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. 2017 Jul 3;37:16. doi: 10.1186/s41232-017-0045-6

Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases

Atsunori Tsuchiya 1,✉, Yuichi Kojima 1, Shunzo Ikarashi 1, Satoshi Seino 1, Yusuke Watanabe 1, Yuzo Kawata 1, Shuji Terai 1
PMCID: PMC5725741  PMID: 29259715

Abstract

Mesenchymal 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 potential applications in a variety of diseases, including liver disease and inflammatory bowel disease. MSCs help prepare the microenvironment, in response to inflammatory cytokines, by producing immunoregulatory factors that modulate the progression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a large amount of cytokines, chemokines, and growth factors, including exosomes that stimulate angiogenesis, prevent apoptosis, block oxidation reactions, promote remodeling of the extracellular matrix, and induce differentiation of 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). In this 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 therapy

Background

The digestive system, which consists of the gastrointestinal tract, liver, pancreas, and biliary tree, functions in digestion, absorption, and metabolism and affects the basis of life. Various diseases, including cancer, inflammatory disease, infection, stones, and ulcers, are studied under the context of gastroenterology. While innovative drugs against Helicobacter pylori [1], hepatitis C virus [2], and inflammatory bowel disease (IBD) [3] have recently been developed, 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 become a major focus in many fields [4]. MSCs are reported to have multiple functions, especially anti-fibrosis and anti-inflammatory effects are focused in acute and chronic liver failure and refractory IBDs. Furthermore, MSCs have low immunogenicity, can expand easily, and can be obtained from medical waste, suggesting their potential to expand regenerative medicine for the treatment of liver diseases and IBDs.

In this paper, we review the current status of clinical trials using autologous/allogeneic MSCs in liver diseases and IBDs.

Characteristics of MSCs

MSCs have recently received attention as potential cell sources for cell therapy due to their ease of expansion and wide range of functions. MSCs can be obtained from not only bone marrow but also medical wastes, such as adipose tissue, umbilical tissue, and dental pulp. MSCs are positive for the common markers CD73, CD90, and CD105; however, they are negative for the endothelial marker CD31 and hematopoietic marker CD45 [4–7]. The expansion of MSCs in culture is relatively easy, and under appropriate conditions, MSCs have trilineage differentiation (osteogenic, chondrogenic, and adipogenic) potential. The effects of MSCs are broadly divided into two mechanisms: (1) recruited MSCs differentiate into functional cells to replace damaged cells, permitting the treatment of bone and cartilage damage; and (2) in response to inflammatory cytokines, MSCs help prepare the microenvironment by producing immunoregulatory factors that modulate the progression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a large amount of cytokines, 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 be applied 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 stage and the use of immunosuppressants.

Although the behaviors of MSCs after administration have been analyzed, and some studies have shown that MSCs migrate to the injured site, MSC behaviors in humans have not been fully elucidated. Some studies have reported that MSCs disappear within a few weeks and do not remain long in the target tissue [5]. Recent studies have reported that only culture-conditioned medium or exosomes induce treatment effects, suggesting that the trophic effect is the most important effect of MSCs [9–11]. Another important characteristic of MSCs is that they generally have low immunogenicity. MSCs have no antigen-presenting properties and do not express major histocompatibility complex class II or costimulatory molecules; thus, injection of autologous or allogeneic MSCs has been employed in clinical studies. Allogeneic MSC therapy has the potential to expand MSC therapy to many patients [4, 7].

Clinical trials using MSCs

Since MSCs can be obtained relatively easily and have multiple functions, more than 680 clinical trials are ongoing according to ClinicalTrials.gov (https://clinicaltrials.gov/); most of these studies are phase I or II trials evaluating 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 of various 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 the liver are derived from the bone marrow (55%), umbilical cord tissue (35%), and adipose tissue (8%). Approximately 50% of MSCs are allogeneic. Additionally, while the major administration route is the peripheral blood, approximately 40% of cases are treated via the hepatic artery, reflecting the fact that hepatologists and radiologists often use catheters to treat hepatocellular carcinoma through the hepatic artery [22, 23] (Fig. 1).

Table 1.

Clinical trials in liver diseases

No. Start year Cell source Autologous/allogeneic Administration route Number of cells infused Etiology Number of patients Follow-up period Phase Study design ClinicalTrials.gov identifier Status Result References
1 2013 Bone marrow Autologous Peripheral vein Unknown LC 20 48 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT01877759 Unknown
2 2009 Bone marrow Autologous Hepatic artery 5 × 106 cells/patient, 2 times LC (alcohol) 11 24 weeks Phase 2 Non-randomized, single group
assignment, open label		 NCT01741090 Unknown Histological improvement. Improvement in Child- Pugh score. Decrease in TGFβ1, collagen type I,
and α-SMA
3 2009 Bone marrow Autologous Peripheral vein 1.0 × 106/kg LC 25 24 weeks Unknown Non-randomized, single group assignment, open label NCT01499459 Unknown Improvement in Alb and MELD scores. 13
4 2014 Umbilical cord Allogeneic Peripheral vein 4.0 × 107/patient, 4 times LC 320 144 weeks Phase 1–2 Non-randomized, parallel assignment, open label NCT01573923 Unknown
5 2016 Adipose tissue Autologous Portal vein or hepatic artery 1.0 × 106/kg via peripheral vein, 3 times or 3.0 × 106/kg via hepatic artery, 3 times LC (HCV) 5 48 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT02705742 Recruiting
6 2007 Bone marrow Autologous Peripheral or portal vein 30–50 × 106/patient LC 8 24 weeks Phase 1–2 Randomized, single group assignment, single blind NCT00420134 Completed Improvement in liver function and MELD scores. 14
7 2016 Bone marrow Allogeneic Peripheral vein 2.0 × 106/kg, 4 times ACLF 30 96 weeks Phase 1 Randomized, parallel assignment, double blind (subject, caregiver, investigator) NCT02857010 Recruiting
8 2009 Umbilical cord Allogeneic Peripheral vein 5.0 × 105/kg, 3 times ACLF (HBV) 43 96 weeks Phase 1–2 Randomized, parallel assignment, double blind (subject, caregiver) NCT01218464 Unknown Improvement in liver function and MELD scores. 15
9 2011 Bone marrow Allogeneic Peripheral vein 2.0 × 105/kg, 4 times or 1.0 × 106/kg, 4 times or 5.0 × 106/kg, 4 times Liver failure (HBV) 120 48 weeks Phase 2 Randomized, parallel assignment, open label NCT01322906 Unknown
10 2010 Umbilical cord Allogeneic Unknown Unknown LC 20 48 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01342250 Completed
11 2012 Bone marrow Allogeneic Hepatic artery Unknown LC (Alcohol) 40 96 weeks Phase 2 Randomized, parallel assignment, open label NCT01591200 Completed
12 2012 Umbilical cord Allogeneic Peripheral vein 1.0 × 105/kg, 4 times Liver failure (HBV) 120 48 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01724398 Unknown
13 2016 Bone marrow Autologous Portal vein 2.0 × 106/kg LC 40 24 weeks Phase 1–2 Non-randomized, parallel assignment, open label NCT02943889 Not yet recruiting
14 2009 Umbilical cord Allogeneic Portal vein or hepatic artery Unknown LC 200 48 weeks Phase 1–2 Randomized, parallel assignment, single blind (subject) NCT01233102 Suspended
15 2009 Bone marrow Autologous Portal vein Unknown LC (HBV) 60 48 weeks Phase 2 Non-randomized, parallel assignment, open label NCT00993941 Unknown
16 2010 Umbilical cord Allogeneic Hepatic artery Unknown LC 50 4 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01224327 Unknown
17 2013 Bone marrow Autologous Hepatic artery 1.0 × 106/kg LC 30 12 weeks Phase 3 Non-randomized, single group assignment, open label NCT01854125 Enrolling by invitation
18 2012 Umbilical cord Allogeneic Hepatic artery 1.0 × 106/kg LC (HBV) 240 48 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01728727 Unknown
19 2013 Umbilical cord or bone marrow Allogeneic Peripheral vein 1.0 × 105/kg, 1.0 × 106/kg or 1.0 × 107/kg, 8 times Liver failure (HBV) 210 72 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01844063 Recruiting
20 2016 Umbilical cord Allogeneic Peripheral vein 4 or 8 times ACLF (HBV) 261 52 weeks Phase 2 Randomized, parallel assignment, open label NCT02812121 Not yet recruiting
21 2010 Menstrual blood Allogeneic Peripheral vein 1.0 × 106/kg, 4 times LC 50 48 weeks Phase 1–2 Randomized, single group assignment, open label NCT01483248 Enrolling by invitation
22 2008 Bone marrow Autologous Hepatic artery Unknown LC 50 96 weeks Phase 2 Randomized, parallel assignment, single blind (subject) NCT00976287 Unknown
23 2012 Bone marrow Autologous Hepatic artery 5 × 107/patient, 1 time or 2 times LC (alcohol) 72 24 weeks Phase 2 Randomized, parallel assignment, open label NCT01875081 Completed Histological improvement. Improvement in AST, ALT, ALP, γ-GTP, Child-Pugh score, and MELD score. 16
24 2014 Bone marrow Autologous Peripheral vein Unknown LC 10 24 weeks Phase 1 Non-randomized, single group assignment, open label NCT02327832 Recruiting
25 2005 Bone marrow Autologous Hepatic artery 3.4 × 108/patient Liver failure (HBV) 158 192 weeks Phase 1–2 Case control, retrospective NCT00956891 Completed Improvement in Alb, T-Bil, PT, and MELD score.
26 2009 Umbilical cord Allogeneic Peripheral vein 5.0 × 105/kg, 3 times LC 45 48 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01220492 Unknown Improvement in Alb, T-Bil, and MELD score.
Reduction of ascites.		 17
27 2010 Bone marrow Autologous Portal vein 1.4–2.5 × 108/patient, 2 times LC 2 48 weeks Phase 1 Non-randomized, single group assignment, open label NCT01454336 Completed Transient improvement in MELD scores. 18
28 2007 Bone marrow Autologous Peripheral vein (1.2–2.95 × 108) 1.95 × 108/patient LC 27 48 weeks Unknown Randomized, parallel assignment, double
blind (subject, outcomes assessor)		 NCT00476060 Unknown No beneficial effect. 19
29 2011 Bone marrow Allogeneic Hepatic artery and peripheral artery 1.0 × 106/kg (5.0 × 107 cells via the hepatic artery and the remaining cells via the peripheral vein) Wilson’s disease 10 24 weeks Unknown Non-randomized, single group assignment, open label NCT01378182 Completed
30 2016 Umbilical cord or bone marrow Allogeneic Portal vein or hepatic artery 2.0 × 107/patient, 4 times LC 20 48 weeks Phase 1 Non-randomized, single group assignment, open label NCT02652351 Recruiting
31 2016 Bone marrow Autologous Hepatic artery 5 × 107/patient, 1 time or 2 times LC (alcohol) 50 144 weeks Phase 2 Randomized, parallel assignment, open label NCT02806011 Enrolling by invitation
32 2011 Umbilical cord Allogeneic Peripheral vein 1.0 × 106/kg, 3 times Liver failure (AIH) 100 96 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01661842 Unknown
33 2009 Adipose tissue Autologous Unknown Unknown LC 6 24 weeks Phase 1 Non-randomized, single group assignment, open label NCT00913289 Terminated
34 2012 Adipose tissue Autologous Hepatic artery Unknown LC 4 4 weeks Unknown Non-randomized, single group assignment, open label NCT01062750 Completed
35 2016 Umbilical cord Allogeneic Lobe 5.0 × 108/patient LC 40 96 weeks Phase 1–2 Randomized, parallel assignment, double blind (subject, outcomes assessor) NCT02786017 Recruiting
36 2011 Bone marrow Unknown Peripheral vein 5.0–50 × 106/kg LC (PBC) 20 96 weeks Phase 1 Randomized, parallel assignment, open label NCT01440309 Unknown
37 2011 Umbilical cord Allogeneic Peripheral vein 5.0 × 105/kg, 3 times LC (PBC) 7 48 weeks Phase 1–2 Randomized, parallel assignment, open label NCT01662973 Unknown Improvement in Alb, T-Bil, and MELD score. Reduction of ascites. 20
38 2010 Bone marrow Allogeneic Portal vein or hepatic artery Unknown Liver failure (HBV) 60 48 weeks Phase 2 Non-randomized, parallel assignment, open label NCT01221454 Unknown
39 2010 Bone marrow Allogeneic Portal vein or hepatic artery Unknown LC 60 48 weeks Phase 2 Non-randomized, parallel assignment, open label NCT01223664 Unknown
40 2010 Bone marrow Autologous Hepatic artery (0.25–1.25 × 106) 0.75 × 106/patient LC (HBV) 39 24 weeks Phase 2–3 Non-randomized, parallel assignment, open label NCT01560845 Unknown Decrease in Th-17 cells, RORγt, IL-17, TNF-α, and IL-6. Increase in Tregs and Foxp3. 21
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LC 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 aspartate transaminase, 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, Foxp3 forkhead box P3, IL interleukin, Th T helper, SMA smooth muscle actin, TGF transforming growth factor, TNF tumor necrosis factor

Fig. 1.

Fig. 1

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Summary of clinical trials in liver diseases

In IBDs, 26 trials are registered (Table 2), 23 of which are investigating the use of MSCs in Crohn’s disease (CD), and 3 of which are investigating the use of MSCs in ulcerative colitis (UC) [24–33]. More than 60% of trials are employing allogeneic MSCs, and in CD, more than 40% of the trials are evaluating intralesional injection into the fistula, which is the major and refractory complication of CD (Fig. 2).

Table 2.

Clinical trials in inflammatory bowel diseases

No. Start year Cell source Autologous/allogeneic Administration route Number of cells infused Diseases Number of patients Follow-up period Phase Study design ClinicalTrials.gov identifier Status Result References
1 2006 Bone marrow Allogeneic Peripheral vein 8 × 106 cells/kg, 2 times or 2 × 106 cells/kg, 2 times Crohn’s disease 10 4 weeks Phase 2 Randomized, parallel assignment, open label NCT00294112 Completed
2 2007 Bone marrow Allogeneic Peripheral vein Total of 6 × 108 cells/patient, 4 times or total of 12 × 108
cells/patient, 4 times		 Crohn’s disease 98 24 weeks Phase 3 Randomized, parallel assignment, double blind NCT00543374 Completed
3 2010 Adipose tissue Autologous Unknown Unknown Fistulizing Crohn’s disease 15 3 years Phase 1–2 Non-randomized, single group assignment, open label NCT01157650 Completed
4 2015 Umbilical cord Allogeneic Peripheral vein Unknown Crohn’s disease 32 1 year Phase 1–2 Randomized, parallel assignment, open label NCT02445547 Completed
5 2012 Bone marrow Allogeneic Peripheral vein 2 × 108 cells/patient, more than 4 times Crohn’s disease 11 4 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT01510431 Completed
6 2010 Bone marrow Allogeneic Peripheral vein 2 × 106 cells/kg, 4 times Crohn’s disease 15 6 weeks Phase 2 Non-randomized, single group assignment, open label NCT01090817 Completed Improvement in CDAI, AQoL score. Decrease in CRP. Endoscopic improvement 24
7 2012 Bone marrow Autologous Peripheral vein 2 × 106 cells/kg, 5 × 106 cells/kg, or 1 × 107 cells/kg Crohn’s disease 16 1 year Phase 1 Non-randomized, single group assignment, open label NCT01659762 Completed
8 2010 Bone marrow Allogeneic Intralesional 1 × 107 cells/patient, 3 × 107 cells/patient, or 9 × 107 cells/patient Fistulizing Crohn’s disease 21 12 weeks Phase 1–2 Randomized, parallel assignment, double blind NCT01144962 Completed Local treatment with MSCs showed promotion of fistula healing. Lower MSC dose seemed superior. 25
9 2009 Adipose tissue Autologous Intralesional 3 × 107 cells/patient (in the event of incomplete closure at 8 weeks, a second injection was given that contained 1.5 times more cells than the f irst) Fistulizing Crohn’s disease 43 8 weeks Phase 1 Non-randomized, single group assignment, open label NCT00992485 Completed Local treatment with MSCs showed promotion of fistula healing. 26
10 2010 Adipose tissue Allogeneic Intralesional 2 × 107 cells/patient (in the event of incomplete closure
at 12 weeks, an additional 4 × 107 cells were administered)		 Fistulizing Crohn’s disease 24 24 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT01372969 Completed Local treatment with MSCs showed promotion of fistula healing. 27
11 2009 Adipose tissue Autologous Intralesional 1 × 107 cells/patient, 2 × 107 cells/patient, or 4 × 107
cells/patient		 Fistulizing Crohn’s disease 10 4 weeks Phase 1 Non-randomized, single group assignment, open label NCT00992485 Completed Local treatment with MSCs showed promotion of fistula healing. All patients with complete healing showed a sustained effect. 28
12 2009 Adipose tissue Allogeneic Intralesional 2 × 107 cells/patient (in the event of incomplete closure at 12 weeks, an additional 4 × 107 cells were administered) Fistulizing Crohn’s disease 10 12 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT00999115 Completed Local treatment with MSCs showed promotion of fistula healing; 60% of patients achieved complete healing. 29
13 2009 Adipose tissue Autologous Intralesional 1 × 107 cells/cm2 Fistulizing Crohn’s disease 43 8 weeks Phase 2 Non-randomized, single group assignment, open label NCT01011244 Completed In most cases, complete closure after initial treatment was well-sustained over a 24-month period. 30
14 2007 Bone marrow Allogeneic Peripheral vein Total of 6 × 108 cells/patient, 4 times or total of 1.2 × 109 cells/patient, 4 times Crohn’s disease 330 4 weeks Phase 3 Randomized, parallel assignment, double blind NCT00482092 Active
15 2012 Adipose tissue Allogeneic Intralesional 1.2 × 108 cells/patient Fistulizing Crohn’s disease 212 24 weeks Phase 3 Randomized, parallel assignment, double blind NCT01541579 Active Local treatment with MSCs showed promotion of fistula healing. 31
16 2010 Bone marrow Allogeneic Peripheral vein 2 × 10^8 cells/patient, 3 times Crohn’s disease 120 180 days Phase 3 Non-randomized, single group assignment, open label NCT01233960 Active
17 2015 Adipose tissue Autologous Intralesional Unknown Fistulizing Crohn’s disease 10 62 weeks Phase 2 Non-randomized, single group assignment, open label NCT02403232 Recruiting
18 2013 Bone marrow Autologous Intralesional Unknown Fistulizing Crohn’s disease 10 16 weeks Phase 1 Randomized, parallel assignment, single blind NCT01874015 Recruiting
19 2015 Adipose tissue Allogeneic Peripheral vein 5 × 107 cells/patient, 7.5 × 107 cells/patient, or 1 × 108 cells/patient Crohn’s disease 9 4 weeks Phase 1 Non-randomized, single group assignment, open label NCT02580617 Recruiting
20 2013 Umbilical cord Allogeneic Peripheral vein 5 × 107 cells/patient or 1 × 108 cells/patient Crohn’s disease 24 12 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT02000362 Recruiting
21 2013 Adipose tissue Autologous Intralesional 2 × 107 cells/patient Fistulizing Crohn’s disease 20 2–24 months Phase 1 Non-randomized, single group assignment, open label NCT01915927 Recruiting
22 Unknown Bone marrow Autologous Peripheral vein 1–2 × 106 cells/kg Crohn’s disease 10 6 weeks Phase 1 Unknown – – Three patients showed clinical response (decrease in CDAI).Three patients required surgery due to disease worsening. 32
23 2016 Bone marrow Allogeneic Intralesional 2 × 107 cells/patient Fistulizing Crohn’s disease 20 7, 10, 16 months Phase 1 Non-randomized, single group assignment, open label NCT02677350 Not yet recruiting
24 2015 Umbilical cord Allogeneic Peripheral vein 1 × 106 cells/kg, 3 times Ulcerative colitis 30 24 weeks Phase 1–2 Randomized, parallel assignment, single blind NCT02442037 Recruiting
25 2015 Adipose tissue Allogeneic Through a colonoscope 6 × 107 cells/patient Ulcerative colitis 8 12 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT01914887 Unknown
26 2015 Umbilical cord Allogeneic First: peripheral vein, second: superior mesenteric artery First: 3.8 ± 1.6 × 107 cells/patient, second: 1.5 × 107 cells/patient Ulcerative colitis 80 12 weeks Phase 1–2 Non-randomized, single group assignment, open label NCT01221428 Unknown Decrease in the median Mayo score and histology score. Improvement in IBDQ scores. 33
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CD Crohn’s disease, CDAI Crohn’s Disease Activity Index, AQoL The Assessment of Quality of Life, CRP C-reactive protein, IBDQ Inflammatory Bowel Disease Questionnaire

Fig. 2.

Fig. 2

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Summary of clinical trials in inflammatory bowel diseases

Clinical trials in liver diseases

Background of liver diseases

Although the liver has high regenerative capacity, acute liver damage caused by viruses, drugs, alcohol, and autoimmune diseases, or chronic liver damage caused by hepatitis B or C virus, alcohol, non-alcoholic steatohepatitis (NASH), autoimmune hepatitis, and primary biliary cholangitis often cause liver failure [34]. The liver has a variety of functions, including metabolism of protein, sugar, and fat; detoxification; production of coagulation factors; and production of bile. Thus, during liver failure, several symptoms, including jaundice, edema, ascites, hepatic encephalopathy, and increased bleeding, can appear at the same time, resulting in life-threatening disease. In addition, during liver failure caused by chronic liver disease, accumulated liver fibrosis (i.e., liver cirrhosis) can cause portal hypertension, which often induces the varices, and long-term liver damage can cause gene abnormalities, leading to liver cancers. The ultimate therapy for liver failure is liver transplantation; however, only a small portion of patients with liver failure can receive liver transplantation 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 regarding the importance of the daily lifestyle to prevent alcoholic liver disease and NASH, can potentially decrease the liver diseases; however, unmet needs to treat advanced liver failure will continue.

Advanced acute liver failure and chronic liver failure (liver cirrhosis) can be good targets for cell therapy. Since 2003, Terai et al. initiated autologous bone marrow cell infusion (ABMi) therapy against decompensated liver cirrhosis and confirmed the improvement of liver fibrosis and liver function [36–38]. However, due to the invasiveness of liver transplantation in patients with liver failure, minimally invasive procedures using specific cells, such as MSCs and macrophages [39–41], are now being developed, with a focus on MSCs. In the next section, we will describe recent reported results using MSCs registered at ClinicalTrials.gov.

Effects of MSC therapy in liver disease from published papers

Animal experiments have shown that MSCs can have anti-apoptotic [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 that MSC injection is safe. Although the effects of cell therapy are not uniform, the majority of therapies have some beneficial effects; in contrast, in a few reports, treatment effects were not observed. For example, Kantarcioglu et al. [13] and Mohamadnejad et al. [19] injected bone marrow-derived MSCs into patients with liver cirrhosis and did not observe treatment effects. However, Kharaziha et al. [14] reported phase I–II clinical trials using autologous bone marrow-derived MSCs against liver cirrhosis with a variety of etiologies, and improvement of liver function was confirmed. Jang et al. and Suk et al. [12, 16] reported a pilot study and a phase II study using autologous bone marrow-derived MSCs injected through the hepatic artery against alcoholic liver cirrhosis, and improvement of histological liver fibrosis and liver function was confirmed. Xu et al. [21] reported trials using autologous bone marrow-derived MSCs against hepatitis B virus-associated cirrhosis and confirmed the improvement of liver function, the decrease of Th17 cells, and the increase of regulatory T cells. Xhang et al. [17] and Wang et al. [20] reported trials using allogeneic umbilical cord-derived MSCs in patients with chronic hepatitis B having decompensated liver cirrhosis and primary biliary cirrhosis, respectively. They confirmed improvement of liver function, particularly reduced ascites and recovery of biliary enzymes, respectively. Shi et al. [15] reported a trial investigating acute or chronic liver failure associated with hepatitis B virus and confirmed that MSCs significantly 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 IBDs

Background of IBDs

IBDs are chronic inflammatory disorders, including UC and CD. The pathogenesis of IBD is thought to be highly complex due to several factors, such as environmental factors, genetic predisposition, and inflammatory abnormalities [47]. UC is characterized by inflammation of the mucosal membrane of the colon continued from the rectum. Type 2 T helper cell (Th2) cytokine profile is associated with the pathogenesis of UC. In contrast, CD is a segmental, transluminal disorder that can arise within the entire 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 are present in both UC and CD. Thus, mucosal CD4+ T cells are key mediators of the driving response [49]. Macrophages that produce tumor necrosis factor (TNF)-α have also been reported to be relevant in IBD. Imbalances in other cytokines, such as interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, and transforming growth factor-β (TGF-β), are also detected during diseases [48]. Recent advancements in the development of drugs for IBD include drugs targeting TNF and new candidate drugs, 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 intestinal sites of inflammation [56, 57]. However, some patients will fail to respond to current medical options, immunosuppressive agents, and anti-TNF biologicals. MSCs may be an effective option in these patients [9, 49]. In the next section, we will describe recently reported results using MSCs registered in ClinicalTrials.gov.

Effects of MSC therapy in IBD from published papers

Eight CD trials and one UC trial have been published in ClinicalTrials.gov. Six papers describing CD are on trials treating fistula, and two papers are trials for luminal CD. Molendijk et al. [25] reported improved healing of refractory perianal fistulas using allogeneic bone marrow-derived MSCs. They administered these allogeneic MSCs locally and concluded that injection of 3 × 107 MSCs appeared to promote the healing of perianal fistula. Panes et al. [31] reported a phase III randomized, double-blind, parallel-group, placebo-controlled study of complex perianal fistula using expanded allogeneic adipose-derived MSCs and confirmed the safety of the MSCs and the healing effects of MSCs on the fistula. Duijvestein et al. [32] reported a phase I study of refractory luminal CD using autologous bone marrow-derived MSCs and confirmed the safety and feasibility of MSC therapy. Forbes et al. [24] reported a phase II study using allogeneic bone marrow-derived MSCs for luminal CD refractory to biologic therapy. They administered 2 × 106 cells/kg weekly for 4 weeks and found that allogeneic MSCs reduced the CD activity index (CDAI) and CD endoscopic index of severity (CDEIS) scores in patients with 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 injection through the peripheral blood and superior mesenteric artery with a 7-day interval. They confirmed the safety of MSCs and alleviation of diffuse and deep ulcer formation and severe inflammatory mucosa by MSCs.

Safety of the MSC therapy

MSC therapy is associated with some concerns, such as adverse events related to infusion, tumor formation during the treatment of liver cirrhosis, and long-term observations of tumor formation. Regarding adverse events related to the infusion, Lalu et al. performed a meta-analysis of the safety of MSCs in clinical trials and showed that autologous and allogeneic MSC therapies were related to transient fever but not infusion toxicity, organ system complications, infection, death, and malignancies (Table 2) [5]. Regarding tumor formation during the treatment of liver cirrhosis, Peng et al. reported that no severe adverse events or no significant differences in tumor formation were detected compared with those in the control group during autologous bone marrow-derived MSC therapy for liver cirrhosis [58]. Regarding long-term observations of tumor formation derived from MSCs, Bahr et al. reported recent autopsy data from patients in a clinical trial of graft-versus-host disease (GvHD) who received MSC therapy between 2002 and 2007 and revealed no ectopic tissues, neoplasms, or donor-derived DNA [6].

Conclusions

Many clinical trials of autologous and allogeneic MSCs have aimed to elucidate the effects and mechanisms of MSCs. MSCs can expand easily and can be obtained from medical waste, suggesting their applications in regenerative medicine for the treatment of liver diseases and IBDs. Recently, limitations of MSCs have been reported. For example, therapeutic effects were not long term and were affected by inflammatory condition [59, 60]. Thus, the results of ongoing clinical studies will be expected to provide further insights.

Acknowledgements

The authors thank Dr. Takayuki Watanabe and Dr. Suguru Takeuchi for their cooperation.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (B) (26293175) from the Ministry of Education, Science, Technology, Sports, and Culture of Japan and by Highway Program for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development, AMED.

Availability of data and materials

There is no available data except the manuscript and tables.

Author’s contributions

AT and ST wrote the paper. YK, SI, SS, YW, and YK prepared the data and made the tables. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

All authors agreed to publish this work.

Ethics approval and consent to participate

There is no ethics approval and consent to participate due to review.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abbreviations

ABMi

Autologous bone marrow cell infusion

CD

Crohn’s disease

CD CDEIS

Endoscopic index of severity

CDAI

CD activity index

ECM

Extracellular matrix

GvHD

Graft-versus-host disease

IBD

Inflammatory bowel disease

IL

Interleukin

MSCs

Mesenchymal stem cells

NASH

Non-alcoholic steatohepatitis

TGF-β

Transforming growth factor

TNF

Tumor necrosis factor

UC

Ulcerative colitis

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