Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol
Barron et al. Systematic Reviews
Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol
Carly C. Barron 0 2 3 4
Manoj M. Lalu 0 3 4 8
Duncan J. Stewart 2 6
Dean Fergusson 3 7
Homer Yang 4
David Moher 3
Peter Liu 5
David Mazer 10
P. J. Devereaux 9
Lauralyn McIntyre 1
0 Equal contributors
1 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Department of Medicine (Division of Critical Care), University of Ottawa , 501 Smyth Rd, Box 201, Ottawa, ON K1H 8L6 , Canada
2 Department of Medicine, McMaster University , Hamilton , Canada
3 Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute , Ottawa , Canada
4 Department of Anesthesiology and Pain Medicine, The Ottawa Hospital , Ottawa , Canada
5 The Ottawa Heart Institute , Ottawa , Canada
6 Department of Cell and Molecular Medicine, University of Ottawa , Ottawa , Canada
7 Department of Epidemiology & Community Medicine, University of Ottawa , Ottawa , Canada
8 Regenerative Medicine Program, Ottawa Hospital Research Institute , Ottawa , Canada
9 Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, McMaster University , Hamilton , Canada
10 Department of Anesthesia, St. Michael's Hospital, University of Toronto , Toronto , Canada
Background: Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial. Methods/design: A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling. Discussion: This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.
Mesenchymal stromal cells; Mesenchymal stem cells; Perioperative myocardial infarction; Myocardial infarction; Preclinical; Systematic review protocol
injury, may result in heart failure and life-threatening
arrhythmia. Despite advances in treatment such as
coronary revascularization, some MI patients are left with
extensive cardiac damage and a poor prognosis,
highlighting the need to develop novel therapies to repair
Over the past decade, mesenchymal stromal cells
(MSCs)—also known as adult stem cells, marrow stromal
cells, or mesenchymal stem cells—have emerged as a
potential new therapy for acute MI. These cells can be isolated
from a variety of tissues including bone marrow, adipose
tissue, and the umbilical cord and (because they appear to be
relatively immune privileged) can be subsequently delivered
as an allogeneic product to patients [
]. In individual studies
using preclinical models of acute MI, MSCs have been
demonstrated to augment tissue repair, improve cardiac function
], dampen the inflammatory response [
], and potentially
reduce mortality [
]. However, these preclinical studies have
not been systematically summarized to examine the efficacy
of these cells in acute MI. Members of our group and others
have demonstrated that MSC therapy acts via a myriad of
paracrine pathways to dampen inflammation and augment
]. Moreover, MSCs can improve cellular
energetics by transferring mitochondria [
]. This is unlike
drug-based therapeutics which largely act via “lock-and-key”
mechanisms in which a specific substrate binds to a single
active site matching its structure.
We are particularly interested in perioperative MI, which
is an MI that occurs in the setting of inflammation and
increased oxygen consumption induced by surgery [
Perioperative MI is associated with poor outcomes,
including a 30-day mortality of ~ 12% (vs. 2% for
postsurgical patients without perioperative MI) . Given the
cytoprotective effects of MSCs, they may be particularly
beneficial in the highly pro-inflammatory and catabolic
setting of perioperative MI (see Fig. 1). Prior to considering
a first-in-human clinical trial of MSC therapy for
perioperative MI, we propose a comprehensive synthesis of
the published literature. These data will determine whether
additional evidence gaps remain to warrant further
preclinical work, as well as future directions of MI research.
The specific aims of this systematic review are as follows:
1. To systematically compare the efficacy and safety of
MSC therapy versus control in preclinical MI. Our
primary outcome is left ventricular ejection fraction.
Secondary endpoints include death, other measures
of cardiac function, inflammatory markers, and
vessel density. Tertiary endpoints will include
cellular retention and differentiation.
2. Threats to internal validity will be evaluated using a
modified version of the Cochrane Risk of Bias Tool
for preclinical studies [
]. We will determine
whether risk of bias influences the magnitude and
direction of the primary endpoint.
3. External validity will be evaluated using subgroup
analyses to measure how various sources of
preclinical study heterogeneity (e.g., type of MI
model, animal species, severity of MI) affect the
direction and magnitude of the primary outcome.
4. Construct validity will be examined to evaluate the
degree preclinical studies of MSC therapy for MI
incorporate elements of clinical perioperative MI
(e.g., pathophysiological elements), as this will be the
focus of our future clinical trial.
Methods and design
This systematic review protocol is reported in accordance
with the Preferred Reporting Items for Systematic Review
and Meta-Analysis Protocols (PRISMA-P) reporting
]. A summary of the protocol will be listed on the
Collaborative Approach to Meta-Analysis and Review of
Animal Data from Experimental Studies (CAMARADES)
website (http://www.camarades.info). The final review will be
reported using the PRISMA guidelines [
We will search the following databases Ovid MEDLINE®,
Ovid MEDLINE® In-Process & Other Non-Indexed
Citations, Embase Classic + Embase, and BIOSIS. In
addition, a manual review of the bibliographies of selected
articles (e.g., reviews) will be performed.
Search strategies will be developed by our research team
in collaboration with an information specialist. Prior to
final implementation, all strategies will undergo Peer
Review of Electronic Search Strategies (PRESS) by another
senior information specialist [
]. Search strategies will
use controlled vocabulary (e.g., Mesenchymal Stromal
Cells) and keywords (e.g., MSCs) with adjustment for each
database. We will apply preclinical filters to increase
search efficiency [
]. Duplicate citations will be
removed. The example search strategy (see Additional file 1)
was used to search in MEDLINE.
Eligible studies include controlled comparative studies of
preclinical MI or cardiac ischemia-reperfusion injury. We
will include studies in which true randomization is
performed using a method with a low risk of selection bias
(such as computer random number generators and random
number tables), as well as those that are quasi-randomized
(i.e., by day of week or alternation) and non-randomized.
This broad range of comparative studies will be included in
order to answer our study question as terminology and
methodology that is commonplace in clinical studies is not
routinely employed in preclinical studies, and previous
reviews have shown that randomization is reported in a third
or less of animal studies [
]. Only peer-reviewed
publications will be eligible with no restriction to publication year.
We will include all preclinical in vivo models of
experimentally induced MI that mimic pathophysiological aspects of
clinical MI (see Table 1). Included studies will be
Ligation of the left
Open chest, closed chest
Liquid nitrogen cooled copper probe used to
injure coronary vessel
Injection of automicrothrombotic particulates
Watanabe heritable hyperlipidemic rabbits with
acute induced infarction
Direct electorcauterization of a coronary vessel
aAll included models must provide an anesthetic either pre-induction or
concurrent with the induction of myocardial infarction
perioperative (i.e., anesthetic provided before or concurrent
to acute MI). In vitro studies, ex vivo studies, and neonatal
MI models will be excluded.
Studies using MSCs will be included; the International
Society of Cellular Therapy consensus statement
defining criteria for MSCs will be used as a guide [
will include MSCs from xenogeneic, syngeneic, or
allogeneic sources of any tissue origin. All delivery routes,
including direct myocardial injection, intravenous and
intra-arterial, will be considered. To be eligible, MSCs
must be administered as a pretreatment or no later than
7 days following the induction of MI. This timing has
been chosen to reflect the possible interventional
window for a perioperative clinical trial.
Our focus will be on non-manipulated cells as this will be
the intervention in a potential future trial. We will exclude
differentiated MSCs (e.g., differentiated into a myocyte),
genetically engineered MSCs, and MSCs administered by a
scaffold system. Studies using MSCs only modified for
cellular identification (e.g., reporter gene systems or
nanoparticles) will be included. We will also exclude studies that
investigate another novel agent as a co-treatment.
All studies with a control arm of animals that have had
experimental MI or cardiac ischemia-reperfusion injury
(diseased control animals) induced and were treated
with placebo/vehicle will be included.
Left ventricular ejection fraction (LVEF), measured as a
continuous variable at specific time points after MSC or
control intervention, will be the primary endpoint. LVEF is
a clinically meaningful endpoint since it has been linked to
mortality following MI [
]. Physiologically, LVEF
determines stroke volume, which together with heart rate
determines cardiac output. It is also a feasible outcome as it is
the most commonly reported cardiac function measure in
preclinical studies [
]. Various techniques are used to
measure LVEF including two- or three-dimensional
echocardiography, magnetic resonance imaging, and computed
tomography. In our review, we will include and describe all
techniques of LVEF measurement.
Secondary outcomes will be a combination of dichotomous
and continuous measures. A detailed listing of secondary/
tertiary outcomes is provided in Table 2. Given the large
number of outcomes, these results will be considered
exploratory and interpreted cautiously. Secondary
endpoints will include measures of cardiac function by
echocardiography (e.g., cardiac output, fractional
shortening, left ventricle end diastolic diameter, left ventricle end
systolic diameter) and cardiac catheterization (e.g., left
ventricular end diastolic pressure, left ventricular end systolic
pressure, mean pulmonary artery pressure, right ventricular
systolic pressure), biochemical outcomes (e.g., cytokines),
infarct size, and vessel density. These measurements will
provide additional support as to whether MSCs preserve
ventricular function and prevent the pathological
remodeling that occurs after MI. Furthermore, data on biochemical
markers will help elucidate the role MSC therapy plays in
regulating cellular and molecular mechanisms involved in
the pro-inflammatory state following MI. Death will also be
recorded; however, few studies use this endpoint due to
considerations for animal welfare [
]. The occurrence of
adverse events/negative effects with MSC administration
will be recorded.
Tertiary endpoints will include MSC retention and
differentiation (see Table 2). While our primary and secondary
endpoints focus on measures that evaluate the efficacy of
MSCs, the homing and potential differentiation of MSCs
in myocardial tissue is also of interest.
The primary outcome of left ventricle ejection fraction
and secondary biochemical outcomes and death will be
collected at baseline, < 6 h, 6–24 h, > 24–72 h, > 72 h–
1 week, > 1–3 weeks, > 3–4 weeks, and > 4 weeks after the
administration of MSCs versus controls. These detailed
intervals reflect the evolution of inflammation and
remodeling in MI, described by our group and others [
In preclinical models of myocardial infarction, robust
increases in expression of cytokines such as TNF-α, IL-1β,
and IL-6 have been noted immediately after myocardial
injury and up to 24 h later [
]. This is followed by a
chronic remodeling phase in which cardiomyocytes are
replaced by granulation tissue and a scar is formed at the
infarct. Scar formation has been demonstrated by
approximately day 14 post-infarct in mice, while a canine
infarct is still evolving at this time point [
our prespecified time intervals will capture outcomes
during the post-infarct inflammatory response and repair of
cardiac function in both small and large animal models of
MI. All other secondary outcomes of cardiac function and
tertiary outcomes of retention and engraftment will be
collected at the latest time point, > 4 weeks after
administration, to capture these measurements after the
proinflammatory state and repair has occurred.
Study selection and data extraction
Studies will be screened independently by two reviewers
using dedicated cloud-based software (DistillerSR, Evidence
Partners, Ottawa, Canada). Using the previously described
a priori inclusion criteria, first level screening (title/abstract)
will be liberal with both reviewers needed to exclude an
article and one reviewer needed to include. We will be using
an accelerated screening method for the title and abstracts
in which the second reviewer will review records excluded
by the first reviewer [
]. Second level screening (full study)
will be performed independently in duplicate. If there are
disagreements, the two individuals involved will review the
case. If they cannot come to an agreement, a senior team
member will provide the final decision. Reasons for
exclusion will be recorded to enable a transparent selection
Information from included studies will be collected on
electronic data extraction forms. General categories
include study characteristics (e.g., design), study population
(e.g., species), MI model (e.g., cryoinjury), intervention
and comparison (e.g., MSC dose), co-interventions (e.g.,
immunosuppressants, antibiotics, and cardiac
medications), and preclinical outcomes (e.g., ejection fraction).
Data extraction forms will be prepared a priori, and a
calibration exercise will pilot five studies to refine the forms
and ensure inter-rater consistency. Examples of data
collection elements can be seen in Table 3.
Risk of bias assessment
As there is no validated tool to assess risk of bias in animal
studies, we will describe potential biases using a modified
version of The Cochrane Risk of Bias Assessment Tool
]. Items include concealment of allocation, random
sequence generation, blinding of personnel and endpoint
measurements, and completeness of endpoint reporting.
We will include additional domains relevant to animal
studies such as source of funding, conflict of interest,
sample size calculations, similarity of groups or adjustment for
confounders at baseline, random housing of animals, and
animal selection at random for outcome assessment. Risk
of bias assessment will be carried out in duplicate by two
independent reviewers. Disagreements will be resolved
using the same process listed above. Each criterion will be
assigned a value of low, high, or unclear risk of bias for each
included study. A summary for all included studies will be
presented in a table format. We have planned an analysis to
determine the effects of high vs. low risk of bias on the
effect size of the primary outcome.
Assessment of external and construct validity
In preclinical studies, external validity describes the ability to
generalize findings to different experimental conditions.
External validity will be assessed by subgroup analysis of the
primary outcome based on species, strain, age, sex, presence
of intercurrent illness, MI model, ischemic time (if an
ischemia-reperfusion model), MSC source (animal/tissue),
timing of MSC administration (pretreatment vs. rescue)
administration route, type of control, use of co-interventions
(antibiotic, immunosuppressant, antihypertensive, statin,
βblocker, antiplatelet, anticoagulant therapies, all yes vs. no),
and single versus multicenter study. Given the large number
of analyses planned, they will be used in an exploratory
manner and the results interpreted with caution. Examining
the effect of differences in experimental design will inform
aspects of a future clinical trial.
In preclinical studies, construct validity refers to the
extent an animal model corresponds to the clinical entity it
is intended to represent [
]. Construct validity will be
assessed in relation to the extent the experimental systems
model the clinical entity of perioperative MI using a
framework based on expert opinion (see Table 4). It will
help determine whether the included studies enable
reliable causal inference and generalization to a potential
clinical study of MSCs for perioperative MI.
Strategy for data synthesis
Search results will be presented in a PRISMA study flow
]. Categorical variables will be summarized by
Abbreviations: MI myocardial infarction, PeriopMI perioperative myocardial
aRecommendations to reduce threats to construct validity were identified by
Henderson et al. [
bConstruct validity criteria suggested by ≥40% of included guidelines included
frequencies/percentages, and continuous variables will be
summarized by means and standard deviations or median
and interquartile ranges, depending on data distribution.
Dichotomous endpoints (e.g., death) from each included
study will be pooled and described as odds ratios and 95%
confidence intervals. Results from outcomes with discrete
data will be pooled, and meta-analysis will be performed
with inverse variance random effects modeling.
Continuous endpoints will be pooled using the ratio of weighted
means method with inverse variance random effects
]. Ratio of means allows for pooling of outcomes
expressed in different units and comparisons of effect
sizes across interventions. As ratio of means is well suited
for the small sample sizes of animal studies, and provides
a result in a form similar to a risk ratio, we have chosen
this method because of its simplified clinical
interpretation. Statistical heterogeneity will be examined using I2
tests with 95% uncertainty intervals [
sensitivity analyses will examine heterogeneity of the primary
outcome. These will be carried out according to risk of bias
assessments. Selective outcome reporting will be assessed
using the excess significance test (comparing the expected
percentage of significant results vs. actual reported effects)
]. An evaluation for the presence of publication bias
will be conducted with funnel plot techniques and Egger’s
regression test [
Several knowledge users of the results of this systematic
review have been identified. These include the Canadian
Perioperative Anesthesia Clinical Trials (PACT) Group,
a network of academic perioperative medicine
researchers that develop team-based approaches to
investigate perioperative clinical and basic science questions
(www.canadianpact.ca). Our other knowledge users
include the Canadian Council on Animal Care, Canadian
Society for Atherosclerosis Thrombosis, and Vascular
Biology (www.csatvb.ca) and the Stem Cell Foundation
of Canada (www.stemcellfoundation.ca). Through these
users, our research will reach key perioperative
researchers, preclinical and translational scientists, and
health professionals as well as the lay community.
This work will identify gaps in the current knowledge of
MSC therapy of MI. Publication of our results will also
identify potential future directions of MSC for MI research
as they specifically relate to perioperative MI. Most
importantly, the publication of key findings of the review and
meta-analysis will directly inform a potential clinical trial.
This review proposes to systematically identify and
summarize preclinical evidence that exists regarding
MSC therapy in myocardial infarction models, using a
rigorous methodology. We will assess the effect of MSC
therapy on clinically important outcomes including
cardiac function, infarct size, inflammation, and death.
In our pilot searches, we have identified two published
preclinical reviews that investigated stem cells in both
acute and chronic ischemia models [
]. Our proposed
preclinical review differs significantly from these studies in
several respects. Both previous studies combined results
from various stem cell types and were restricted to large
animal models, whereas our review will focus on MSCs
and consider both small and large animal models. The
search strategies used in these papers identified 39 studies
that used MSCs; however, based on our pilot search using
a comprehensive strategy, we have identified
approximately 200 studies to be included in our review. Most
importantly, the data from these reviews included cell
therapy for chronic heart failure (48% of studies); therapy
of established chronic heart failure has little construct
validity for the acute treatment of MI. Thus, our review will
provide novel evidence to determine if a clinical study of
MSCs for MI is warranted.
Given that less than 5% of high impact preclinical
reports are clinically translated [
] and only 11% of
clinically tested agents receive licensing, rigorous appraisal
of preclinical data is needed prior to clinical testing of
novel therapeutics. Historically, failed translation
(preclinical to clinical) of specific therapies for stroke [
and heart failure [
] could have been predicted by
systematic reviews of animal data. Thus, our review is
critical prior to conducting a resource intensive trial.
Furthermore, since the design of these preclinical
studies wil include administration of anesthetic and
disease induction that likely differs from spontaneous
MI, this review also provides a unique opportunity to
determine if MSCs may have efficacy in clinical
perioperative MI. This question is of particular interest to our
group as therapies that are effective in prevention of
nonoperative MI have failed to show benefit in perioperative
] and there are currently few therapies for
established perioperative MI. Given what is known about
the mechanism of action of MSCs, they may be highly
effective in the pro-inflammatory state that occurs with
In summary, this review will be the first to provide an
estimate of efficacy and safety of MSC therapy in preclinical
models of MI. This will ultimately help determine whether
sufficient evidence exists to support a first-in-human
evaluation of MSC therapy for perioperative MI. Additionally,
the results of this study will identify knowledge gaps and
potential future areas of study in MI research.
Additional file 1: Description: representative search strategy. (DOCX 13 kb)
LVEF: Left ventricular ejection fraction; MI: Myocardial infarction;
MSCs: Mesenchymal stromal cells
CB was funded by a Faculty of Medicine Canadian Institutes of Health
Research Summer Studentship and an Undergraduate Research Opportunity
Award both from the University of Ottawa, ON, Canada.
MML was a post-doctoral fellow supported by the Heart and Stroke Foundation of
Canada and The Ottawa Hospital Anesthesia Alternate Funds Association. We thank
Risa Shorr (Librarian and Information Specialist, The Ottawa Hospital, Ottawa, ON,
Canada) for providing assistance with the generation of a systematic search strategy.
This work received no external funding.
Availability of data and materials
MML, LM, and CCB conceived the study design and were responsible for the
initial drafting and manuscript revisions. DJS, DF, HY, DMo, PL, DMa and PJD
provided critical feedback for protocol development and the final
manuscript. MML is the guarantor of the review. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
David Moher is the chief editor of Systematic Reviews. Duncan Stewart is the
President CEO of Northern Therapeutics. The remaining authors have no
competing interests to declare.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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