Publications by authors named "Bernard Thébaud"

132 Publications

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage.

Nat Commun 2021 03 10;12(1):1565. Epub 2021 Mar 10.

Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.
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http://dx.doi.org/10.1038/s41467-021-21865-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946947PMC
March 2021

Fully automated estimation of the mean linear intercept in histopathology images of mouse lung tissue.

J Med Imaging (Bellingham) 2021 Mar 4;8(2):027501. Epub 2021 Mar 4.

Carleton University, Department of Systems and Computer Engineering, Ottawa, Ontario, Canada.

The mean linear intercept (MLI) score is a common metric for quantification of injury in lung histopathology images. The automated estimation of the MLI score is a challenging task because it requires accurate segmentation of different biological components of the lung tissue. Therefore, the most widely used approaches for MLI quantification are based on manual/semi-automated assessment of lung histopathology images, which can be expensive and time-consuming. We describe a fully automated pipeline for MLI estimation, which is capable of producing results comparable to human raters. We use a convolutional neural network based on U-Net architecture to segment the diagnostically relevant tissue segments in the whole slide images (WSI) of the mouse lung tissue. The proposed method extracts multiple field-of-view (FOV) images from the tissue segments and screen the FOV images, rejecting images based on presence of certain biological structures (i.e., blood vessels and bronchi). We used color slicing and region growing for segmentation of different biological structures in each FOV image. The proposed method was tested on ten WSIs from mice and compared against the scores provided by three human raters. In segmenting the relevant tissue segments, our method obtained a mean accuracy, Dice coefficient, and Hausdorff distance of 98.34%, 98.22%, and , respectively. Our proposed method yields a mean precision, recall, and -score of 93.37%, 83.47%, and 87.87%, respectively, in screening of FOV images. There was substantial agreement found between the proposed method and the manual scores (Fleiss Kappa score of 0.76). The mean difference between the calculated MLI score between the automated method and average rater's score was ( ). The proposed pipeline for automated calculation of the MLI score demonstrates high consistency and accuracy with human raters and can be a potential replacement for manual/semi-automated approaches in the field.
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http://dx.doi.org/10.1117/1.JMI.8.2.027501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932085PMC
March 2021

Benefits and obstacles to cell therapy in neonates: The INCuBAToR (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research).

Stem Cells Transl Med 2021 Feb 11. Epub 2021 Feb 11.

Clinical Epidemiology Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, Ontario, Canada.

Cell-based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard-earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell-based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence-based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence-based fashion.
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http://dx.doi.org/10.1002/sctm.20-0508DOI Listing
February 2021

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

Crit Care Med 2021 Feb;49(2):311-323

Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Faculty of Medicine, University of Ottawa, ON, Canada.

Objectives: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia.

Design: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation.

Setting: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results.

Subjects: None.

Interventions: None.

Measurements And Main Results: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback.

Conclusions: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.
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http://dx.doi.org/10.1097/CCM.0000000000004734DOI Listing
February 2021

Looking at the Developing Lung in Single-cell Resolution.

Am J Physiol Lung Cell Mol Physiol 2020 Nov 18. Epub 2020 Nov 18.

Ottawa Hospital Research Institute, Canada.

Lung development is a complicated and delicate process, facilitated by spatially and temporarily coordinated crosstalk of up to 40 cell types. Developmental origin and heterogeneity of lung cell lineages in context of lung development have been a focus of research efforts for decades. Bulk RNA and protein measurements, RNA and protein labelling, and lineage tracing techniques have been traditionally employed. However, the complex and heterogeneous nature of lung tissue presents a particular challenge when identifying subtle changes in gene expression in individual cell types. Rapidly developing single-cell RNA sequencing (scRNA-seq) techniques allow for unbiased and robust assessment of complex cellular dynamics during biological processes in unprecedented ways. Discovered a decade ago, scRNA-seq has been applied in respiratory research to understand lung cellular composition and to identify novel cell types. Still, very few studies to date have addressed the single-cell transcriptome in healthy or aberrantly developing lung. In this mini-review, we discuss principal discoveries with scRNA-seq in the field of prenatal and postnatal lung development. In addition, we examine challenges and expectations, and propose future steps associated with the use of scRNA-seq to study developmental lung diseases.
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http://dx.doi.org/10.1152/ajplung.00385.2020DOI Listing
November 2020

Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

Cochrane Database Syst Rev 2020 08 19;8:CD013202. Epub 2020 Aug 19.

Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.

Background: Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials.

Objectives: To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs.

Data Collection And Analysis: For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence.

Main Results: Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded.

Authors' Conclusions: There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.
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http://dx.doi.org/10.1002/14651858.CD013202.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438027PMC
August 2020

Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants.

Paediatr Child Health 2020 Aug 1;25(5):322-331. Epub 2020 Aug 1.

Canadian Paediatric Society, Fetus and Newborn Committee, Ottawa, Ontario.

Historically, postnatal corticosteroids have been used to prevent and treat bronchopulmonary dysplasia (BPD), a significant cause of morbidity and mortality in preterm infants. Administering dexamethasone to prevent BPD in the first 7 days post-birth has been associated with increasing risk for cerebral palsy, while early inhaled corticosteroids appear to be associated with an increased risk of mortality. Neither medication is presently recommended to prevent BPD. New evidence suggests that prophylactic hydrocortisone, when initiated in the first 48 hours post-birth, at a physiological dose, and in the absence of indomethacin, improves survival without BPD, with no adverse neurodevelopmental effects at 2 years. This therapy may be considered by clinicians for infants at highest risk for BPD. Routine dexamethasone therapy for all ventilator-dependent infants is not recommended, but after the first week post-birth, clinicians may consider a short course of low-dose dexamethasone (0.15 mg/kg/day to 0.2 mg/kg/day) for individual infants at high risk for, or with evolving, BPD. There is no evidence that hydrocortisone is an effective or safe alternative to dexamethasone for treating evolving or established BPD. Current evidence does not support inhaled corticosteroids for the treatment of BPD.
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http://dx.doi.org/10.1093/pch/pxaa073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395322PMC
August 2020

A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency.

Nat Commun 2020 08 6;11(1):3929. Epub 2020 Aug 6.

Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, K1Y 4E9, Canada.

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.
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http://dx.doi.org/10.1038/s41467-020-17577-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414154PMC
August 2020

Characterization of the innate immune response in a novel murine model mimicking bronchopulmonary dysplasia.

Pediatr Res 2020 May 20. Epub 2020 May 20.

Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Background: Bronchopulmonary dysplasia (BPD), the most common complication of prematurity, arises from various factors that compromise lung development, including oxygen and inflammation. Hyperoxia has been used to mimic the disease in newborn rodents. The use of a second hit to induce systemic inflammation has been suggested as an added strategy to better mimic the inflammatory aspect of BPD. Here we report a novel 2 hit (2HIT) BPD model with in-depth characterization of the innate immune response, enabling mechanistic studies of therapies with an immunomodulatory component.

Methods: C57BL/6N mice were exposed to 85% O from postnatal day (P)1 to P7, and received postnatally (P3) Escherichia coli LPS. At various timepoints, immune activation in the lung and at the systemic level was analyzed by fluorescence-activated cell sorting (FACS), and gene and protein expressions.

Results: 2HIT mice showed fewer alveoli, increased lung compliance, and right ventricular hypertrophy. A transient proinflammatory cytokine response was observed locally and systemically. Type 2 anti-inflammatory cytokine expression was decreased in the lung together with the number of mature alveolar macrophages. Simultaneously, a Siglec-F intermediate macrophage population emerged.

Conclusion: This study provides long-term analysis of the 2HIT model, suggesting impairment of type 2 cytokine environment and altered alveolar macrophage profile in the lung.

Impact: We have developed a novel 2HIT mouse BPD model with postnatal LPS and hyperoxia exposure, which enables mechanistic studies of potential therapeutic strategies with an immunomodulatory component. This is the first report of in-depth characterization of the lung injury and recovery describing the evolution of the innate immune response in a standardized mouse model for experimental BPD with postnatal LPS and hyperoxia exposure. The 2HIT model has the potential to help understand the link between inflammation and impaired lung development, and will enable testing of new therapies in a short and more robust manner.
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http://dx.doi.org/10.1038/s41390-020-0967-6DOI Listing
May 2020

Closing gaps, opening doors: an experimental collaboration in stem cell intervention.

Mol Biol Rep 2020 May 6;47(5):4105-4108. Epub 2020 May 6.

University of British Columbia, Vancouver, BC, Canada.

Despite years of warnings by the academic community that for most of the stem cell-based therapies offered in the private arena little evidence of efficacy exists, these services have been increasingly offered by Canadian private clinics. Recently, as the culmination of years of clashes between stem cell researchers and therapy providers, Health Canada issued a statement prohibiting any type of cell therapy that is not specifically approved. In this climate of conflict, a small group representing both these communities as well as the government gathered in Vancouver to identify common values, and agree on principles to move forward constructively. This historic moment demonstrated that even in this contentious space a meeting-of-minds in between researchers, clinicians, ethicists, entrepreneurs and other stakeholders is possible.
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http://dx.doi.org/10.1007/s11033-020-05469-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239812PMC
May 2020

Effect of oxygen saturation targets on the incidence of bronchopulmonary dysplasia and duration of respiratory supports in extremely preterm infants.

Paediatr Child Health 2020 Apr 31;25(3):173-179. Epub 2019 May 31.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario.

Background: Recent clinical practice changes in neonatal care resulted in higher, narrower oxygen saturation target ranges for preterm infants. The effect of targeting higher or lower oxygen saturations on respiratory outcomes of preterm infants and duration of hospitalization has not been extensively reviewed in the context of current care, but could have significant implications.

Methods: A multicentre retrospective cohort of 145 preterm infants was conducted; 105 had lower oxygen saturation targets (88 to 92%), 40 had higher targets (90 to 95%). The primary outcome was bronchopulmonary dysplasia (BPD). Secondary outcomes included duration of invasive/noninvasive respiratory support, oxygen therapy, and hospitalization. The primary outcome was compared using Fisher's exact test. Secondary outcomes were evaluated with survival analysis and Wilcoxon rank sum test.

Results: The difference in incidence of BPD in the lower (N=56, 53.3%) and higher saturation groups (N=14, 35.0%) was not statistically significant (relative risk [RR]=0.66 [0.41, 1.04], P=0.06). The difference in duration of mechanical ventilation in the lower (median 7.8 days, interquartile range [IQR] 3.7 to 15.9) and higher saturation groups (median 4.5, IQR 1.9 to 12.3) approached statistical significance (P=0.05). There were no statistically significant differences in the durations of other respiratory supports or hospital stay between the two groups.

Conclusions: The results of this study approached statistical significance and suggest that higher, narrower oxygen saturation targets may result in a clinically important reduction in BPD incidence and duration of mechanical ventilation. These results require validation in a larger sample to refine optimal targets.
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http://dx.doi.org/10.1093/pch/pxz058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147701PMC
April 2020

Lifetime patient outcomes and healthcare utilization for Bronchopulmonary dysplasia (BPD) and extreme preterm infants: a microsimulation study.

BMC Pediatr 2020 03 25;20(1):136. Epub 2020 Mar 25.

Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada.

Background: Bronchopulmonary dysplasia (BPD) is among the most severe chronic lung diseases and predominantly affects premature infants. There is a general understanding of BPD's significant impact on the short-term outcomes however there is little evidence on long-term outcomes. Our study estimates the lifetime clinical outcomes, quality of life, and healthcare costs of BPD and associated complications.

Methods: We developed a microsimulation model to estimate lifetime clinical and economic burden of BPD among extreme preterm infants (≤28 weeks gestational age at birth) and validated it against the best available Canadian data. We further estimate the cumulative incidence of major complications associated with BPD, differentiated by BPD severity and gestational age category.

Results: We find, on average, patients with BPD and resulting complications will incur over CAD$700,000 in lifetime health systems costs. We also find the average life expectancy of BPD patients to be moderately less than that of the general population and significant reductions in quality-adjusted life year due to major complications. Healthcare utilization and quality of life measures vary dramatically according to BPD severity, suggesting significant therapeutic headroom for interventions that can prevent or mitigate the effects of BPD for patients.

Conclusions: Our study adds a significant expansion of existing evidence by presenting the lifetime burden of BPD based on key patient characteristics. Given the extreme cost burden at the earliest stage of life and lifetime negative impact on quality of life, there is larger headroom for investment in prevention and mitigation of severe BPD than is currently available.
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http://dx.doi.org/10.1186/s12887-020-02037-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093972PMC
March 2020

How to introduce MSC-based therapy for the developing lung safely into clinical care?

Pediatr Res 2020 09 13;88(3):365-368. Epub 2020 Jan 13.

Department of Pediatrics, Division of Neonatology, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Extreme prematurity is associated with an increased risk to develop bronchopulmonary dysplasia (BPD). Severe BPD is associated with a significant long-term burden for the affected infant, families and society. Currently there are limited prevention and treatment options. Regenerative approaches using mesenchymal stromal cells (MSC) are associated with promising benefits in animal experiments. First clinical studies, using MSC in humans, suggest safety. To accelerate the process of bench to bed-side development of MSC-based therapies, a global and collaborative approach is needed that includes all key stakeholders. Results of a workshop that was held during the Pediatric Academic Societies meeting in 2019 are summarized. A roadmap is provided discussing next steps of bringing MSC-based interventions into clinical practice.
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http://dx.doi.org/10.1038/s41390-020-0758-0DOI Listing
September 2020

Late Rescue Therapy with Cord-Derived Mesenchymal Stromal Cells for Established Lung Injury in Experimental Bronchopulmonary Dysplasia.

Stem Cells Dev 2020 03 10;29(6):364-371. Epub 2020 Feb 10.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Sinclair Center for Regenerative Medicine, Ottawa, Canada.

Bronchopulmonary dysplasia (BPD), the main complication of extreme prematurity, has lifelong consequences for lung health. Mesenchymal stromal cells (MSCs) prevent lung injury in experimental BPD in newborn rodents when given in the immediate neonatal period. Whether MSC therapy can restore normal lung growth after established lung injury in adulthood is clinically relevant, but currently unknown. Experimental BPD was achieved by exposing newborn rats to 95% O from postnatal days 4-14. Human umbilical cord-derived MSCs were intratracheally administered to rats (1 × 10cells/kg body weight) as a single dose at 3 or 6 months of age followed by assessment at 5 or 8 months of age, respectively. Lung alveolar structure and vessel density were histologically analyzed. O-exposed rats exhibited persistent lung injury characterized by arrested alveolar growth with airspace enlargement and a lower vessel density at both 5 and 8 months of age compared with controls. Single-dose MSC treatment at 3 months partially attenuated O-induced alveolar injury and restored vessel density at 5 months. Treatment with a single dose at 6 months did not attenuate alveolar injury or vessel density at 8 months. However, treatment with multiple MSC doses at 6, 6.5, 7, and 7.5 months significantly attenuated alveolar injury and improved vessel density at 8 months of age. Treatment of the adult BPD lung with MSCs has the potential to improve lung injury if administered in multiple doses or at an early stage of adulthood.
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http://dx.doi.org/10.1089/scd.2019.0116DOI Listing
March 2020

Are all stem cells equal? Systematic review, evidence map, and meta-analyses of preclinical stem cell-based therapies for bronchopulmonary dysplasia.

Stem Cells Transl Med 2020 Feb 20;9(2):158-168. Epub 2019 Nov 20.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Regenerative stem cell-based therapies for bronchopulmonary dysplasia (BPD), the most common preterm birth complication, demonstrate promise in animals. Failure to objectively appraise available preclinical data and identify knowledge gaps could jeopardize clinical translation. We performed a systematic review and network meta-analysis (NMA) of preclinical studies testing cell-based therapies in experimental neonatal lung injury. Fifty-three studies assessing 15 different cell-based therapies were identified: 35 studied the effects of mesenchymal stromal cells (MSCs) almost exclusively in hyperoxic rodent models of BPD. Exploratory NMAs, for select outcomes, suggest that MSCs are the most effective therapy. Although a broad range of promising cell-based therapies has been assessed, few head-to-head comparisons and unclear risk of bias exists. Successful clinical translation of cell-based therapies demands robust preclinical experimental design with appropriately blinded, randomized, and statistically powered studies, based on biological plausibility for a given cell product, in standardized models and endpoints with transparent reporting.
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http://dx.doi.org/10.1002/sctm.19-0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988768PMC
February 2020

Bronchopulmonary dysplasia.

Nat Rev Dis Primers 2019 11 14;5(1):78. Epub 2019 Nov 14.

Cincinnati Children's Hospital Medical Center, Division of Neonatology, Pulmonary Biology, University of Cincinnati, Cincinnati, OH, USA.

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.
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http://dx.doi.org/10.1038/s41572-019-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986462PMC
November 2019

Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants.

Cochrane Database Syst Rev 2019 09 24;9:CD013201. Epub 2019 Sep 24.

Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden.

Background: Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a substantial issue in neonatal intensive care units worldwide. Current therapies to prevent or treat GMH-IVH are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, and/or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies.

Objectives: To determine the benefits and harms of stem cell-based interventions for prevention or treatment of germinal matrix-intraventricular haemorrhage (GM-IVH) in preterm infants.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; MEDLINE via PubMed (1966 to 7 January 2019); Embase (1980 to 7 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 7 January 2019). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: We attempted to identify randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing (1) stem cell-based interventions versus control; (2) mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; (3) stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or (4) MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH.

Data Collection And Analysis: For each of the included trials, two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs, other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). Primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, GM-IVH, and extension of pre-existing non-severe GM-IVH. We planned to use the GRADE approach to assess the quality of evidence.

Main Results: Our search strategy yielded 769 references. We did not find any completed studies for inclusion. One randomised controlled trial is currently registered and ongoing. Five phase 1 trials are described in the excluded studies.

Authors' Conclusions: Currently no evidence is available to show the benefits or harms of stem cell-based interventions for treatment or prevention of GM-IVH in preterm infants.
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http://dx.doi.org/10.1002/14651858.CD013201.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757514PMC
September 2019

Factors Impacting Physician Recommendation for Tracheostomy Placement in Pediatric Prolonged Mechanical Ventilation: A Cross-Sectional Survey on Stated Practice.

Pediatr Crit Care Med 2019 09;20(9):e423-e431

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.

Objectives: To characterize the stated practices of qualified Canadian physicians toward tracheostomy for pediatric prolonged mechanical ventilation and whether subspecialty and comorbid conditions impact attitudes toward tracheostomy.

Design: Cross sectional web-based survey.

Subjects: Pediatric intensivists, neonatologists, respirologists, and otolaryngology-head and neck surgeons practicing at 16 tertiary academic Canadian pediatric hospitals.

Interventions: Respondents answered a survey based on three cases (Case 1: neonate with bronchopulmonary dysplasia; Cases 2 and 3: children 1 and 10 years old with pediatric acute respiratory distress syndrome, respectively) including a series of alterations in relevant clinical variables.

Measurements And Main Results: We compared respondents' likelihood of recommending tracheostomy at 3 weeks of mechanical ventilation and evaluated the effects of various clinical changes on physician willingness to recommend tracheostomy and their impact on preferred timing (≤ 3 wk or > 3 wk of mechanical ventilation). Response rate was 165 of 396 (42%). Of those respondents who indicated they had the expertise, 47 of 121 (38.8%), 23 of 93 (24.7%), and 40 of 87 (46.0%) would recommend tracheostomy at less than or equal to 3 weeks of mechanical ventilation for cases 1, 2, and 3, respectively (p < 0.05 Case 2 vs 3). Upper airway obstruction was associated with increased willingness to recommend earlier tracheostomy. Life-limiting condition, severe neurologic injury, unrepaired congenital heart disease, multiple organ system failure, and noninvasive ventilation were associated with a decreased willingness to recommend tracheostomy.

Conclusion: This survey provides insight in to the stated practice patterns of Canadian physicians who care for children requiring prolonged mechanical ventilation. Physicians remain reluctant to recommend tracheostomy for children requiring prolonged mechanical ventilation due to lung disease alone at 3 weeks of mechanical ventilation. Prospective studies characterizing actual physician practice toward tracheostomy for pediatric prolonged mechanical ventilation and evaluating the impact of tracheostomy timing on clinically important outcomes are needed as the next step toward harmonizing care delivery for such patients.
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http://dx.doi.org/10.1097/PCC.0000000000002046DOI Listing
September 2019

Stem Cells for Extreme Prematurity.

Authors:
Bernard Thébaud

Am J Perinatol 2019 07 25;36(S 02):S68-S73. Epub 2019 Jun 25.

Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Regenerative medicine is a bourgeoning field promising to repair damaged organs and thus has created high hopes in neonatology to curb some of the complications due to extreme preterm birth. Extensive laboratory investigations over the past 15 years have tried to harness the regenerative potential of a variety of (stem) cell-based therapies. Most preclinical studies have focused on experimental neonatal lung and brain injury. These promising results lead to the initiation of phase I clinical trials for chronic lung disease of prematurity and severe intraventricular hemorrhage, two of the most devastating complications of extreme preterm birth. Despite this relative rapid clinical translation, major gaps persist in our understanding of the biology of these putative repair cells and our ability to predict the quality and thus the efficacy of the cell product. This review will provide a brief overview of the various cell-based therapies that have been investigated in experimental neonatal lung injury and the remaining challenges in utilizing these new, disruptive therapies to their full extend to realize the promise of regenerative medicine in neonatology.
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http://dx.doi.org/10.1055/s-0039-1691774DOI Listing
July 2019

Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges.

Pediatr Res 2020 01 14;87(2):265-276. Epub 2019 May 14.

Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.

Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.
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http://dx.doi.org/10.1038/s41390-019-0425-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854309PMC
January 2020

So You Want to Give Stem Cells to Babies? Neonatologists and Parents' Views to Optimize Clinical Trials.

J Pediatr 2019 07 17;210:41-47.e1. Epub 2019 Apr 17.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Objective: To identify barriers and enablers that may influence parents' and neonatologists' participation in clinical trials of mesenchymal stromal cells for bronchopulmonary dysplasia.

Study Design: This qualitative study involved one-on-one semistructured interviews with parents of extremely preterm infants (n = 18) and neonatologists (n = 16). Interview guides and directed content analysis were framed using the theoretical domains framework, a tool specifically developed for implementation research to identify influences on behavior.

Results: Key barriers for parents included their lack of knowledge about clinical trial processes in general, stem cells, and concerns about their risks and side effects. Importantly, parents preferred to be approached for recruitment directly by a neonatologist, either before delivery or 1 or 2 weeks after birth. However, the majority of neonatologists felt that approaching parents was not part of their role. Neonatologists reported competing priorities, time commitment, costs, and lack of institutional support as significant barriers to their ability to recruit patients.

Conclusions: By integrating stakeholders early into the development of a clinical trial of mesenchymal stromal cell therapy, we identified and can address important barriers to enrollment. Some identified barriers were unanticipated and could have compromised recruitment had they not been identified by this study. We suggest that this approach can be used more broadly for other early phase clinical trials in pediatrics.
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http://dx.doi.org/10.1016/j.jpeds.2019.03.005DOI Listing
July 2019

Endothelial cells of different organs exhibit heterogeneity in von Willebrand factor expression in response to hypoxia.

Atherosclerosis 2019 03 12;282:1-10. Epub 2019 Jan 12.

Department of Medicine, University of Alberta, Edmonton, Canada. Electronic address:

Background And Aims: We have previously demonstrated that in response to hypoxia, von Willebrand factor (VWF) expression is upregulated in lung and heart endothelial cells both in vitro and in vivo, but not in kidney endothelial cells. The aim of our current study was to determine whether endothelial cells of different organs employ distinct molecular mechanisms to mediate VWF response to hypoxia.

Methods: We used cultured human primary lung, heart and kidney endothelial cells to determine the activation of endogenous VWF as well as exogenously expressed VWF promoter in response to hypoxia. Chromatin immunoprecipitation and siRNA knockdown analyses were used to determine the roles of VWF promoter associated transacting factors in mediating its hypoxia response. Platelet aggregates formations in vascular beds of mice were used as a marker for potential functional consequences of hypoxia-induced VWF upregulation in vivo.

Results: Our analyses demonstrated that while Yin Yang 1 (YY1) and specificity protein 1 (Sp1) participate in the hypoxia-induced upregulation of VWF specifically in lung endothelial cells, GATA6 mediates this process specifically in heart endothelial cells. In both cell types, the response to hypoxia involves the decreased association of the NFIB repressor with the VWF promoter, and the increased acetylation of the promoter-associated histone H4. In mice exposed to hypoxia, the upregulation of VWF expression was concomitant with the presence of thrombi in heart and lung, but not kidney vascular beds.

Conclusions: Heart and lung endothelial cells demonstrated VWF upregulation in response to hypoxia, using distinct mechanisms, while this response was lacking in kidney endothelial cells.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.01.002DOI Listing
March 2019

Oxygen Disrupts Human Fetal Lung Mesenchymal Cells. Implications for Bronchopulmonary Dysplasia.

Am J Respir Cell Mol Biol 2019 05;60(5):592-600

3 Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Exogenous mesenchymal stromal cells (MSCs) ameliorate experimental bronchopulmonary dysplasia. Moreover, data from term-born animal models and human tracheal aspirate-derived cells suggest altered mesenchymal signaling in the pathophysiology of neonatal lung disease. We hypothesized that hyperoxia, a factor contributing to the development of bronchopulmonary dysplasia, perturbs human lung-resident MSC function. Mesenchymal cells were isolated from human fetal lung tissue (16-18 wk of gestation), characterized and cultured in conditions resembling either intrauterine (5% O) or extrauterine (21% and 60% O) atmospheres. Secretome data were compared with MSCs obtained from term umbilical cord tissues. The human fetal lung mesenchyme almost exclusively contains CD146 MSCs expressing SOX-2 and OCT-4, which secrete elastin, fibroblast growth factors 7 and 10, vascular endothelial growth factor, angiogenin, and other lung cell-protecting/-maturing proteins. Exposure to extrauterine atmospheres leads to excessive proliferation, reduced colony-forming ability, alterations in the cell's surface marker profile, decreased elastin deposition, and impaired secretion of factors important for lung growth. Conversely, umbilical cord-derived MSCs abundantly secreted factors that impaired lung MSCs are unable to produce. Oxygen-impaired human fetal lung MSC function may contribute to disrupted repair capacity and arrested lung growth. Exogenous MSCs may act by triggering the signaling pathways lost by impaired endogenous lung mesenchymal cells.
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http://dx.doi.org/10.1165/rcmb.2018-0358OCDOI Listing
May 2019

Endothelial colony-forming cell therapy for heart morphological changes after neonatal high oxygen exposure in rats, a model of complications of prematurity.

Physiol Rep 2018 Nov;6(22):e13922

Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Very preterm birth is associated with increased cardiovascular diseases and changes in myocardial structure. The current study aimed to investigate the impact of endothelial colony-forming cell (ECFC) treatment on heart morphological changes in the experimental model of neonatal high oxygen (O )-induced cardiomyopathy, mimicking prematurity-related conditions. Sprague-Dawley rat pups exposed to 95% O or room air (RA) from day 4 (P4) to day 14 (P14) were randomized to receive (jugular vein) exogenous human cord blood ECFC or vehicle at P14 (n = 5 RA-vehicle, n = 8 RA-ECFC, n = 8 O -vehicle and n = 7 O -ECFC) and the hearts collected at P28. Body and heart weights and heart to body weight ratio did not differ between groups. ECFC treatment prevented the increase in cardiomyocyte surface area in both the left (LV) and right (RV) ventricles of the O group (O -ECFC vs. O -vehicle LV: 121 ± 13 vs. 179 ± 21 μm , RV: 118 ± 12 vs. 169 ± 21 μm ). In O rats, ECFC treatment was also associated with a significant reduction in interstitial fibrosis in both ventricles (O -ECFC vs. O -vehicle LV: 1.07 ± 0.47 vs. 1.68 ± 0.41% of surface area, RV: 1.01 ± 0.74 vs. 1.77 ± 0.67%) and in perivascular fibrosis in the LV (2.29 ± 0.47 vs. 3.85 ± 1.23%) but in not the RV (1.95 ± 0.95 vs. 2.74 ± 1.14), and with increased expression of angiogenesis marker CD31. ECFC treatment had no effect on cardiomyocyte surface area or on tissue fibrosis of RA rats. Human cord blood ECFC treatment prevented cardiomyocyte hypertrophy and myocardial and perivascular fibrosis observed after neonatal high O exposure. ECFC could constitute a new regenerative therapy against cardiac sequelae caused by deleterious conditions of prematurity.
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http://dx.doi.org/10.14814/phy2.13922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260919PMC
November 2018

Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Pediatr Res 2019 03 21;85(4):432-441. Epub 2018 Nov 21.

Pediatric Cardiology Department, Ramón y Cajal University Hospital, Madrid, Spain.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.
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http://dx.doi.org/10.1038/s41390-018-0228-0DOI Listing
March 2019

Target oxygen saturation and development of pulmonary hypertension and increased pulmonary vascular resistance in preterm infants.

Pediatr Pulmonol 2019 01 20;54(1):73-81. Epub 2018 Nov 20.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Objective: Determine whether higher targeted oxygen levels are associated with reduced incidence of pulmonary hypertension (PH) and elevated pulmonary vascular resistance (PVR) in extremely premature infants.

Study Design: Retrospective chart review of 252 extremely preterm infants (<29 weeks), who underwent echocardiogram prior to discharge. PH rates were compared during periods (June 2012-May 2015 and June 2015-April 2016) when lower (88-92%) or higher (90-95%) oxygen saturation targets were used. PH was determined on echocardiography. The ratio of pulmonary artery acceleration time to right ventricular ejection time was computed, with values <0.31 indicative of elevated PVR. Survival analysis compared the effects of oxygen saturation group on development/resolution of PH and elevated PVR.

Results: The higher saturation group had significantly lower risk of developing PH (hazard ratio (HR) = 0.50, 95%CI 0.26-0.95; P = 0.03) or elevated PVR (HR = 0.55, 95%CI 0.38-0.81; P = 0.002), compared to the lower oxygen saturation group. Median time to PH development was significantly shorter in the lower saturation group than in the higher saturation group (5 days vs 12 days; P = 0.02), as was time to development of elevated PVR (4 days vs 6 days; P < 0.001). Duration of PH (P = 0.12) and elevated PVR (P = 0.86) did not differ significantly between groups. Cumulative incidence of PH (P = 0.04) and elevated PVR (P = 0.01) at 36 weeks post-menstrual age was significantly lower in the high saturation group compared to the lower saturation group.

Conclusion: Higher targeted oxygen saturation was associated with reduced risk of PH or elevated PVR in extremely preterm infants compared to lower oxygen saturation target.
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http://dx.doi.org/10.1002/ppul.24193DOI Listing
January 2019

Nanotherapies for micropreemies: Stem cells and the secretome in bronchopulmonary dysplasia.

Semin Perinatol 2018 11 6;42(7):453-458. Epub 2018 Oct 6.

Ottawa Hospital Research Institute, Sinclair Centre for Regenerative Medicine, 501 Smyth Rd, Ottawa K1H 8L6, ON, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. Electronic address:

Improved survival of extreme preterm infants has made the task of protecting the ever more immature lung from injury more challenging. As a consequence, the incidence of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, has remained unchanged. The multifactorial disease pathogenesis of BPD - including amongst others inflammation, oxidative stress and excessive lung stretch - adds further complexity to finding effective therapies that would prevent lung injury and promote lung growth. Mesenchymal stromal cells and the discovery of their pleiotropic effects represent an appealing approach for the prevention of BPD. Mesenchymal stromal cells do not engraft but exert their therapeutic benefit through paracrine effects. These paracrine effects seem to be mediated through the release of nanosized extra-cellular vesicles used for cell-cell communication. This review will summarize our current knowledge on these potential nanotherapies for micropreemies.
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http://dx.doi.org/10.1053/j.semperi.2018.09.007DOI Listing
November 2018

Cell-based therapy for bronchopulmonary dysplasia in preterm infants .

Can J Physiol Pharmacol 2019 Mar 5;97(3):232-234. Epub 2018 Oct 5.

a Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Currently, there is no specific treatment available. Preclinical studies support cell therapy as a promising therapy for BPD in preterm infants. A successful translation to a safe and effective clinical intervention depends on multiple factors including the perspective of neonatal health care providers. A 2-hour workshop with 40 Canadian neonatologists was held to enhance the design of a phase II trial of stem cells for babies at risk for BPD, with a focus on the population to target and the outcomes to measure in such a trial. The consensus was that infants recruited in an early trial of stem cells should be the ones with the highest risk of developing severe BPD. This risk should be established based on known antenatal, perinatal, and postnatal risk factors. The primary outcome in a phase II trial will be focussed on a non-clinical outcome (e.g., a dose-finding study or a safety study). With other aspects of a translational study discussed, this workshop contributed to accelerate the design of a first Canadian clinical cell-therapy study for BPD in preterm infants.
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http://dx.doi.org/10.1139/cjpp-2018-0342DOI Listing
March 2019

The Therapeutic Potential of Stem Cells for Bronchopulmonary Dysplasia: "It's About Time" or "Not so Fast" ?

Curr Pediatr Rev 2018 ;14(4):227-238

Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada.

Objective: While the survival of extremely premature infants has improved over the past decades, the rate of complications - especially for bronchopulmonary dysplasia (BPD) - remains unacceptably high. Over the past 50 years, no safe therapy has had a substantial impact on the incidence and severity of BPD.

Methods: This may stem from the multifactorial disease pathogenesis and the increasing lung immaturity. Mesenchymal Stromal Cells (MSCs) display pleiotropic effects and show promising results in neonatal rodents in preventing or rescuing lung injury without adverse effects. Early phase clinical trials are now underway to determine the safety and efficacy of this therapy in extremely premature infants.

Results And Conclusion: This review summarizes our current knowledge about MSCs, their mechanism of action and the results of preclinical studies that provide the rationale for early phase clinical trials and discuss remaining gaps in our knowledge.
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http://dx.doi.org/10.2174/1573396314666180911100503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416190PMC
January 2019

Endothelial Colony-Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease.

J Am Heart Assoc 2018 07 9;7(14). Epub 2018 Jul 9.

Sainte-Justine University Hospital Research Center, Université de Montréal, Quebec, Canada

Background: Preterm birth is linked to cardiovascular risks and diseases. Endothelial progenitor cells play a critical role in vascular development and repair. Cord blood endothelial progenitor cells of preterm-born infants, especially endothelial colony-forming cells (ECFC), show enhanced susceptibility to prematurity-related pro-oxidant stress. Whether ECFC dysfunction is present in adulthood following preterm birth is unknown.

Methods And Results: This cross-sectional observational study includes 55 preterm-born (≤29 gestational weeks) young adults (18-29 years old, 38% male) and 55 sex- and age-matched full-term controls. ECFC were isolated from peripheral blood; cell proliferative and vascular cord formation capacities were assessed in vitro. Daytime systolic blood pressure was higher, whereas glucose tolerance and body mass index were lower in preterm-born subjects. ECFC colonies grew in culture for 62% of full-term- and 58% of preterm-born participants. Preterm-born participants have formed ECFC colonies later in culture and have reduced proliferation compared with controls. Only in preterm-born individuals, we observed that the later the ECFC colony grows in culture, the worse was overall ECFC function. In addition, in preterms, elevated systolic blood pressure significantly correlated with reduced ECFC proliferation (r=-0.463; =0.030) and numbers of branches formed on matrigel (r=-0.443; =0.039). In preterm-born subjects, bronchopulmonary dysplasia was associated with impaired ECFC function, whereas exposure to antenatal steroids related to better ECFC function.

Conclusions: This study is the first to examine ECFC in preterm-born adults and to demonstrate ECFC dysfunction compared with full-term controls. In the preterm-born group, ECFC dysfunction was associated with bronchopulmonary dysplasia, the major prematurity-related neonatal morbidity, and with increased systolic blood pressure into adulthood.
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http://dx.doi.org/10.1161/JAHA.118.009720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064846PMC
July 2018