Gastroenterology 2017;152:389–397
Is Stem Cell Therapy Ready for Prime Time in Treatment of
Inflammatory Bowel Diseases?
Christopher J. Hawkey1,* Daniel W. Hommes2,*
1
Nottingham Digestive Diseases Center, University of Nottingham, Nottingham, United Kingdom; and 2Center for Inflammatory
Bowel Diseases, University of California Los Angeles, Los Angeles, California
Autologous hematopoietic stem cell transplantation
(HSCT) and mesenchymal stromal cell therapy have been
proposed for patients with refractory Crohn’s disease (CD)
and fistulizing CD, respectively. Will these highly advanced
techniques be available only for select patients, at
specialized centers, or is further clinical development
justified, with the aim of offering widespread, more
definitive therapeutic options for often very difficult to
treat disease? Patients with CD who are eligible for HSCT
have typically been failed by most approved therapies,
have undergone multiple surgeries, and have coped with
years of disease activity and poor quality of life. The
objective of HSCT is to immediately shut down the immune
response and allow the transplanted stem cells to develop
into self-tolerant lymphocytes. For patients with fistulizing
CD, mesenchymal stromal cell therapy deposits MSCs
locally, into fistulizing tracts, to down-regulate the local
immune response and induce wound healing. Recent trials
have produced promising results for HSCT and mesen-
chymal stromal cell therapy as alternatives to systemic
therapies and antibiotics for patients with inflammatory
bowel diseases, but are these immunotherapies ready for
prime time?
Keywords: Inflammatory Bowel Diseases; Hematopoietic Stem
Cell Transplantation; Mesenchymal Stem Cell Transplantation.
T here are 2 types of hematopoietic stem cell trans-
plantation (HSCT). In allogeneic HSCT, the patient’s
bone marrow is ablated and replaced with donor-derived
stem cells.1,2 Allogeneic HSCT is used for patients with
congenital or acquired erythroid, myeloid, and lymphoid
diseases, with the aim of replacing a diseased cell line with a
genetically different healthy one. Autologous HSCT uses the
patient’s own stem cells. Autologous HSCT is commonly
used in patients with diseases with an immune component,
including multiple sclerosis and systemic sclerosis, as well
as Crohn’s disease (CD).3–7 After lympho-ablation and stem
cell rescue, thymic reprocessing results in de novo
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generation of a new T-cell repertoire,8 with restoration of
regulatory T cells (Tregs)9 and resetting of the adaptive
immune system6,7,9,10 including suppression of T-helper 17
cell activities.9,10
Initial Reports of Hematopoietic Stem
Cell Transplantation for Inflammatory
Bowel Diseases
Since the 1990s there have been reports of improve-
ments in incidental CD activity in patients undergoing
autologous HSCT for other indications.11–13 In some these
have been dramatic, amounting to apparent cure in some
patients, while in others improvements have been partial
and/or temporary. This stimulated investigation of HSCT
specifically as a CD treatment. Burt and colleagues14
reported a case series in which all 12 patients improved
before hospital discharge, with slower improvement in
objective measures of disease, and 11 entered sustained
remission during a median follow-up of 18.5 months.
However, in a subsequent larger series, the same group
reported that most patients relapsed, and required rein-
troduction of therapy after 3–4 years. In this way, most
patients achieved disease control with 70% in remission
based on a Crohn’s Disease Activity Index (CDAI) <150, at
any time, >5 years after transplantation.15 Similar results
have been reported from Europe.6,16–19 In a single-center
*Authors share co-first authorship.
Abbreviations used in this paper: AD, adipocyte-derived; BM, bone
marrow; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index;
HSCT, hematopoietic stem cell transplantation; IBD, inflammatory bowel
diseases; IL, interleukin; IPEX, immune dysregulation polyendocrinopathy
enteropathy x-linked; MSCT, mesenchymal stromal cell therapy; SES-CD,
simple endoscopic score for Crohn’s disease; Treg, regulatory T cell;
VEO-IBD, very-early-onset inflammatory bowel diseases.
Most current article
© 2017 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.11.003
390 Hawkey and Hommes
study from Germany, stem cells were successfully collected
after mobilization chemotherapy in 11 of 12 patients and
resulted in a clinical and endoscopic improvement in 7 pa-
tients.16 Subsequent conditioning and HSCT were per-
formed in 9 patients, 5 of whom achieved a clinical and
endoscopic remission within 6 months, although relapses
occurred in 7 patients during follow-up, but disease activity
could be controlled by low-dose corticosteroids and con-
ventional immunosuppressive therapy.16
A Controlled Study of Hematopoietic Stem
Cell Transplantation
The possibility that HSCT might benefit patients with CD
led European investigators to organize the ASTIC (Autolo-
gous Stem Cell Transplantation for Crohn’s Disease) tri-
al20—a multicenter randomized controlled trial in which all
patients underwent stem cell mobilization before they were
randomly assigned to groups given cyclophosphamide-
based HSCT or a control treatment. The primary purpose
of the trial was to investigate how often HSCTs lead to major
improvements that might amount to potential cure, based
on a highly stringent end point that required patients to be:
in symptomatic remission (CDAI <150) for a least 3 months
at the end of the first year after HSCT, off all immunosup-
pressive or biological therapies, and to have a normal
gastrointestinal tract (assessed by endoscopy and radiology
analyses). An important feature of the study was that con-
trol patients were able to undergo deferred HSCT at the end
of the first year, A highly stringent primary end point at 12
months required that patients be off all immunosuppressive
drugs or biological agents, with a normal CDAI and no evi-
dence of active CD which increased the number of patients
with post-HSCT data. Only 2 of 23 patients achieved the
primary end point of the study compare with 1 of 22 in the
control group, showing that cure of CD was rare. However,
exploratory analyses of individual components of the pri-
mary end point, as well as other secondary end points,
suggested significant benefit. Compared with the control
group there was a significant increase in the proportion of
patients able to stop immunosuppressive drugs and near
significant (P < .055) improvement of ileocolonoscopic
findings (Figure 1) and in disease activity measured by CDAI
for the final 3 months.
More recently, data have been presented the course of
all patients undergoing HSCT (including the post-HSCT
course, after the delayed HSCT of the control group).21
Compared to baseline, there were highly significant im-
provements at 1 year for CDAI, patient-reported outcomes,
quality of life (based on IBDQ and EQ-5D questionnaires),
and ileocolonoscopic findings, based on the simple endo-
scopic score for CD (SES-CD). Remarkably 26% of patients
had no ileocolonoscopic evidence of CD (SES-CD score of
0 in all segments examined) and there was complete healing
of active ulceration in 50% of patients. There was a poor
correlation in outcomes based on CDAI and on ileocolono-
scopic assessment. On univariate analysis, baseline factors
associated with steroid free clinical remission (CDAI <150)
at 1 year included an inflammatory phenotype with colonic
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Gastroenterology Vol. 152, No. 2
localization and a high SES-CD score, indicating objectively
active disease. This finding indicates that some patients may
have failed to respond because their symptoms more re-
flected secondary structural or functional consequences of
prolonged severe disease. There was no suggestion that
HSCT had a favorable effect on fistula healing.
The probable benefits of HSCT suggested by these
exploratory analyses must be balanced against the risks of
the procedure.19,20 In the ASTIC trial, adverse events and
serious adverse events were frequent and particularly com-
mon in the 100 days after conditioning and trans-
plantation.20,21 Both bacterial and viral infections were
increased, but it is not clear whether they were more com-
mon compared with use of HSCT in other conditions, as might
be expected as a result of prolonged immunosuppression and
the risks of sepsis associated with CD. One patient died and
had evidence of the sinusoidal obstructive syndrome after-
ward. This is a recognized complication of HSCT chemo-
therapy. It is unclear whether sinusoidal obstructive
syndrome was directly drug induced in this patient or a
consequence of sepsis, but there is a need to minimize
exposure to cytotoxic drugs in future studies.22,23 Strict
management protocols may reduce risks of infection.19
Allogeneic Hematopoietic Stem
Cell Transplantation
Allogeneic HSCT has been used in the treatment of very-
early-onset IBD (VEO-IBD), defined as IBD presenting in
patients younger than 6 years old. VEO-IBD may be caused
by well recognized primary immunodeficiency syndromes,
such as chronic granulomatous disease, Wiskott
Aldrich
syndrome, agammaglobulinemia, or subacute combined
immunodeficiency syndrome.24 Modern methods of genetic
screening have led to the identification of new monogenic
defects associated with VEO-IBD, including those affecting
interleukin (IL) 10 or the IL10 signaling pathway, which has
been associated with development of IBD, with colonic
localization and fistulization as prominent features.24–30 In
addition, VEO-IBD may be part of a broader pattern of im-
mune dysregulation, observed in patients with immune
dysregulation polyendocrinopathy enteropathy x-linked
(IPEX) syndrome (in which mutations in FOXP3 lead to
dysfunction of Tregs and multiple autoimmune manifesta-
tions) or patients with mutations of X-linked inhibitor of
apoptosis, (which cause lymphoproliferative disease and
predispose to hemophagocytic syndrome).24,31–33 The
greatest reported experience of allogeneic HSCT has been in
patients with IL10 signaling defects25–30 and IPEX,31,32 with
regression of enterocolitis and healing of perianal disease
and fistulae, as well as regression of other manifestations in
IPEX. Similar improvements have also been reported for X-
linked inhibitor of apoptosis,33 although not necessarily for
mutations associated with defective barrier function, such
as nuclear factor kB essential modulator protein (NEMO),
where development of IBD after allogeneic HSCT, despite
correction of immune dysfunction, has been reported.24
Remission of CD in adults undergoing allogeneic HSCT for
other reasons has also been described, with outcomes that
January 2017
Figure 1. Changes in Ileo-
colonoscopic activity. Pa-
tients undergoing
immediate (left panel) or
delayed (by 1 year, left
panel) HSCT, based on
SES-CD score. Individual
data are shown. Bold
hatched lines indicate pa-
tients that had entirely
normal appearances at 1
and/or 2 years.
can fairly be described as cure in many patients,27 but the
risks of the procedure and availability of other treatments
have inhibited specific investigation for CD.
Is Hematopoietic Stem Cell Transplantation
Ready for Patients With Inflammatory
Bowel Diseases?
The poor outcome in untreated patients with VEO-IBD,
the limited range of alternative treatments and the
apparent benefit of allogeneic HSCT, albeit in a small num-
ber of cases, indicate that this therapy may be ready for
treatment of some patients with severe VEO-IBD. Positive
results have been reported, particularly in patients with
IL10 signaling defects, IPEX, and probably X-linked inhibitor
of apoptosis. Early diagnosis based on a high index of sus-
picion and candidate gene or next generation sequencing in
young children with suggestive features is important in the
identification of candidates for HSCT. Although there are
few data from controlled trials (and there are unlikely to be
any soon, for ethical reasons), the improvements seen in
appropriately selected cases are convincing. It is possible,
however, that allogenic HSCT could be overtaken by gene
therapy manipulations of endogenous T cells in some
conditions.
HSCT is not ready for prime time in adults with idio-
pathic CD. Arguably, HSCT may be more effective than an-
tagonists of tumor necrosis factor
a, adhesion molecules,
or IL12 and IL23,28 but the greater safety of these treat-
ments undermines any case for HSCT. If HSCT is to become a
significant treatment approach for CD, patient populations
who will benefit need to be better identified and safer
treatment protocols need to be devised. Findings from the
ASTIC trial indicate a greater benefit for patients with a
severe uncomplicated colonic phenotype, which implies
early intervention before complicated penetrating or sten-
ozing phenotypes develop. An important mechanistic
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Stem Cell Therapy for IBD 391
question is whether HSCT has different effectiveness in
patients whose Crohn’s disease is predominantly due to
abnormalities in innate vs adaptive immune processes.
Predictive genotypic analyses and expression studies may
need to be developed. Lower-intensity conditioning regi-
mens, with reduced cytotoxic exposure, including its
reduction or elimination in mobilization protocols and the
use of strict safety protocols will also be important.
Mesenchymal Stromal Cell Therapy
Alexander Friedenstein (1924–1998) discovered the
cellular basis of the hematopoietic microenvironment in
bone marrow (BM) and established its reservoir function of
stem cells for mesenchymal tissues, including osteoblasts,
chondrocytes, and adipocytes. In the early 1970s he isolated
adherent, fibroblast-like, clonogenic cells (colony-forming
unit-fibroblast) with a high replicative capacity in vitro.34 It
took 2 decades before the term mesenchymal stromal cell
(MSC) was generally adopted. However, it was not clear
whether MSCs were true stem cells or multipotent precur-
sor cells.35 The terms stem cell and stromal cell were used
interchangeably due to the mix of stem- and stromal cell-
like properties of these cells, but the ability to self-renew
and the tri-lineage differentiation potential (osteogenic,
chondrogenic, and adipogenic) seemed essential. In 2006,
the International Society for Cellular Therapy published
their position statement on the definition for MSCs. These
state that MSCs must be plastic-adherent when maintained
in standard culture conditions; must express CD105, CD73,
and CD90; must lack expression of CD45, CD34, CD14, or
CD11b, CD79a or CD19 and HLA-DR surface molecules; and
must be able to differentiate in vitro into osteoblasts, adi-
pocytes, and chondroblasts.36
In addition to BM, MSCs can be found in a variety of
tissues including adipose tissue,37 synovial tissue,38 lung
tissue,39 umbilical cord blood,40 and peripheral blood.41 It
392 Hawkey and Hommes
has been proposed, however, that these cell populations
might be intrinsically different based upon secretome dif-
ferences: cell-specific differences at transcriptional and
proteomic levels were reported between adipocyte-derived
(AD) MSCs and BM-derived MSCs, as well as functional
differences in their differentiation potential.42 Whereas only
0.001%
0.002% of BM cells are MSCs, up to 1% of adipose
cells are estimated to be stem cells, which offers economy of
scale for production purposes.43
How Do Mesenchymal Stromal Cells
Reduce Inflammation?
Although the specific mechanisms of the immunoregula-
tory abilities of MSCs are poorly understood, these cells ex-
press immunosuppressive molecules and various growth
factors that facilitate tissue repair and maintain immune
homeostasis (Figure 2). Importantly, MSCs do not constitu-
tively exert their immunomodulating properties, but require
priming by inflammatory mediators released from activated
immune cells, such as interferon gamma, IL1B, or tumor ne-
crosis factor.44,45 MSCs have shown potential in tissue repair,
increasing epithelialization, formation of granulation tissue,
and neovascularization.46 This accelerated wound healing
could be of particular importance in fistulizing CD.
One reason that translational MSC research and devel-
opment have increased in popularity is due to their low
immunogenicity and their expansion potential, allowing off
the shelf treatment with allogeneic cells.47 MSCs have no
antigen-presenting properties and do not express major
histocompatibility complex class II or co-stimulatory mole-
cules. Expanded MSCs do not stimulate T-cell proliferation
in mixed lymphocyte reactions and are also able to down-
regulate alloreactive T-cell responses when added to
mixed lymphocyte cultures.48–51
Figure 2. Effects of MSCs on the immune response. MSCs effectively avoid immune recognition (A). They have immune-
modulatory properties (B) and promote tissue healing (C).
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Gastroenterology Vol. 152, No. 2
Immune Modulatory Properties of Mesenchymal
Stromal Cells
MSCs suppress activation of many different types of
immune cells, including dendritic cells and B and T
cells.52–54 Cell interactions seem to be required to suppress
T-cell proliferation48; high-affinity binding is achieved
through the expression of integrins and adhesion mole-
cules.55 In addition, primed MSCs secrete a wide range of
soluble immunomodulatory factors, including hepatic
growth factor, transforming growth factor
b, indoleamine
2,3-dioxygenase, prostaglandin E2, nitric oxide, and IL6 and
IL10.56 Prostaglandin E2 is a potent immunosuppressive
molecule produced by MSCs when primed by inflammatory
cytokines such as interferon gamma and tumor necrosis
factor.57 MSC expression of indoleamine 2,3-di-oxygenase
induces T-cell apoptosis and cell cycle arrest, which greatly
contribute to the immunosuppressive effects.58 Regulatory
T cells express the receptor for IL2 (CD25) and FOXP3, and
are essential in restoring IBD immune homeostasis. Primed
MSCs are capable to promote the generation of classic
CD4þCD25þFoxp3 Tregs.59,60 MSC-exposed Tregs are more
immunosuppressive than nonexposed Tregs, which is likely
to be regulated by an up-regulation of programmed cell
death 1 receptor on Treg cells.61
Tissue Regenerative Properties of Mesenchymal
Stromal Cells
In addition to the anti-inflammatory properties of MSCs
described here, which are most likely enhanced due to sig-
nificant priming in the cytokine-rich environment of active
fistulizing tracts, MSCs are believed to have critical roles in
repairing damaged tissues.62 They have been shown to
regulate wound healing through secretion of paracrine
growth factors, including transforming growth factor
b and
January 2017
fibroblast growth factor.63 Transforming growth factor
b
mediates the wound healing process as a potent fibrosis
promoting factor driving the formation of granulation tissue,
myofibroblast transformation and re-epithelialization.64
MSCs can differentiate into regenerative effector cells,
such as keratinocytes, fibroblasts, and endothelial cells,
which accelerate wound closure and increase vasculariza-
tion, granulation, tissue formation, and re-epi-
thelialization.65–69
Findings From Preclinical Studies
Preclinical studies of cell-based therapies investigate
issues, such as safety, feasibility, dose, and mechanism of
action. Preclinical studies of MSC therapy (MSCT) for IBD
are a challenge because mice and rats with colitis are not
good models of IBD, there are no accurate models for fis-
tulizing disease, and MSCs differ from human MSCs.70
What has been a relevant preclinical evaluation is the,
not yet completely understood and complex process of
migration and homing to sites of inflammation after intra-
venous administration. After intravenous injection, cells
initially become entrapped in the lungs before migrating to
the liver and spleen and further down to other sites of
inflammation in response to inflammatory mediators. Re-
searchers have used bioluminescence imaging to track MSCs
post-infusion and found them to be rapidly cleared from the
circulation. The MSCs initially become entrapped within the
lungs for a few days until they begin to exit and migrate to
the liver, spleen, kidneys, and BM.71–73 This process is
accelerated in the presence of injury or inflammation, pre-
sumably regulated by inflammatory mediators.71
Mesenchymal Stromal Cells Therapies for
Different Disorders
More than 700 studies are registered at ClinicalTrials.
gov that evaluate MSCT for a wide range of diseases,
including graft vs host disease, kidney diseases, myocardial
infarction, joint disorders, acute respiratory distress syn-
drome, diabetes, liver diseases, and many more. Less than
3% of these studies involve patients with IBD; in these,
development is focused mainly on early and mid-stage dis-
ease, safety, and dose.
The safety of MSCT was analyzed for 36 clinical MSC
trials involving 1087 patients with cardiovascular, neuro-
logical, hemato-oncologic, or gastrointestinal diseases; the
maximum follow-up period was 60 months.74 Except for a
transient fever, no significant safety signals were identified,
including no evidence of increased susceptibility to infec-
tion. Although concerns from preclinical studies were raised
related to potential tumorigenicity of MSCs,75 pooled ana-
lyses did not find an association between MSCs and tumor
formation.74
Relevant for clinical application is whether freezing and
thawing has a negative effect on MSC potency. Despite the
use of various cryopreservatives, frozen MSCs may undergo
apoptosis during the thawing process. Two studies
demonstrated that indeed the freeze
thaw process nega-
tively influenced MSC potency: they were not as effective in
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Stem Cell Therapy for IBD 393
potency assays as continuously cultured MSCs of the same
passage number and it took up to 24 hours for the cells to
regain potency.76 Another study demonstrated reduced MSC
responsiveness to pro-inflammatory stimuli, impaired pro-
duction of anti-inflammatory mediators, and complement
activation of freeze-thawed MSCs compared with continu-
ously cultured cells.72 In this study, the authors performed a
retrospective evaluation of patients who underwent HSCT
and MSCT. The authors showed that the use of MSCs
continuously cultured MSCs at low passage produced a rate
of response twice that observed in a comparable group of
patients given freshly thawed cells at higher passage (100%
vs 50%).77
More recently, freshly thawed vs continuously cultured
MSC potency was tested in a mouse model of allergic airway
inflammation.78 Researchers observed no difference in ef-
fects of fresh vs thawed MSCs on any of the outcomes,
except for some variability in the effects on the bron-
choalveolar lavage fluid composition. These results
demonstrated that thawed MSCs were as effective as fresh
MSCs. So it seems that for commercial purposes, very
rigorous quality assessment and quality control protocols
need to be in place for potency testing before clinical use.
Mesenchymal Stromal Cell Therapy for Patients
With Inflammatory Bowel Diseases
Most studies have been evaluating MSCs for treatment of
luminal or fistulizing CD. Only 2 studies of patients with ul-
cerative colitis are recruiting patients. These studies will
administer 3  106 cells/kg umbilical-cord-derived (UM)
MSCs intravenously each week for 3 weeks, and 1  106 cells/
kg BM MSCs intravenously each week for 8 weeks.79,80 Two
other studies of patients with ulcerative colitis, posted in 2010
and 2013, evaluate intravenous or intra-mesenteric artery
administered UM MSCs and intra-mucosal delivered AD-MSCs.
Findings have not been reported from these studies.81,82
Table 1 summarizes findings published on MSCT for
fistulizing or luminal CD. Four open-label studies have been
performed for patients with luminal CD.83–86
Intravenous Mesenchymal Stromal Cell Therapy
In 2006, an open-label, randomized phase 2 pilot study
investigated the safety and efficacy of a low (2 million cells/
kg) or high (8 million cells/kg) intravenous dose of
prochymal—a BM-derived universal donor formulation of
human MSCs, in 10 patients with moderate to severe CD. In
an abstract, the authors reported a significant decrease in
CDAI score in 9 patients by day 28 (mean decrease in CDAI
score of 105).83 However, in 2009, Osiris Therapeutics
discontinued a follow-up phase 3 study of prochymal in
patients with CD after enrollment of 210 patients, due to a
significantly higher than expected rate of response to
placebo.
In the 3 other studies, designed primarily to assess safety
and feasibility, different concentrations of BM MSCs were
given at various weekly intervals; the CDAI was used to assess
clinical response (see Table 1). One study included 10
refractory CD patients who underwent bone marrow
 394
Hawkey and Hommes
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Table 1.Effects of Mesenchymal Stromal Cell Therapy for Fistulizing and Luminal Crohn’s Disease

Patients,
No. Year Study phase Design n Cell type Dose Observation Reference
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Fistulizing CD
1 2005 1 Open-label 4 AD-MSC Unknown Remission: 50% of 87
patients, 75% fistulas
2 2009 2 Nonblinded, randomized 14 AD-MSC 20/60.10E6 Remission: 71% 88,89
vs 14% placebo
3 2011 1 Open-label 10 BM-MSC 50.10E6 Remission: 7 of 10 (70%) 90,91
4 2013 1 Open-label, dose-escalating 10 AD-MSC 10/20/40.10E6 Remission: 0%/50%/33% 92
5 2013 1 Open-label 43 AD-MSC 30/60.10E6 Remission: 27 of 33 (82%) 93,94
6 2013 1 Open-label 24 AD-MSC 20/60.10E6 Remission: 56.3% 95
7 2015 Compassionate use Open-label 3 AD-MSC Unknown Remission 1 of 3 (33%) 96
8 2015 2 Double-blind 21 BM-MSC 10/30/90.10E6 Remission: 40%/80%/20% 97
RCT vs 16.7% placebo
9 2016a 1–2 Open-label 10 AD-MSC 20/40.10E6 Remission: 60% 98
10 2016b 3 Double-blind 212 AD-MSC 120.10E6 Remission: 49.5% 99
RCT vs 34.3% placebo
Luminal CD
1 2006b 1 Open-label 9 BM-MSC 2  2/8.10E6/kg Response: 9 of 9 83
patients, mean
decrease CDAI ¼ 105
2 2010 1 Open-label 9 BM-MSC 2  1/2.10E6/kg Response: 3 of 9 patients, 84
CDAI decrease >70
3 2014 2 Open-label 15 BM-MSC 4  2.10E6/kg Response: 12 of 15 85
patients, mean
decrease CDAI ¼ 211
1  2/5/10.10E6/kg

Gastroenterology Vol. 152, No. 2

4 2016 1 Open-label 12 BM-MSC Response: 5 of 12 patients 86

RCT, randomized controlled trial.

a
Rectovaginal fistula.
b
Published in abstract form only.
January 2017
aspiration to harvest their own BM MSCs which, after ex vivo
expansion, were given back in 2 doses of 1–2  106 cells/kg
body weight, intravenously, 7 days apart.84 Reduced pe-
ripheral blood mononuclear cell proliferation was observed
in vitro. MSC infusion was without side effects, besides a mild
allergic reaction probably due to the cryopreserving dimethyl
sulfoxide in 1 patient. The baseline median CDAI score was
326 (range, 224–378). Three patients had a clinical response
(decrease in CDAI score 70 from baseline) 6 weeks after the
procedure. Conversely, 3 patients required surgery due to
disease worsening.84 Currently, 2 trials of i.v. MSCT are
registered as active but not completed.79,80
Local Mesenchymal Stromal Cell Therapy for
Fistulizing Crohn’s Disease
Table 1 presents findings from studies of MSCT in patients
with fistulizing CD.87–99 After a range of phase 1 and phase 2
studies, in which, in some cases, remarkable fistula healing
was observed, a controlled, dose-finding study was per-
formed.97 Twenty-one patients with CD with refractory
perianal fistulas were randomly assigned to groups given
injections of 1, 3, or 9  10E7 of allogeneic MSCs derived from
BM aspirate of healthy donors, or placebo, into the fistula
wall. The primary efficacy end point at week 12 was a
reduction in the number of draining fistulas determined by
absence of discharge at physical examination and absence of
collections of 2 cm directly related to the treated fistula tracts,
measured by magnetic resonance imaging. This end point
was observed in 2 patients in group 1 (40.0%), 4 patients in
group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2
patients in the placebo group (33.3%). A similar pattern was
observed at weeks 6 (significant) and 24.
Results have been reported from a randomized double-
blind, multicenter phase 3 study of allogeneic expanded
adipose-derived stem cells.99 This study included 212 pa-
tients with complex active perianal fistulas; patients
received a single injection of 120 million AD-MSCs or pla-
cebo. The primary end point (measured at week 24) was
combined remission (absence of fistula discharge and <2
cm of fluid collection, based on magnetic resonance imaging
analysis). A significantly greater percentage of patients
receiving MSCs achieved remission (49.5%) than patients
given placebo (34.3%). Median time to clinical remission
was 6.7 weeks for MSC treatment vs 14.6 weeks for placebo.
Cell therapy was well tolerated, with a lower proportion of
patients experiencing treatment-related adverse events
compared with placebo: 17.5% vs 29.4%.99 There are 7
trials evaluating local administration of MSCs (BM-
MSC,80,100–102 AD-MSCs103 and a MSC-loaded bio-absorb-
able fistula plug) for patients with CD.104
Future Directions
MSCT for patients with complex CD and fistulas is nearing
prime time. There are many challenges, such as which type of
MSC is most suitable to achieve optimal immunosuppression
and tissue healing. Studies are also needed to standardize
MSC injection in often complex fistulas with multiple tracts,
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Stem Cell Therapy for IBD 395
to determine optimal dosing and where in the treatment
algorithms should this therapy be placed. Systemic infusion
of MSCs is definitely not yet ready for the clinic and faces
multiple development challenges. Although findings from
preclinical models have revealed the impressive immuno-
modulatory effects of MSCT, studies are needed to determine
the fate of MSCs after infusion—there is evidence that they
are short-lived and do not migrate beyond the lungs after
infusion.105
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tronic version of the article. To access the supplementary
material accompanying this article, visit the online version
of Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.11.003.
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Received August 9, 2016. Accepted November 8, 2016.
Reprint requests
Address requests for reprints to: Daniel Hommes, MD, PhD, Center for
Inflammatory Bowel Diseases, University of California Los Angeles, Los
Angeles, California. e-mail: dhommes@mednet.ucla.edu; fax: (310)206-9906.
Conflicts of interest
The authors disclose no conflicts.
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