Macrophage Immunomodulation by Mesenchymal Stem Cell Exosome Treatment and Restoration of Lung Architecture in Models of Bronchopulmonary Dysplasia

Background

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants related to oxygen exposure or mechanical ventilation of the developing, immature lungs. BPD occurs approximately in 40% of infants < 28 weeks gestation and could later lead to multiple systemic illnesses such as pulmonary hypertension, gastrointestinal dysfunction, immune complications, and neurodevelopmental disorders. Current treatments including gentler mechanical ventilation or administration of steroids are either ineffective or, in the case of steroids, pose severe side effects, implicating an urgent need to develop a more effective and safer therapeutic option.

Technology Overview

Drs. Kourembanas and Mitsialis with their research team at Boston Children’s Hospital reported that mesenchymal stem cells (MSCs) can be isolated from tissues such as bone marrow, blood and umbilical cord and do not induce immune rejection. Importantly, they showed that the main therapeutic modality of MSCs resides in their secretome, and the chief therapeutic vector therein is represented by ‘small’ extracellular vesicles (sEVs), an EV subset that includes exosomes that act via paracrine signaling mechanisms.

This group successfully isolated exosomes/sEVs from conditioned human MSC cultures. By delivering these naturally occurring exosomes into the murine hyperoxia model of BPD, they demonstrated effective amelioration of pulmonary pathologies, including alveolar simplification, vascular remodeling, and hypertension. Genetic sequencing of hyperoxic lung tissues from mice displayed pronounced inflammation-associated gene sets. MSC-derived exosomes are sufficient to dampen inflammatory responses by specifically modulating macrophage phenotypes from the pro-inflammatory “M1” state to an anti-inflammatory “M2-like” state in both cell culture and BPD mouse models.

Accumulating research using exosome therapy to treat BPD has been reproduced by other groups in similar disease models. Most recently, Drs. Kourembanas and Mitsialis in collaboration with Dr. Kurt Albertine who has a lamb model of BPD extended these studies in this preterm lamb model and reported significant protection from ventilator induced lung injury.  The potential pleiotropic effects of exosomes are now being validated in various injury and degeneration models of disease.

Applications

• Prevention of lung injury for premature infants at high risk of developing BPD and its long-term developmental consequences.
• Potential therapeutic option to prevent and treat neural diseases that involve CNS myelin degeneration such as ischemic stroke and traumatic injury.
• Therapy for mothers suffering from preeclampsia and protection of their infants from lung injury and immune dysfunction.
• Targeted medication to treat diseases that arise from severe systemic inflammation, including but not limited to diabetes, autoimmune encephalomyelitis, hypoxic ischemic encephalopathy, and rheumatoid arthritis.

Advantages

• Modulation of innate macrophage response to prevent and treat both local and systemic inflammation without introducing exogeneous immunoglobulins.
• No immune rejection
• Therapeutic effects on multiple organs and systems including but not limited to pulmonary function, vascular remodeling, neural regeneration, and systemic anti-inflammation.
• High potential to expand the treatment to groups with various neurological and autoimmune diseases other than BPD.

Publications

• Mansouri N, Willis GR, Fernandez-Gonzalez A, Reis M, Nassiri S, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI Insight. 2019 Nov 1;4(21):e128060. doi: 10.1172/jci.insight.128060. PMID: 31581150
• Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation. Am J Respir Crit Care Med. 2018 Jan 1;197(1):104-116. doi: 10.1164/rccm.201705-0925OC. PMID: 28853608; PMCID: PMC5765387.
• Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012 Nov 27;126(22):2601-11. doi: 10.1161/CIRCULATIONAHA.112.114173. Epub 2012 Oct 31. PMID: 23114789
• Willis GR, Fernandez-Gonzalez A, Reis M, Yeung V, Liu X, Ericsson M, Andrews NA, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. J Extracell Vesicles. 2020 Jul 13;9(1):1790874. doi: 10.1080/20013078.2020.1790874. PMID: 32939235; PMCID: PMC7480622.
• Taglauer ES, Fernandez-Gonzalez A, Willis GR, Reis M, Yeung V, Liu X, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation. Biol Reprod. 2021 Feb 11;104(2):457-467. doi: 10.1093/biolre/ioaa198. PMID: 33112369
• Fernandez-Gonzalez A, Willis GR, Yeung V, Reis M, Liu X, Mitsialis SA, Kourembanas S. Therapeutic Effects of Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Oxygen-Induced Multi-Organ Disease: A Developmental Perspective.Front Cell Dev Biol. 2021 Mar 16;9:647025. doi: 10.3389/fcell.2021.647025. eCollection 2021. PMID: 33796534
• Reis M, Willis GR, Fernandez-Gonzalez A, Yeung V, Taglauer E, Magaletta M, Parsons T, Derr A, Liu X, Maehr R, Kourembanas S, Mitsialis SA. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia. Front Immunol. 2021 Apr 15;12:640595. doi: 10.3389/fimmu.2021.640595. eCollection 2021. PMID: 33936055.
• Willis GR, Reis M, Gheinani AH, Fernandez-Gonzalez A, Taglauer ES, Yeung V, Liu X, Ericsson M, Haas E, Mitsialis SA, Kourembanas S. Extracellular Vesicles Protect the Neonatal Lung from Hyperoxic Injury through the Epigenetic and Transcriptomic Reprogramming of Myeloid Cells. Am J Respir Crit Care Med. 2021 Dec 15;204(12):1418-1432. doi: 10.1164/rccm.202102-0329OC. PMID: 34699335
• Taglauer ES, Fernandez-Gonzalez A, Willis GR, Reis M, Yeung V, Liu X, Prince LS, Mitsialis SA, Kourembanas S. Antenatal Mesenchymal Stromal Cell Extracellular Vesicle Therapy Prevents Preeclamptic Lung Injury in Mice. Am J Respir Cell Mol Biol. 2022 Jan;66(1):86-95. doi: 10.1165/rcmb.2021-0307OC. PMID: 34614384
• Albertine KH, Rebentisch A, Dawson E, Van Boerum J, Major E, Štipka J, Foreman H, Headden D, Vordos Z, Beck E, Wang Z, Yang H, Yu B, Dahl MJ, Null DM, Bizzotto D, Veneroni C, Lavizzari A, Dellacà RL, Delavogia E, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol. 2024 Apr 2. doi: 10.1152/ajplung.00349.2023. Online ahead of print. PMID: 38563994
• Abele AN, Taglauer ES, Almeda M, Wilson N, Abikoye A, Seedorf GJ, Mitsialis SA, Kourembanas S, Abman SH. Antenatal mesenchymal stromal cell extracellular vesicle treatment preserves lung development in a model of bronchopulmonary dysplasia due to chorioamnionitis. Am J Physiol Lung Cell Mol Physiol. 2022 Feb 1;322(2):L179-L190. doi: 10.1152/ajplung.00329.2021. Epub 2021 Dec 8. PMID: 34878940