Open Access

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

  • Atsunori Tsuchiya1Email author,
  • Yuichi Kojima1,
  • Shunzo Ikarashi1,
  • Satoshi Seino1,
  • Yusuke Watanabe1,
  • Yuzo Kawata1 and
  • Shuji Terai1
Inflammation and Regeneration201737:16

DOI: 10.1186/s41232-017-0045-6

Received: 30 January 2017

Accepted: 13 April 2017

Published: 3 July 2017

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 [47]. 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 [911]. 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) [1221]. 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

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

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) [2433]. 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

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

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 [3638]. However, due to the invasiveness of liver transplantation in patients with liver failure, minimally invasive procedures using specific cells, such as MSCs and macrophages [3941], 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 [5153], 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.

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

Declarations

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.

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Authors’ Affiliations

(1)
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University

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