Research Activities

Extreme prematurity is the main cause of child death under age 5. Lung disease remains the leading cause of disease burden in these patients. At no other stage in life is the impact of disability-adjusted life years higher than during the neonatal period. Effective interventions at this stage provide exceptional value. Over the past 10 years, we have focused on umbilical cord cell-based therapies to provide cures for newborns. Optimizing this ideal source of repair cells will also reveal its potential for adult diseases and offers commercialization opportunities. Over the coming 5 years, we will translate our findings into the clinic.

1. Mesenchymal stromal cells (MSCs) for lung repair
We were the first to show that MSCs prevent experimental bronchopulmonary dysplasia (BPD) (Am J Respir Crit Care Med 2009; Thorax 2013). We confirmed these findings in the first neonatal preclinical systematic review and meta-analysis (Stem Cell Transl Med 2017). MSCs, contrary to initial belief, act via a paracrine mechanism rather than by cell replacement. We showed that MSCs can be enhanced by preconditioning (Stem Cells Dev 2012), secrete lung protective factors and modulate lung inflammation (Am J Respir Cell Mol Biol 2012; AJP Lung 2012). We developed the INCuBAToR (Stem Cell Transl Med 2021) to accelerate clinical translation. We are now conducting the first Phase I trial testing the safety and feasibility of cord-derived MSCs in preterm infants.

2. Lung angiogenesis for lung regeneration and pulmonary hypertension (PH)
We showed the critical role of the vascular growth factor VEGF for normal alveolar development and regeneration of alveolar damage after lung injury (Circulation 2005). These findings suggest angiogenesis, previously seen as a passive bystander during lung growth, as a new therapeutic avenue for lung diseases characterized by arrested lung growth. We investigated various strategies to promote angiogenesis and attenuate PH (Circulation 2011; Am J Respir Crit Care Med 2012; Am J Respir Cell Mol Biol 2014). We then described resident endothelial colony forming cells (ECFCs) in the developing human and rat lung and their dysfunction in experimental BPD; cord blood-derived ECFCs promoted lung vascular growth and attenuated PH (Circulation 2014; Nat Protoc 2015). We used single-cell RNA sequencing to show depletion of distal capillary progenitor cells (Nat Commun 2021).

3. AAV-mediated gene therapy for lethal surfactant protein deficiencies
We showed, together with our uGuelph collaborators, that a modified AAV vector with enhanced tropism for distal lung epithelial cells efficiently transduces surfactant protein B in deficient mice leading to dramatic improvement in survival, lung structure and function (Nat Commun 2020). These findings suggest AAV-mediated gene therapy as a clinically viable option for surfactant protein deficiencies. We are currently expanding our AAV platform to other monogenetic lung diseases. 

Our work is supported by:
Canadian Institutes of Health Research
Heart & Stroke Foundation of Canada
Ontario Institute for Regenerative Medicine
Stem Cell Network
Children's Hospital of Eastern Ontario Research Institute
The Ottawa Hospital Foundation
Canada Foundation for Innovation