diseases, including cancer, inflammatorydisease, infection, stones, and ulcers, are studied underthe context of gastroenterology. While innovative drugsagainst Helicobacter pylori [1], hepatitis C virus [2], andinflammatory bowel disease (IBD) [3] have recently beendeveloped, there are still unmet needs in this field, including in acute and chronic liver failure and refractory IBDs.Cell therapy may fulfill these unmet needs, and cell therapies using mesenchymal stem cells (MSCs) have becomea major focus in many fields [4]. MSCs are reported tohave multiple functions, especially anti-fibrosis and antiinflammatory effects are focused in acute and chronic liverfailure and refractory IBDs. Furthermore, MSCs have lowimmunogenicity, can expand easily, and can be obtainedfrom medical waste, suggesting their potential to expand* Correspondence: atsunori@med.niigata-u.ac.jpDivision of Gastroenterology and Hepatology, Graduate School of Medicaland Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku,Niigata 951-8510, Japanregenerative medicine for the treatment of liver diseasesand IBDs.In this paper, we review the current status of clinicaltrials using autologous/allogeneic MSCs in liver diseasesand IBDs.Characteristics of MSCsMSCs have recently received attention as potential cellsources for cell therapy due to their ease of expansion andwide range of functions. MSCs can be obtained from notonly bone marrow but also medical wastes, such as adiposetissue, umbilical tissue, and dental pulp. MSCs are positivefor the common markers CD73, CD90, and CD105; however, they are negative for the endothelial marker CD31 andhematopoietic marker CD45 [4–7]. The expansion of MSCsin culture is relatively easy, and under appropriate conditions, MSCs have trilineage differentiation (osteogenic,chondrogenic, and adipogenic) potential. The effects ofMSCs are broadly divided into two mechanisms: (1) recruited MSCs differentiate into functional cells to replacedamaged cells, permitting the treatment of bone and cartilage damage; and (2) in response to inflammatory cytokines,MSCs help prepare the microenvironment by producing The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication o/1.0/) applies to the data made available in this article, unless otherwise stated.

Tsuchiya et al. Inflammation and Regeneration (2017) 37:16immunoregulatory factors that modulate the progression ofinflammation by affecting dendritic cells, B cells, T cells,and macrophages. MSCs also produce a large amount ofcytokines, chemokines, and growth factors, including exosomes, which stimulate angiogenesis, prevent apoptosis,block oxidation reactions, promote remodeling of the extracellular matrix (ECM), and induce the differentiation of tissue stem cells [4, 7, 8]. These latter mechanisms can beapplied for many diseases, including liver disease and IBSs.Some studies have reported that the effects of MSCs are determined by host conditions, such as inflammation stageand the use of immunosuppressants.Although the behaviors of MSCs after administrationhave been analyzed, and some studies have shown thatMSCs migrate to the injured site, MSC behaviors inhumans have not been fully elucidated. Some studieshave reported that MSCs disappear within a few weeksand do not remain long in the target tissue [5]. Recentstudies have reported that only culture-conditionedmedium or exosomes induce treatment effects, suggesting that the trophic effect is the most important effect ofMSCs [9–11]. Another important characteristic of MSCsis that they generally have low immunogenicity. MSCshave no antigen-presenting properties and do not express major histocompatibility complex class II or costimulatory molecules; thus, injection of autologous orallogeneic MSCs has been employed in clinical studies.Allogeneic MSC therapy has the potential to expandMSC therapy to many patients [4, 7].Clinical trials using MSCsSince MSCs can be obtained relatively easily and havemultiple functions, more than 680 clinical trials are ongoing according to ClinicalTrials.gov (https://clinicaltrials.gov/); most of these studies are phase I or II trialsevaluating the use of MSCs in bone/cartilage, heart,neuron, immune/autoimmune, diabetes/kidney, lung,liver, and gastrointestinal fields. These studies aim to elucidate the safety/effectiveness of MSCs in the treatment ofvarious diseases. In liver diseases, 40 trials are registered,most of which target liver cirrhosis or acute liver diseases(Table 1) [12–21]. The MSCs used in clinical trials of theliver are derived from the bone marrow (55%), umbilicalcord tissue (35%), and adipose tissue (8%). Approximately50% of MSCs are allogeneic. Additionally, while the majoradministration route is the peripheral blood, approximately 40% of cases are treated via the hepatic artery,reflecting the fact that hepatologists and radiologists oftenuse catheters to treat hepatocellular carcinoma throughthe hepatic artery [22, 23] (Fig. 1).In IBDs, 26 trials are registered (Table 2), 23 of which areinvestigating the use of MSCs in Crohn’s disease (CD), and3 of which are investigating the use of MSCs in ulcerativecolitis (UC) [24–33]. More than 60% of trials are employingPage 2 of 15allogeneic MSCs, and in CD, more than 40% of the trialsare evaluating intralesional injection into the fistula, whichis the major and refractory complication of CD (Fig. 2).Clinical trials in liver diseasesBackground of liver diseasesAlthough the liver has high regenerative capacity, acuteliver damage caused by viruses, drugs, alcohol, andautoimmune diseases, or chronic liver damage caused byhepatitis B or C virus, alcohol, non-alcoholic steatohepatitis (NASH), autoimmune hepatitis, and primary biliarycholangitis often cause liver failure [34]. The liver has avariety of functions, including metabolism of protein,sugar, and fat; detoxification; production of coagulationfactors; and production of bile. Thus, during liver failure,several symptoms, including jaundice, edema, ascites, hepatic encephalopathy, and increased bleeding, can appear atthe same time, resulting in life-threatening disease. Inaddition, during liver failure caused by chronic liver disease, accumulated liver fibrosis (i.e., liver cirrhosis) cancause portal hypertension, which often induces the varices, and long-term liver damage can cause gene abnormalities, leading to liver cancers. The ultimate therapy forliver failure is liver transplantation; however, only a smallportion of patients with liver failure can receive livertransplantation due to the shortage of donor organs,invasiveness of operations, and economic reasons [35].Revolutionary treatments, such as interferon-free treatment for hepatitis C and providing information regardingthe importance of the daily lifestyle to prevent alcoholicliver disease and NASH, can potentially decrease the liverdiseases; however, unmet needs to treat advanced liverfailure will continue.Advanced acute liver failure and chronic liver failure(liver cirrhosis) can be good targets for cell therapy. Since2003, Terai et al. initiated autologous bone marrow cell infusion (ABMi) therapy against decompensated liver cirrhosis and confirmed the improvement of liver fibrosisand liver function [36–38]. However, due to the invasiveness of liver transplantation in patients with liver failure,minimally invasive procedures using specific cells, such asMSCs and macrophages [39–41], are now being developed, with a focus on MSCs. In the next section, we willdescribe recent reported results using MSCs registered atClinicalTrials.gov.Effects of MSC therapy in liver disease from publishedpapersAnimal experiments have shown that MSCs can have antiapoptotic [42] and antioxidant effects in hepatocytes [43],and antifibrotic [44, 45], angiogenic [46], and immunosuppressive effects in T cells, macrophages, and dendritic cells[8]. In human clinical trials, all reports have shown thatMSC injection is safe. Although the effects of cell therapy

2009 Bonemarrow2009 Bonemarrow2014 Umbilicalcord2016 Adiposetissue2007 Bonemarrow2016 Bonemarrow2009 Umbilicalcord2011 Bonemarrow23456789Peripheral veinPeripheral veinAllogeneicAllogeneicPeripheral veinPeripheral orportal veinPortal vein orhepatic arteryPeripheral veinPeripheral veinHepatic logousAutologousAutologous2013 Bonemarrow1Peripheral veinAutologous/ AdministrationallogeneicrouteNo. Start Cellyear sourceTable 1 Clinical trials in liver diseases2.0 105/kg,4 times or5.0 105/kg,3 times2.0 106/kg,4 times30–50 106/patient1.0 106/kg viaperipheral vein,3 times or3.0 106/kg viahepatic artery,3 times4.0 107/patient,4 times1.0 106/kg5 106 cells/patient, 2 timesUnknownNumber of cellsinfused20Number ofpatients32025ACLF(HBV)ACLFLC12043308LC (HCV) 5LCLCLC11(alcohol)LCEtiology48 weeks96 weeks96 weeks24 weeks48 weeks144 weeks24 weeks24 weeks48 weeksFollow-upperiodNonrandomized,single groupassignment,open labelNonrandomized,single groupassignment,open labelStudy designPhase 2Phase1–2Phase Randomized,parallelassignment,double ent,double ngle groupassignment,single blindNonrandomized,single groupassignment,open labelNonrandomized,parallelassignment,open labelUnknown Nonrandomized,single groupassignment,open labelPhase .gov Statusidentifier13ReferencesImprovement in15liver function andMELD scores.Improvement in14liver function andMELD scores.Improvement inAlb and MELDscores.Histologicalimprovement.Improvementin Child- Pughscore. Decreasein TGFβ1,collagen type I,and α-SMAResultTsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 3 of 15

2012 Bonemarrow2012 Umbilicalcord2016 Bonemarrow2009 Umbilicalcord2009 Bonemarrow2010 Umbilicalcord2013 Bonemarrow2012 Umbilicalcord2013 Umbilicalcord AllogeneicAllogeneic2010 Umbilicalcord10Peripheral veinHepatic arteryHepatic arteryHepatic arteryPortal veinPortal vein orhepatic arteryPortal veinPeripheral veinHepatic arteryUnknownAutologous/ AdministrationallogeneicrouteNo. Start Cellyear source1.0 105/kg,1.0 106/kg1.0 106/kg1.0 106/kgUnknownUnknownUnknown2.0 106/kg1.0 105/kg,4 timesUnknown20Number 2 weeks48 weeks24021012 weeks4 weeks48 weeks48 weeks24 weeks48 weeks96 weeks48 iverfailure(HBV)1.0 106/kg,4 times or5.0 106/kg,4 timesUnknownEtiologyNumber of cellsinfusedTable 1 Clinical trials in liver diseases (Continued)Phase1–2Phase1–2Phase 3Phase1–2Phase 2Phase1–2Phase1–2Phase1–2Phase llelassignment,open labelNonrandomized,single groupassignment,open labelRandomized,parallelassignment,open labelNonrandomized,parallelassignment,open labelRandomized,parallelassignment,single n labelRandomized,parallelassignment,open labelRandomized,parallelassignment,open labelRandomized,parallelassignment,open labelassignment,open labelStudy 91200NCT01342250RecruitingUnknownEnrolling byinvitationUnknownUnknownSuspendedNot ls.gov StatusidentifierResultReferencesTsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 4 of 15

2010 Menstrual Allogeneicblood2008 Bonemarrow2012 Bonemarrow2014 Bonemarrow2005 Bonemarrow2009 Umbilicalcord2010 Bonemarrow2007 geneicAutologousAutologousAutologousAutologous2016 UmbilicalcordAllogeneicPeripheral veinPortal veinPeripheral veinHepatic arteryPeripheral veinHepatic arteryHepatic arteryPeripheral veinPeripheral veinAutologous/ Administrationallogeneicroute20bonemarrowNo. Start Cellyear source(1.2–2.95 108)1.95 108/patient5050261Number 2.5 108/patient, LC2 times5.0 105/kg,3 times3.4 108/patientUnknown5 107/patient,1 time or2 timesUnknown1.0 106/kg,4 times4 or 8 timesor 1.0 107/kg,8 timesNumber of cellsinfusedTable 1 Clinical trials in liver diseases (Continued)48 weeks48 weeks48 weeks192 weeks24 weeks24 weeks96 weeks48 weeks52 weeksFollow-upperiodNonrandomized,single groupassignment,open labelRandomized,parallelassignment,open labelCase control,retrospectiveNonrandomized,single groupassignment,open labelRandomized,parallelassignment,open labelRandomized,parallelassignment,single blind(subject)Randomized,single groupassignment,open labelRandomized,parallelassignment,open labelassignment,open labelStudy designUnknown Randomized,parallelassignment,doublePhase 1Phase1–2Phase1–2Phase 1Phase 2Phase 2Phase1–2Phase nCompletedRecruitingCompletedUnknownEnrolling byinvitationNot ials.gov StatusidentifierReferencesNo beneficialeffect.Transientimprovement inMELD scores.Improvement inAlb, T-Bil, andMELD score.Reduction ofascites.Improvement inAlb, T-Bil, PT, andMELD score.191817Histological16improvement.Improvement inAST, ALT, ALP,γ-GTP, Child-Pughscore, and MELDscore.ResultTsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 5 of 15

2016 Umbilicalcord orbonemarrow2016 Bonemarrow2011 Umbilicalcord2009 Adiposetissue2012 Adiposetissue2016 Umbilicalcord2011 Bonemarrow2011 geneicAllogeneic2011 Bonemarrow29PeripheralveinPeripheral veinLobeHepatic arteryUnknownPeripheral veinHepatic arteryPortal vein orhepatic arteryHepatic arteryandperipheralarteryAutologous/ AdministrationallogeneicrouteNo. Start Cellyear source5.0 105/kg,3 times5.0–50 106/kg5.0 108/patientUnknownUnknown1.0 106/kg,3 times5 107/patient,1 time or 2 times2.0 107/patient,4 times1.0 106/kg(5.0 107 cellsvia the hepaticartery and theremaining cellsvia the peripheralvein)Number of cellsinfusedTable 1 Clinical trials in liver diseases (Continued)2010Number re(AIH)LC50(alcohol)LCWilson’sdiseaseEtiology48 weeks96 weeks96 weeks4 weeks24 weeks96 weeks144 weeks48 weeks24 weeksFollow-upperiodblind (subject,outcomesassessor)Study designNonrandomized,single groupassignment,open labelRandomized,parallelassignment,open labelRandomized,parallelassignment,open labelNonrandomized,single groupassignment,open labelPhase1–2Phase ssignment,open labelRandomized,parallelassignment,double blind(subject,outcomesassessor)Unknown Nonrandomized,single groupassignment,open labelPhase 1Phase1–2Phase 2Phase 1Unknown Nonrandomized,single groupassignment,open edUnknownEnrolling byinvitationRecruitingCompletedClinicalTrials.gov StatusidentifierImprovement inAlb, T-Bil, andMELD score.Result20ReferencesTsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 6 of 15

2010 Bonemarrow2010 Bonemarrow3940Hepatic arteryPortal vein orhepatic artery(0.25–1.25 106)0.75 106/patientUnknownUnknownNumber of 60Number ofpatients24 weeks48 weeks48 weeksFollow-upperiodPhase2–3Phase 2Phase 2PhaseNonrandomized,parallelassignment,open labelNonrandomized,parallelassignment,open labelNonrandomized,parallelassignment,open labelassignment,open labelStudy ownUnknownClinicalTrials.gov StatusidentifierReferencesDecrease in Th-17 21cells, RORγt, IL-17,TNF-α, and IL-6.Increase in Tregsand Foxp3.Reduction ofascites.ResultLC liver cirrhosis, ACLF acute-on-chronic liver failure, HBV hepatitis B virus, HCV hepatitis C virus, AIH autoimmune hepatitis, PBC primary biliary cholangitis, MELD Model for End-Stage Liver Disease, AST aspartatetransaminase, ALT alanine transaminase, ALP alkaline phosphatase, γ-GTP gamma-glutamyl transpeptidase, Alb albumin, T-bill total bilirubin, PT prothrombin time, PC protein C, ROR RAR-related orphan receptor, Foxp3forkhead box P3, IL interleukin, Th T helper, SMA smooth muscle actin, TGF transforming growth factor, TNF tumor necrosis factorAutologousAllogeneicAllogeneic2010 Bonemarrow38Portal vein orhepatic arteryAutologous/ AdministrationallogeneicrouteNo. Start Cellyear sourceTable 1 Clinical trials in liver diseases (Continued)Tsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 7 of 15

Tsuchiya et al. Inflammation and Regeneration (2017) 37:16Fig. 1 Summary of clinical trials in liver diseasesare not uniform, the majority of therapies have some beneficial effects; in contrast, in a few reports, treatment effectswere not observed. For example, Kantarcioglu et al. [13]and Mohamadnejad et al. [19] injected bone marrowderived MSCs into patients with liver cirrhosis and did notobserve treatment effects. However, Kharaziha et al. [14]reported phase I–II clinical trials using autologous bonemarrow-derived MSCs against liver cirrhosis with a varietyof etiologies, and improvement of liver function wasconfirmed. Jang et al. and Suk et al. [12, 16] reported a pilotstudy and a phase II study using autologous bone marrowderived MSCs injected through the hepatic artery againstalcoholic liver cirrhosis, and improvement of histologicalliver fibrosis and liver function was confirmed. Xu et al.[21] reported trials using autologous bone marrow-derivedMSCs against hepatitis B virus-associated cirrhosis andconfirmed the improvement of liver function, the decreaseof Th17 cells, and the increase of regulatory T cells. Xhanget al. [17] and Wang et al. [20] reported trials using allogeneic umbilical cord-derived MSCs in patients with chronichepatitis B having decompensated liver cirrhosis andprimary biliary cirrhosis, respectively. They confirmed improvement of liver function, particularly reduced ascitesand recovery of biliary enzymes, respectively. Shi et al. [15]reported a trial investigating acute or chronic liver failureassociated with hepatitis B virus and confirmed that MSCssignificantly increased survival rates. From these reports,MSCs appeared to improve liver function; however, additional trials are needed to confirm these effects and to elucidate the mechanisms in more detail.Clinical trials in IBDsBackground of IBDsIBDs are chronic inflammatory disorders, including UCand CD. The pathogenesis of IBD is thought to be highlycomplex due to several factors, such as environmental factors, genetic predisposition, and inflammatory abnormalities [47]. UC is characterized by inflammation of themucosal membrane of the colon continued from thePage 8 of 15rectum. Type 2 T helper cell (Th2) cytokine profile is associated with the pathogenesis of UC. In contrast, CD is asegmental, transluminal disorder that can arise within theentire gastrointestinal tract from the mouth to the anus.Th1 cells are associated with the pathogenesis of CD [48].Furthermore, a recent report showed that Th17 cells arepresent in both UC and CD. Thus, mucosal CD4 T cellsare key mediators of the driving response [49]. Macrophages that produce tumor necrosis factor (TNF)-α havealso been reported to be relevant in IBD. Imbalances inother cytokines, such as interleukin (IL)-1β, IL-6, IL-8,IL-10, IL-12, IL-17, IL-23, and transforming growthfactor-β (TGF-β), are also detected during diseases [48].Recent advancements in the development of drugs forIBD include drugs targeting TNF and new candidatedrugs, such as antibodies against IL-6 [50] and IL-12/23[51–53], small molecules including Janus kinase inhibitors[54], antisense oligonucleotides against SMAD7 mRNA[55], and inhibitors of leukocyte trafficking to intestinalsites of inflammation [56, 57]. However, some patients willfail to respond to current medical options, immunosuppressive agents, and anti-TNF biologicals. MSCs may bean effective option in these patients [9, 49]. In the nextsection, we will describe recently reported results usingMSCs registered in ClinicalTrials.gov.Effects of MSC therapy in IBD from published papersEight CD trials and one UC trial have been published inClinicalTrials.gov. Six papers describing CD are on trialstreating fistula, and two papers are trials for luminal CD.Molendijk et al. [25] reported improved healing of refractory perianal fistulas using allogeneic bone marrow-derivedMSCs. They administered these allogeneic MSCs locallyand concluded that injection of 3 107 MSCs appeared topromote the healing of perianal fistula. Panes et al. [31] reported a phase III randomized, double-blind, parallelgroup, placebo-controlled study of complex perianal fistulausing expanded allogeneic adipose-derived MSCs and confirmed the safety of the MSCs and the healing effects ofMSCs on the fistula. Duijvestein et al. [32] reported a phaseI study of refractory luminal CD using autologous bonemarrow-derived MSCs and confirmed the safety and feasibility of MSC therapy. Forbes et al. [24] reported a phase IIstudy using allogeneic bone marrow-derived MSCs for luminal CD refractory to biologic therapy. They administered2 106 cells/kg weekly for 4 weeks and found that allogeneic MSCs reduced the CD activity index (CDAI) and CDendoscopic index of severity (CDEIS) scores in patientswith luminal CD refractory to biologic therapy. Hu et al.[33] reported a phase I/II study for severe UC using umbilical cord-derived allogeneic MSCs by combination injectionthrough the peripheral blood and superior mesenteric artery with a 7-day interval. They confirmed the safety of

bilical gous/ AdministrationallogeneicrouteNo. Start year Cellsource3 107 cells/patient (in theevent of incompleteclosure at 8 weeks,a second injection1 107 cells/patient, 3 107cells/patient, or9 107 cells/patient2 106 cells/kg, 5 106 cells/kg, or 1 107cells/kg2 106 cells/kg, 4 times2 108 cells/patient, morethan 4 timesUnknownUnknownTotal of 6 108cells/patient,4 times or total of 12 108cells/patient,4 times8 106 cells/kg, 2 timesor 2 106 cells/kg, 2 timesNumber ofcells infusedTable 2 Clinical trials in inflammatory bowel diseases981016151132Fistulizing 43Crohn’sdiseaseFistulizing 6weeks4weeks1year3years24weeks4weeksPhase NonNCT009924851randomized,single groupassignment,open labelPhase Randomized, NCT011449621–2parallelassignment,double blindPhase NonNCT016597621randomized,single groupassignment,open NCT01510431Phase Nonrandomized,1–2single groupassignment,open labelPhase NonNCT010908172randomized,single groupassignment,open labelCompletedCompletedCompletedPhase Randomized, NCT024455471–2parallelassignment,open labelPhase NonNCT011576501–2randomized,single groupassignment,open labelPhase Randomized, NCT005433743parallelassignment,double blindCompletedClinicalTrials.gov StatusidentifierPhase Randomized, NCT002941122parallelassignment,open labelNumberFollow-up Phase Studyof patients perioddesignFistulizing DiseasesLocal treatmentwith MSCs showedpromotion offistula healing.Local treatmentwith MSCsshowedpromotion offistula healing.Lower MSCdose seemedsuperior.Improvementin CDAI, AQoLscore. Decreasein chiya et al. Inflammation and Regeneration (2017) 37:16Page 9 of 15

Autologous/ AdministrationallogeneicrouteNo. Start year Cellsource1.2 108 cells/patient330Fistulizing 212Crohn’sdiseaseCrohn’sdiseaseFistulizing 43Crohn’sdisease1 107 cells/cm2Total of 6 108cells/patient,4 times or totalof 1.2 109 cells/patient, 4 timesFistulizing 10Crohn’sdiseaseFistulizing 24weeksPhase Randomized, NCT015415793parallelassignment,double blindPhase Randomized, NCT004820923parallelassignment,double blindPhase NonNCT010112442randomized,single groupassignment,open labelPhase NonNCT009991151–2randomized,single groupassignment,open labelPhase NonNCT009924851randomized,single groupassignment,open tedClinicalTrials.gov StatusidentifierPhase NonNCT013729691–2randomized,single groupassignment,open labelNumberFollow-up Phase Studyof patients perioddesignFistulizing 24Crohn’sdiseaseDiseases2 107 cells/patient(in the event ofincomplete closureat 12 weeks, anadditional 4 107cells wereadministered)1 107 cells/patient,2 107 cells/patient,or 4 107cells/patient2 107 cells/patient(in the event ofincomplete closureat 12 weeks, anadditional 4 107cells wereadministered)was given thatcontained 1.5 timesmore cells thanthe f irst)Number ofcells infusedTable 2 Clinical trials in inflammatory bowel diseases (Continued)Local treatmentwith MSCsshowedpromotion offistula healing.In most cases,completeclosure afterinitial treatmentwas wellsustained overa 24-monthperiod.Local treatmentwith MSCsshowedpromotion offistula healing;60% of patientsachievedcompletehealing.Local treatmentwith MSCsshowedpromotion offistula healing.All patientswith completehealingshowed asustainedeffect.Local treatmentwith MSCsshowedpromotion offistula healing.Result3130292827ReferencesTsuchiya et al. Inflammation and Regeneration (2017) 37:16Page 10 of 15

2013201520132013Unknown usAllogeneicAutologousAutologousUmbilical AllogeneiccordBonemarrowAdiposetissueUmbilical 1016BonemarrowAutologous/ AdministrationallogeneicrouteNo. Start year Cellsource1 106 cells/kg, 3 times2 107 cells/patient1–2 106 cells/kg2 107 cells/patient5 107 cells/patient or1 108 cells/patient5 107 cells/patient,7.5 107 cells/patient, or1 108 cells/patientUnknownUnknown2 10 8 cells/patient, 3 timesNumber ofcells infusedTable 2 Clinical trials in inflammatory bowel diseases (Continued)12024910Ulcerative 30colitisFistulizing 20Crohn’sdiseaseCrohn’sdiseaseFistulizing Fistulizing 10Crohn’sdisease24weeks7, 10, eks180days–Phase Randomized, NCT024420371–2parallelPhase NonNCT026773501randomized,single groupassignment,open labelPhase Unknown1RecruitingNot se Non1–2randomized,single groupassignment,open labelPhase NonNCT0191

tissue stem cells. According to ClinicalTrials.gov, more than 680 clinical trials using MSCs are registered for cell therapy of many fields including liver diseases (more than 40 trials) and inflammatory bowel diseases (more than 20 trials).

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