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Therapeutic potential of mesenchymal stromal cells in experimental
Bronchopulmonary dysplasia: protocol for a systematic review.
1Sajit Augustine, 2Marc T Avey, 2,3David Moher, 4,5Bernard Thébaud.
* Corresponding Author: Bernard Thébaud. Email: [email protected], Ottawa
Hospital Research Institute, Sprott Centre for Stem Cell Research, 501 Smyth Rd.,
Ottawa, ON K1H 8L6, Canada, Phone: 613-737-8899, Fax: 613-739-6294.
1. Department of Neonatology, Children’s Hospital of Eastern Ontario, Ottawa,
ON, Canada.
2. Clinical Epidemiology Program, The Ottawa Hospital Research Institute,
Ottawa, ON, Canada
3. School of Epidemiology, Public Health and Preventive Medicine, Faculty of
Medicine, University of Ottawa, Ottawa, ON, Canada
4. Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott
Centre for Stem Cell Research, Ottawa, Ontario, Canada
5. Department of Pediatrics, Children’s Hospital of Eastern Ontario Research
Institute, University of Ottawa, Ottawa, Ontario, Canada
Abstract
Background: Bronchopulmonary dysplasia (BPD), the chronic lung disease
of prematurity, complicates the medical course of approximately 40% of
infants born <28 weeks preterm, resulting in long term pulmonary and
neurodevelopmental sequelae with a high economic burden. Current
therapies are supportive. Preclinical evidence suggests that mesenchymal
stromal cells (MSC) improve neonatal lung inflammation, function and
structure in experimental models of BPD. This systematic review of
preclinical studies in experimental BPD will assess the current evidence on
the therapeutic potential of MSC in experimental BPD and thus help guide
the design of human clinical trials.
Methods/Design: We will include preclinical, in vivo, controlled comparative
studies of neonatal animal models of BPD who would have received MSCs
or cell free MSC-derived conditioned media compared to healthy controls or
animal models of BPD that haven’t received MSCs. The primary outcome
measure is improved lung histology and secondary outcomes will include
survival, lung function, exercise capacity, lung fibrosis, lung inflammation,
oxidative stress, pulmonary hypertension and right ventricular hypertrophy,
pulmonary vascular growth, safety, weight gain, and long term outcome.
Electronic searches of MEDLINE, Embase, Pubmed and Web of Science will
be constructed and results will be screened independently and in duplicate.
Study selection would be according to PRISMA guidelines. Data from
eligible studies will be analyzed using random effects models. Risk of bias
will be assessed by two reviewers using SYRCLE’s Risk of Bias tool for
animal studies.
Discussion: The results of this systematic review would put into perspective
all the preclinical evidence on the therapeutic potential and safety of MSC in
BPD and also highlight methodological flaws and bring more rigour in the
design of future studies, both experimental and clinical.
Keywords: Mesenchymal stromal cells, Mesenchymal stem cells,
Bronchopulmonary dysplasia, Preclinical, Systematic review protocol.
Background
Bronchopulmonary dysplasia (BPD), the chronic lung disease of
prematurity, is the most common and serious sequelae in extreme
premature infants. BPD, defined as oxygen dependence at 36 weeks post-
menstrual age, complicates the course of approximately 40% of infants
born <28 weeks gestation (1). Over the last decade, the incidence of BPD
increased slightly (2, 3). BPD is a multifactorial disease. While the
strongest association is with preterm birth, other factors such as prenatal
infection and inflammation, mechanical ventilation, oxygen toxicity,
decreased host antioxidant defenses, patent ductus arteriosus, and
postnatal infection all contribute to the pathogenesis of BPD (4).
The “old form” of BPD, originally described by Northway and colleagues (5)
was characterized by severe lung injury, including inflammation, protein-
rich lung edema, extensive airway epithelial metaplasia, peribronchial
fibrosis, and marked airway and pulmonary vascular smooth muscle
hypertrophy (6–8). In contrast, in the era of antenatal steroids, surfactant
replacement, lung protective ventilation and improved nutrition, survival of
more immature infants born during the canalicular and saccular stages of
lung development appears to disrupt the normal program of alveolar and
vascular development, resulting in the “new BPD,” characterized by
alveolar simplification, dysmorphic capillaries, and remodeling of the
vascular and airway smooth muscle layer (9-11).
Although of great clinical relevance, elucidating the pathophysiology of
neonatal chronic lung disease in the postsurfactant era has become
increasingly challenging. With the reduction in BPD-associated mortality
(12), the availability of pathologic specimens has decreased. Furthermore,
there is a paucity of in vitro systems that effectively model the complex 3-
dimensional processes of alveolar formation and vascularization. Thus,
defining the pathophysiology of BPD has relied, to a large extent, on the
detailed observations made in animal models that mimic many features of
this condition. Knowledge gained from these animal models has provided
great insight into the pathophysiology of the old and new forms of BPD and
has led to changes in clinical management (13).
BPD results in long term pulmonary and neurodevelopmental sequelae that
extend beyond childhood with a high economic burden (14) (15)(16). Many
pharmacological and non-pharmacological approaches have been tested for
the prevention and treatment of BPD. Antenatal steroids, protective
ventilation strategies, targeted oxygen saturation goals, caffeine, vitamin
A, and optimization of nutrition have contributed modestly in decreasing
the incidence/severity of BPD. Most current therapies are supportive.
Recently the therapeutic potential of stem cells has attracted attention.
Stem cells have the potential of self-renewal and can differentiate into
specialized cell types thereby promoting organogenesis, tissue
regeneration, maintenance and repair (17). Mesenchymal stromal cells
(MSCs) attracted particular interest because of their ease of isolation,
characterization, apparent multipotency and pleiotropic effects (18). In
experimental models of BPD, MSC reverse alveolar injury and vascular
remodelling, promote alveolarization, attenuate lung fibrosis and
inflammation, decrease pulmonary hypertension, improve exercise
tolerance and survival (19). MSCs exert their therapeutic benefit mainly
through a paracrine activity and this may explain their pleiotropic effects
(20). These data suggest MSCs as a promising therapy to reduce the
incidence/severity of BPD in extreme premature infants.
This systematic review of preclinical studies in animal models mimicking
BPD will assess the current evidence on the therapeutic potential of MSC in
experimental BPD and thus help guide the design of human clinical trials.
Research question
The aim of this systematic review is to address the following research
question: In controlled preclinical studies of BPD, do MSCs reduce the
severity of lung injury?
Methods & Design
Protocol & Registration
The systematic review protocol was developed after extensive discussion
with the scientific research team consisting of clinical (SA, BT) and
preclinical research scientists (BT) and experts in knowledge synthesis and
translation (DM, MA). The PRISMA-P checklist was used to draft the
protocol (21). The PRISMA-P checklist contains 17 items considered to be
essential and minimum components of a systematic review or meta-
analysis protocol. The systematic review protocol is registered on the
Collaborative Approach to Meta-Analysis and Review of Animal Data from
Experimental Studies website (Date XXXX;
http://www.dcn.ed.ac.uk/camarades/research.html#protocols). In the
event of protocol amendments, the date of each amendment will be
accompanied by description of the change and the rationale behind it.
Study eligibility criteria for Experimental Model
Study Design
We will include preclinical, in vivo, controlled comparative studies of
neonatal animal models of BPD. The studies may be randomised, quasi-
randomized, or non-randomised and evaluate the therapeutic potential and
safety of MSCs. Non-interventional studies, studies without controls will be
excluded.
Population
The state of development of the lung at birth greatly varies among species.
At term, the human lung is at the alveolar stage of lung development.
Sheep possess already alveolarized lungs at birth. Conversely, marsupials
and rodents are born with lungs in the late canalicular/early saccular stage,
equivalent to the lung developmental stage of extreme preterm infants,
and are thus ideally suited for structural, ultrastructural and quantitative
investigations. Therefore studies in neonatal rodents have provided
excellent insights into postnatal developmental events (22-24). We will
include all neonatal preclinical in vivo animal models of experimentally
induced BPD. The model will replicate a pattern that is similar to human
BPD. The similarities will include impaired alveolarization, resulting in fewer
and enlarged alveolar air spaces, pulmonary hypertension, disrupted
vascular growth, vascular leakage, accumulation of plasma proteins,
extravascular fibrin deposition, increased lung collagen content, increased
inflammatory cell influx, and disorganized elastin deposition (25).
Experimental BPD may be induced by hyperoxia, mechanical ventilation,
chemical induction (for example Bleomycin, thalidomide, Su-5416 and
fumagillin), or inflammatory mediators (for example LPS, TGF-, TNF-).
We will exclude non-neonatal animal models of lung injury because many of
the pulmonary responses to injury are developmentally regulated. For
example, chronic O2 exposure induces opposite apoptotic and proliferative
responses in neonatal and adult lung cells in rats (26). In mice, hyperoxia
reduces endothelial progenitor cells in the developing lung but not in adult
animals (27).
Intervention
The intervention groups will receive MSCs or cell free MSC-derived
conditioned media (MSC-CM). MSCs can be syngenic or xenogenic and be
derived from various sources (bone marrow, umbilical cord blood, Wharton
jelly, placenta and adipose tissue). MSCs will be defined using the minimal
criteria set out in the International Society for Cellular Therapy (ISCT)(28)
consensus statement. MSCs will be administered intravenously,
intratracheally, intraperitoneally or any other route. MSCs can be
administered prior, during or following the induction of experimental BPD.
Comparison
The comparison group will consist of experimental BPD animal models that
haven’t received MSCs to evaluate the therapeutic potential and safety of
MSC. The comparison group may have received a control cell (for example
pulmonary artery smooth muscle cell, PASMC, lung fibroblasts, dermal
fibroblasts), a control vehicle (phosphate buffered saline) or media (for
example Dulbecco’s modified Eagle’s medium, DMEM). To examine the
severity of BPD we will use other comparison groups with healthy or sham-
surgery animals.
Outcome
Primary outcome: Improved lung histology
The primary outcome measure is improved lung histology as determined by
lung morphometry on histopathology using the following parameters: mean
linear intercept (MLI), radial alveolar count (RAC), or the number of
secondary crests. This will be determined in the experimental BPD animal
model group, which has received MSC or MSC-CM as well as in
experimental BPD animal controls.
Secondary outcome:
Our secondary outcome will include
1. Survival
2. Lung function (for example reversal of bronchial hypereactivity
following methacholine)
3. Exercise capacity (for example by tread mill test)
4. lung fibrosis ( for example by collagen content etc)
5. Lung inflammation (lung macrophage influx, lung neutrophil influx,
TNF-, TGF-, interleukins, myeloperoxidase activity)
6. Oxidative stress
7. Pulmonary hypertension as assessed by echodoppler (pulmonary
arterial acceleration time, PAAT), right ventricular hypertrophy
(Fulton index), and remodelling of the smooth muscle layer of
pulmonary arteries (medial wall thickness)
8. Pulmonary vascular density (von Willebrand positive lung blood
vessels using immunohistochemistry, barium lung angiogram).
9. Safety as determined by tumor formation at predetermined time
points
10. Weight gain
11. Long term outcome (histology, lung function, exercise capacity)
Information sources
Search Strategy: No study design, date or language limits will be imposed
on the search. MEDLINE, EMBASE and Web of Science will be searched
from database inception, PubMed will be searched for specific categories of
records not yet added to MEDLINE. The search strategies will be created by
a Health Sciences Librarian with expertise in systematic review searching,
and may incorporate published strategies to increase the yield of animal
studies (29). The MEDLINE strategy will be developed with input from the
project team, then peer reviewed by a second librarian, not otherwise
associated with the project, using the PRESS standard (30). An exploratory
MEDLINE search strategy is included in Appendix 1. After the MEDLINE
strategy is finalized, it will be adapted to the syntax and subject headings
of the other database.
We will perform a grey literature search of selected conference websites not
covered in the aforementioned databases, and will search the websites of
animal research organizations. The research team will contact authors of
included studies to invite further contribution of any unpublished data
relevant to this review. The bibliographies of included studies and pertinent
reviews will also be hand searched for further preclinical studies.
Unpublished studies will be described in the results section and data from
these studies will be included in any quantitative analyses.
The search will be updated toward the end of the review, after being
validated to ensure that the MEDLINE strategy retrieves a high proportion
of eligible studies found through any means but indexed in MEDLINE.
Information Source Data Management
The literature search results will be used to build the Reference Manager
database and to de-duplicate references.
Study selection
The titles and abstracts of search results will be screened independently by
two investigators. The full text of all potentially eligible studies will be
retrieved and reviewed for eligibility, independently, by two members of the
team using the a priori inclusion criteria described above. Disagreements
between reviewers will be resolved by consensus or by a third member of
the systematic review team. Reasons for exclusion of potentially eligible
studies will be recorded to enable a transparent selection process and to be
in accordance with the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA)(31) guidelines developed for proper reporting
of clinical systematic reviews.
Data Collection and Data Items
Using standardized forms, two reviewers would independently extract data
from each study. Data abstracted will include study design, animal model,
methodology, intervention details, and all reported outcomes. The research
team will contact (maximum of three email attempts) authors of included
studies to invite further contribution of any unpublished data relevant to
this review. Data collected would be deposited in a public repository.
Assessment of Risk of Bias
Risk of bias will be assessed by two reviewers, for each included preclinical
study, using SYRCLE’s Risk of Bias tool for animal studies (32). This tool
contains 10 entries. These entries are related to selection bias,
performance bias, detection bias, attrition bias, reporting bias and other
biases.
Assessment of Construct and External Validity
We will extract study characteristics that are related to the construct and
external validity (33). For construct validity these will include: age, sex,
strain, and animal species, co-morbidities, type of BDP model, timing, dose
and mode of MSC administration, and the use of any co-interventions. For
external validity these will include: if treatment effects have been
demonstrated in more than one model and if they have been replicated by
an independent research group.
Data Synthesis
We will conduct meta-analyses using random-effects model if the data
extracted from eligible studies are homogenous. Dichotomous data
(survival, lung histology, exercise capacity, lung inflammation, lung
fibrosis) will be determined by using risk ratio (RR) with 95% confidence
interval (CI). Continuous outcomes will be analyzed using mean differences
(with 95% CI) or standardized mean differences (95% CI) if different
measurement scales are used.
Sensitivity analyses to examine heterogeneity on the primary outcome of
improvement in lung histology will be carried out according to risk of bias
assessments. Several subgroup analyses to examine preclinical
heterogeneity will be conducted on the primary outcome and will include:
the study design, animal age, sex, species and strain; presence of co-
morbidities; type of experimental induction of BPD; severity of BPD; MSC
preparation; timing of administration of MSCs from induction of
experimental BPD; dose of MSCs; route of MSC administration; type of
controls; use of co-interventions, antibiotics, and mechanical ventilation;
single versus multi-centre study; and presence of an a priori sample size
calculation.
Knowledge Translation
This systematic review will be reported using PRISMA (30). The results of
this systematic review will be distributed by our principal knowledge user
(BT) in Canada through the Stem Cell Network and CellCAN and
internationally through the International Society for Cell Therapies (ISCT).
Several others like Canadian Council on Animal Care in science (CCAC),
Canadian Premature Babies foundation, would be identified and invited to
act as a knowledge user.
BT will also facilitate organization of an end of study knowledge translation
workshop at the Annual Academy of Pediatrics meetings and at the
Canadian Pediatric Society (CPS) meetings with the Canadian Neonatal
Network. Abstracts will be presented at the Academy of Pediatrics meeting,
at CPS and at the Till&McCulloch meeting (Canadian Stem cell meeting).
Discussion
The results of this systematic review will put all the preclinical evidence on
the therapeutic potential of MSC in perspective. The timing cannot be more
appropriate considering the fact that MSCs have attracted most attention
and numerous clinical trials are underway to test their therapeutic potential
for regenerative purposes (34). This systematic review should help
highlight methodological flaws and bring more rigour in the design of new
studies, both experimental and clinical.
Authors’ contributions
BT is the guarantor and principal knowledge user. SA and BT were
responsible for initial drafting and manuscript revisions. SA will be
responsible for the data collection. MA and DM provided critical revisions.
All authors reviewed several drafts of the manuscript and approved the
final version.
Acknowledgements
BT holds a University of Ottawa Partnership Research Chair in Regenerative
Medicine, and is supported by the Canadian Institutes of Health Research
(CIHR), the Canadian Stem Cell Foundation, the Ontario Lung Association,
the Children’s Hospital of Eastern Ontario Research Institute and the
Ottawa Hospital Research Institute. DM holds a University Research Chair.
MTA is funded by a Canadian Institutes of Health Research (CIHR) post-
doctoral fellowship in Knowledge Translation.
Appendix 1
Exploratory MEDLINE search – Ebscohost interface
S3 (MH "Mesenchymal Stromal Cells") AND (MH
"Bronchopulmonary Dysplasia") Limiters – Animals
13
S2 (MH "Mesenchymal Stromal Cells") 16,385
S1 (MH "Bronchopulmonary Dysplasia") 3,175
Appendix 2: Data Collection Form
Category Specific Items
Study Characteristics Study title, authors, language, date of
publication,
journal published, sponsorship, country
of publication, email address
Animal Model Animal species, strain, age, sex, and
weight, presence of co-morbid illnesses
BPD Model Model & Method to mimic BPD: chronic
hyperoxia, mechanical ventilation, chemical
induction (for example Bleomycin,
thalidomide, Su-5416 and fumagillin), or
inflammatory mediators (for example LPS,
TGF-, TNF-)
Severity of BPD
Intervention and comparison Time, dose and route given, description of
preparation and suspension of MSCs and
controls, use of any co-interventions
Outcomes Primary outcome of improved lung histology
as determined by lung morphometry (mean
linear intercept, radial alveolar count,
secondary septae). Secondary outcomes of
survival, lung function, exercise capacity,
lung fibrosis, lung inflammation, pulmonary
hypertension, pulmonary vessel density,
safety as determined by tumor formation at
predetermined time points, weight gain and
long-term outcome
Risk of Bias assessement Using SYRCLE’s Risk of Bias tool for animal
studies containing 10 entries related to
selection bias, performance bias, detection
bias, attrition bias, reporting bias and other
biases.
Quality of reporting In accordance to ARRIVE guidelines
Other Funding source, confict of interest
statement, treatment effect demonstrated
in more than one model replication by
independent group, and presence of a priori
sample size calculation.
Appendix 3
STUDY ELIGIBILITY FORM STUDY ELIGIBILITY FORM FACTORS ASSESSMENT COMMENTS
TYPE OF STUDY
1. Is the study described as Preclinical?
NB: Preclinical can be in vivo animals or non-human
Yes Unclear No
Exclude
2. Is the study described as interventional?
Yes Unclear No
Exclude
3. Is there a control group? Yes Unclear No
Exclude
PARTICIPANTS
4. Is it an animal model of BPD? Yes Unclear No
Exclude
5. Is it a “neonatal” animal model?
Yes Unclear No
Exclude
Subgroups available?
INTERVENTIONS
6. Were comparison groups treated with Mesenchymal
Stromal Cells (MSC) or MSC-Conditioned media (MSC-
CM) in one group and control intervention in other
group?
NB: study can have 3 arms, if so please cross “Yes“ and
state it as comments.
Yes Unclear No
Exclude
6. Intervention with Mesenchymal Stromal Cells (MSC)
or MSC-Conditioned media (MSC-CM) does NOT involve
co-treatment?
Yes Unclear No
Exclude
OUTCOMES
7. Did the study report pre-specified outcomes? Yes Unclear No
Exclude
FINAL DECISION
1 X “No” = EXCLUDE
1 X “Unclear” = UNCLEAR
ORGANISATIONAL ASPECTS EX IN
REF ID Reviewer, Date Checked by
Author, Year
Journal/Source Study ID Not Reported /
Country of origin
Publication type
Fulltext
Abstract
Book chapter
internal progress report
other (please specify)
Other relevant
publications in DE-form
Decision pending
Check references
Use for discussion /
Fate EX without listing
EX with listing
Other (please specify)
Notes / Short description
REASONS FOR EXCLUSION OF STUDY FROM REVIEW (PLEASE SPECIFY according to
protocol
Methods
No Intervention Not MSC/ MSC-CM No Control Other
Population
Not BPD
Human
Invitro Age
Subgroups available?
Outcomes
No relevant outcomes assessed
No data for relevant subgroup extractable
Other
Duplicate publication / Other
NONE Included
CURRENT STATUS: (NAME OF REVIEWER + DATE)
Question to clinician
Question to author
Status verified with study investigators or sponsors: Yes / No
Enter name of the source (e.g. PI, sponsor, etc.) ___________________
Contact address:
3
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