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MSC Exosome Treatment for BPD: Impact on Immunity and Lung Development

Award Number: R01HL146128
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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MSC Exosome Treatment for BPD: Impact on Immunity and Lung Development - Abstract Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity whose incidence is on the rise associated with the increased survival of extremely preterm infants. The etiology of BPD is multifactorial resulting from prenatal risk factors such as preeclampsia, chorioamnionitis, and perinatal insults including oxygen exposure, infection, and mechanical ventilation. Inflammation is a key pathway underlying the pathogenesis of BPD which can result in significant long-term multisystem morbidities, including adverse neurological outcomes, immune dysregulation with susceptibility to infections, and pulmonary morbidities including asthma and, in some cases, emphysematous changes that persist into adulthood. Thus, BPD is no longer considered a lung disease of the neonatal period, but a complex condition with multiorgan involvement and lifelong consequences. To date, effective treatments are lacking and there is a need to deliver effective strategies for the prevention and management of BPD. Mesenchymal stem/stromal cells (MSCs) are in clinical trials as potential cellular therapy for BPD. We and others have shown that the main therapeutic modality of MSCs resides in their secretome represented by `small' extracellular vesicles (sEVs), an EV subset that includes exosomes. We demonstrated that treatment with purified human MSC-derived sEvs, termed MEx, ameliorated and even reversed core histological and functional outcomes of BPD in several experimental models. In the neonatal hyperoxia (HYRX) murine BPD model, MEx protected other organs from injury including the brain, retina, and the thymus whose architecture was disrupted by HYRX. We demonstrated that MEx localize in the lung and interact with myeloid cells altering their phenotype from proinflammatory to immunosuppressive. Importantly, adoptive transfer of in vitro MEx-educated bone marrow derived myeloid cells, but not naïve cells, restored alveolar architecture, blunted fibrosis and vascular remodeling, and improved exercise capacity. We hypothesize that MEx regulate the immune landscape of the developing lung and promote a distinct macrophage phenotype that, through release of anti-inflammatory cytokines and enhanced efferocytosis of apoptotic cells, resolves tissue inflammation and orchestrates signals to promote lung growth disrupted by HYRX. In this proposal we plan to (1) Elucidate mechanisms by which MEx promote the establishment of the alveolar macrophage niche and development of innate immunity that is disrupted by neonatal HYRX; (2) Explore the functionality of lung myeloid cells instructed by MEx in resolving inflammation and promoting lung development; and (3) Elucidate the effects of neonatal HYRX and MEx treatment on long term immune cell function and susceptibility to airway disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $867,215 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	8	3/23/2026	NON-COMPETING CONTINUATION	$867,215
														Subtotal = $867,215

Issue Date FY: 2025 ( Subtotal = $884,913 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	7	6/4/2025	NON-COMPETING CONTINUATION	$88,491
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	7	4/22/2025	NON-COMPETING CONTINUATION	$796,422
														Subtotal = $884,913

Issue Date FY: 2024 ( Subtotal = $867,215 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	6	6/21/2024	NON-COMPETING CONTINUATION	$70,793
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	6	3/2/2024	NON-COMPETING CONTINUATION	$796,422
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	003	5	7/5/2024	COMPETING CONTINUATION	$367,710
2024	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	002	4	7/5/2024	NON-COMPETING CONTINUATION	-$367,710
														Subtotal = $867,215

Issue Date FY: 2023 ( Subtotal = $884,913 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	2/21/2023	COMPETING CONTINUATION	$884,913
														Subtotal = $884,913

Issue Date FY: 2022 ( Subtotal = $772,586 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	4	6/29/2022	NON-COMPETING CONTINUATION	$77,259
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	2/19/2022	NON-COMPETING CONTINUATION	$695,327
														Subtotal = $772,586

Issue Date FY: 2021 ( Subtotal = $772,586 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	2/25/2021	NON-COMPETING CONTINUATION	$772,586
														Subtotal = $772,586

Issue Date FY: 2020 ( Subtotal = $772,586 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	2/29/2020	NON-COMPETING CONTINUATION	$772,586
														Subtotal = $772,586

Issue Date FY: 2019 ( Subtotal = $772,586 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	2/26/2019	NEW	$772,586
														Subtotal = $772,586

Grand Total All Awards = $6,594,600

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MSC Exosome Treatment for BPD: Impact on Immunity and Lung Development

Award Number: R01HL146128

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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