Labs and Groups
Xplore Lab
Xplore Lab
Team Leader
Bernard Thébaud
Senior Scientist, Regenerative MedicineWhat We Do
Our lab is focused on understanding the mechanisms of lung development, injury and repair in order to design new treatments for incurable lung diseases. We have an ambitious research program set out to study clinically relevant questions in the lab for translation into real-life applications. All animal models of human lung disease are available in our lab, and we correlate structural and functional changes to assess the clinical relevance of the experimental therapies we are testing.
Over the past 10 years, our major research contributions include: (i) the discovery of the role of angiogenesis for normal lung development and repair; (ii) the demonstration of the therapeutic potential of stem cells in experimental bronchopulmonary dysplasia (the chronic lung disease of prematurity), asthma, acute lung injury and pulmonary hypertension; and more recently, (iii) the therapeutic potential of adeno-associated virus (AAV)-mediated gene therapy for surfactant protein deficiency.
We are now translating innovative cell and gene therapies from the lab into patients to improve outcomes.
Over the past 10 years, our major research contributions include: (i) the discovery of the role of angiogenesis for normal lung development and repair; (ii) the demonstration of the therapeutic potential of stem cells in experimental bronchopulmonary dysplasia (the chronic lung disease of prematurity), asthma, acute lung injury and pulmonary hypertension; and more recently, (iii) the therapeutic potential of adeno-associated virus (AAV)-mediated gene therapy for surfactant protein deficiency.
We are now translating innovative cell and gene therapies from the lab into patients to improve outcomes.
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. We are now translating innovative cell and gene therapies from the lab into patients to improve outcomes.
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). Both papers were editorialized. 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: they secrete lung protective factors, modulate lung inflammation and can be enhanced by preconditioning (Am J Respir Cell Mol Biol 2012; AJP Lung 2012; Stem Cells Dev 2012). We developed the INCuBAToR (Stem Cell Transl Med 2021) to accelerate the clinical translation of these innovative therapies. We are now conducting the first phase I trial testing the safety and feasibility of cord-derived MSC in preterm infants (NCT04255147). We used single-cell RNA sequencing to establish the first atlas of normal and impaired lung growth (Nat Commun 2021).
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 lung regeneration after 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 confirmed the role of angiocrine factors in lung angiogenesis and their ability to attenuate PH (Circulation 2011, Am J Respir Crit Care Med 2012, Am J Respir Cell Mol Biol 2014). We then identified resident endothelial colony forming cells (ECFCs) in the developing lung and their dysfunction in experimental BPD; cord blood-derived ECFCs promoted lung vascular growth and attenuated PH (Circulation 2014; Nat Protoc 2015).
3. AAV-mediated gene therapy for lethal surfactant protein deficiencies
We showed 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), suggesting 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.
Funded by:
Canadian Institutes of Health Research
Heart & Stroke Foundation of Canada
Stem Cell Network
Children's Hospital of Eastern Ontario Research Institute
The Ottawa Hospital Foundation
Canada Foundation for Innovation
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). Both papers were editorialized. 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: they secrete lung protective factors, modulate lung inflammation and can be enhanced by preconditioning (Am J Respir Cell Mol Biol 2012; AJP Lung 2012; Stem Cells Dev 2012). We developed the INCuBAToR (Stem Cell Transl Med 2021) to accelerate the clinical translation of these innovative therapies. We are now conducting the first phase I trial testing the safety and feasibility of cord-derived MSC in preterm infants (NCT04255147). We used single-cell RNA sequencing to establish the first atlas of normal and impaired lung growth (Nat Commun 2021).
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 lung regeneration after 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 confirmed the role of angiocrine factors in lung angiogenesis and their ability to attenuate PH (Circulation 2011, Am J Respir Crit Care Med 2012, Am J Respir Cell Mol Biol 2014). We then identified resident endothelial colony forming cells (ECFCs) in the developing lung and their dysfunction in experimental BPD; cord blood-derived ECFCs promoted lung vascular growth and attenuated PH (Circulation 2014; Nat Protoc 2015).
3. AAV-mediated gene therapy for lethal surfactant protein deficiencies
We showed 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), suggesting 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.
Funded by:
Canadian Institutes of Health Research
Heart & Stroke Foundation of Canada
Stem Cell Network
Children's Hospital of Eastern Ontario Research Institute
The Ottawa Hospital Foundation
Canada Foundation for Innovation
Selected Publications
Cyr-Depauw C, Cook DP, Mizik I, Lesage F, Vadivel A, Renesme L, Deng Y, Zhong S, Bardin P, Möbius MA, Marzahn J, Freund D, Stewart DJ, Vanderhyden BC, Rüdiger M, Thébaud B. Single-cell RNA sequencing reveals repair features of human umbilical cord mesenchymal stromal cells. Am J Respir Crit Care Med. 2024 Sep 15;210(6):814-827.
Lithopoulos MA, Toussay X, Zhong S, Xu L, Mustafa SB, Ouellette J, Freitas-Andrade M, Comin CC, Bassam HA, Baker AN, Sun Y, Wakem M, Moreira AG, Blanco CL, Vadivel A, Tsilfidis C, Seidner SR, Slack RS, Lagace DC, Wang J, Lacoste B, Thébaud B. Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis. J Clin Invest. 2022 Nov 15;132(22):e146095.
Lithopoulos MA, Strueby L, O'Reilly M, Zhong S, Möbius MA, Eaton F, Fung M, Hurskainen M, Cyr-Depauw C, Suen C, Xu L, Collins JJP, Vadivel A, Stewart DJ, Burger D, Thébaud B. Pulmonary and neurologic effects of mesenchymal stromal cell extracellular vesicles in a multifactorial lung injury model. Am J Respir Crit Care Med. 2022 May 15;205(10):1186-1201.
Hurskainen M, Mizikova I, Cook DP, Andersson N, Cyr-Depauw C, Lesage F, Helle E, Renesme L, Jankov RP, Heikinheimo M, Vanderhyden BC, Thébaud B. Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage. Nat Commun. 2021 Mar 10;12(1):1565.
Thébaud B, Lalu M, Renesme L, van Katwyk S, Presseau J, Thavorn K, Cobey KD, Hutton B, Moher D, Soll RF, Fergusson D. 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 Jul;10(7):968-975.
Kang MH, van Lieshout LP, Xu L, Domm JM, Vadivel A, Renesme L, Mühlfeld C, Hurskainen M, Mizikova I, Pei Y, van Vloten JP, Thomas SP, Milazzo C, Cyr-Depauw C, Whitsett JA, Nogee LM, Wootton SK, Thébaud B. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat Commun. 2020 Aug 6;11(1):3929.
Augustine S, Cheng W, Avey MT, Chan ML, Lingappa SMC, Hutton B, Thébaud B. Are all stem cells equal? Systematic review, evidence map, and meta-analyses of preclinical stem cell-based therapies for bronchopulmonary dysplasia: concise review. Stem Cells Transl Med. 2020 Feb;9(2):158-168.
Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary Dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78.
Augustine S, Avey MT, Harrison B, Locke T, Ghannad M, Moher D, Thébaud B. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cell Transl Med. 2017 Dec;6(12):2079-2093.
Alphonse RS, Vadivel A, Zhong S, McConaghy S, Ohls R, Yoder MC, Thébaud B. A method to isolate and culture lung vascular endothelial colony-forming cells. Nat Protoc. 2015 Nov;10(11):1697-708.
Alphonse RS, Vadivel A, Fung M, Shelley WC, Critser PJ, Ionescu L, O’Reilly M, Ohls RK, McConaghy S, Eaton F, Zhong S, Yoder M, Thébaud B. Existence, functional impairment and lung repair potential of endothelial colony forming cells in oxygen-induced arrested alveolar growth. Circulation. 2014 May 27;129(21):2144-57.
Pierro M, Ionescu L, Montemurro T, Vadivel A, Weissmann G, Oudit G, Emery D, Bodiga S, Eaton F, Péault B, Mosca F, Lazzari L, Thébaud B. Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax. 2013 May;68(5):475-84.
Luong C, Rey-Perra J, Vadivel A, Gilmour G, Sauve Y, Koonen D, Walker D, Todd KG, Gressens P, Kassiri Z, Nadeem K, Morgan B, Eaton F, Dyck JR, Archer SL,? Thébaud B. Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia. Circulation. 2011 May 17;123(19):2120-31.
van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, GJ Rey-Parra, Bouchentouf M, Galipeau J, Haromy A, Eaton F, Chen M, Hashimoto K, Abley D, Korbutt G, Archer SL, Thébaud B. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. 2009; 180(11):1131-42.
Thébaud B, Ladha F, Michelakis E, Sawika M, Thurston G, Eaton F, Hashimoto K, Harry G, Haromy A, Korbutt G, Archer SL. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation. 2005 Oct 18;112(16):2477-86.
Lithopoulos MA, Toussay X, Zhong S, Xu L, Mustafa SB, Ouellette J, Freitas-Andrade M, Comin CC, Bassam HA, Baker AN, Sun Y, Wakem M, Moreira AG, Blanco CL, Vadivel A, Tsilfidis C, Seidner SR, Slack RS, Lagace DC, Wang J, Lacoste B, Thébaud B. Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis. J Clin Invest. 2022 Nov 15;132(22):e146095.
Lithopoulos MA, Strueby L, O'Reilly M, Zhong S, Möbius MA, Eaton F, Fung M, Hurskainen M, Cyr-Depauw C, Suen C, Xu L, Collins JJP, Vadivel A, Stewart DJ, Burger D, Thébaud B. Pulmonary and neurologic effects of mesenchymal stromal cell extracellular vesicles in a multifactorial lung injury model. Am J Respir Crit Care Med. 2022 May 15;205(10):1186-1201.
Hurskainen M, Mizikova I, Cook DP, Andersson N, Cyr-Depauw C, Lesage F, Helle E, Renesme L, Jankov RP, Heikinheimo M, Vanderhyden BC, Thébaud B. Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage. Nat Commun. 2021 Mar 10;12(1):1565.
Thébaud B, Lalu M, Renesme L, van Katwyk S, Presseau J, Thavorn K, Cobey KD, Hutton B, Moher D, Soll RF, Fergusson D. 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 Jul;10(7):968-975.
Kang MH, van Lieshout LP, Xu L, Domm JM, Vadivel A, Renesme L, Mühlfeld C, Hurskainen M, Mizikova I, Pei Y, van Vloten JP, Thomas SP, Milazzo C, Cyr-Depauw C, Whitsett JA, Nogee LM, Wootton SK, Thébaud B. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat Commun. 2020 Aug 6;11(1):3929.
Augustine S, Cheng W, Avey MT, Chan ML, Lingappa SMC, Hutton B, Thébaud B. Are all stem cells equal? Systematic review, evidence map, and meta-analyses of preclinical stem cell-based therapies for bronchopulmonary dysplasia: concise review. Stem Cells Transl Med. 2020 Feb;9(2):158-168.
Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary Dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78.
Augustine S, Avey MT, Harrison B, Locke T, Ghannad M, Moher D, Thébaud B. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cell Transl Med. 2017 Dec;6(12):2079-2093.
Alphonse RS, Vadivel A, Zhong S, McConaghy S, Ohls R, Yoder MC, Thébaud B. A method to isolate and culture lung vascular endothelial colony-forming cells. Nat Protoc. 2015 Nov;10(11):1697-708.
Alphonse RS, Vadivel A, Fung M, Shelley WC, Critser PJ, Ionescu L, O’Reilly M, Ohls RK, McConaghy S, Eaton F, Zhong S, Yoder M, Thébaud B. Existence, functional impairment and lung repair potential of endothelial colony forming cells in oxygen-induced arrested alveolar growth. Circulation. 2014 May 27;129(21):2144-57.
Pierro M, Ionescu L, Montemurro T, Vadivel A, Weissmann G, Oudit G, Emery D, Bodiga S, Eaton F, Péault B, Mosca F, Lazzari L, Thébaud B. Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax. 2013 May;68(5):475-84.
Luong C, Rey-Perra J, Vadivel A, Gilmour G, Sauve Y, Koonen D, Walker D, Todd KG, Gressens P, Kassiri Z, Nadeem K, Morgan B, Eaton F, Dyck JR, Archer SL,? Thébaud B. Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia. Circulation. 2011 May 17;123(19):2120-31.
van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, GJ Rey-Parra, Bouchentouf M, Galipeau J, Haromy A, Eaton F, Chen M, Hashimoto K, Abley D, Korbutt G, Archer SL, Thébaud B. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. 2009; 180(11):1131-42.
Thébaud B, Ladha F, Michelakis E, Sawika M, Thurston G, Eaton F, Hashimoto K, Harry G, Haromy A, Korbutt G, Archer SL. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation. 2005 Oct 18;112(16):2477-86.