Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation

Willis, Gareth R.; Fernandez-Gonzalez, Angeles; Anastas, Jamie N.; Vitali, Sally H.; Liu, Xianlan; Ericsson, Maria; Kwong, April; Mitsialis, S. Alex; Kourembanas, Stella

doi:10.1164/rccm.201705-0925oc

Cited by 467 publications

(495 citation statements)

References 49 publications

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“…Plasma exosomes from mice with monocrotaline-induced PAH were demonstrated to cause pulmonary hypertension in healthy mice and this effect was reversed by administering exosomes derived from mesenchymal stem cells (23). Mesenchymal stem cell–derived exosomes have also been reported to help suppress the hypoxia-induced lung inflammation, thereby mitigating vascular remodeling and development of hypoxic pulmonary hypertension (22, 56). Furthermore, the role of HIV infection in formation and secretion of EVs is well known (57, 58).…”

Section: Discussionmentioning

confidence: 99%

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

Sharma¹,

Chinnappan²,

Agarwal³

et al. 2018

FASEB j.

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Our previous studies consistently demonstrate enhanced pulmonary vascular remodeling in HIV–infected intravenous drug users, and in simian immunodeficiency virus–infected macaques or HIV-transgenic rats exposed to opioids or cocaine. Although we reported an associated increase in perivascular inflammation, the exact role of inflammatory cells in the development of pulmonary vascular remodeling remains unknown. In this study, HIV–infected and cocaine (H+C)–treated human monocyte derived macrophages released a higher number of extracellular vesicles (EVs), compared to HIV-infected or uninfected cocaine-treated macrophages, with a significant increase in the particle size range to 100–150 nm. Treatment of primary human pulmonary arterial smooth muscle cells (HPASMCs) with these EVs resulted in a significant increase in smooth muscle proliferation. We also observed a significant increase in the miRNA-130a level in the EVs derived from H+C-treated macrophages that corresponded with the decrease in the expression of phosphatase and tensin homolog and tuberous sclerosis 1 and 2 and activation of PI3K/protein kinase B signaling in HPASMCs on addition of these EVs. Transfection of HPASMCs with antagomir-130a–ameliorated the EV-induced effect. Thus, we conclude that EVs derived from H+C-treated macrophages promote pulmonary smooth muscle proliferation by delivery of its prosurvival miRNA cargo, which may play a crucial role in the development of PAH.—Sharma, H., Chinnappan, M., Agarwal, S., Dalvi, P., Gunewardena, S., O’Brien-Ladner, A., Dhillon, N. K. Macrophage-derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse.

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Section: Discussionmentioning

confidence: 99%

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

Sharma¹,

Chinnappan²,

Agarwal³

et al. 2018

FASEB j.

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“…Exposure of newborn rats to hyperoxia disrupts both alveolarization and angiogenesis displaying BPD like pathology, including alveolar simplification, reduction in blood vessels density, and pulmonary hypertension [12]. Exosome treatment can be applied by intravenous, intratracheal, subcutaneous, or intraperitoneal injection.…”

Section: Discussionmentioning

confidence: 99%

“…Exosome treatment can be applied by intravenous, intratracheal, subcutaneous, or intraperitoneal injection. A single intravenous injection of exosomes in preclinical models partially protects rodent lungs from hypoxia induced pulmonary hypertension or hyperoxia induced BPD [12, 26]. Intratracheal instillation of exosomes protects lungs from endotoxin induced lung injury [27].…”

Section: Discussionmentioning

confidence: 99%

“…MSCs exert their biological effects mainly in a paracrine manner including the release of exosomes [13, 14]. Indeed, MSC-derived exosome treatment of hyperoxia exposed newborn mice blunts the resulting inflammation and stimulates neovascularization and immunosuppression after myocardial injury [12, 15, 16]. VEGF-A is essential for the development of the lung vascular system and alveolarization.…”

Section: Introductionmentioning

confidence: 99%

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Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia

Braun

Chetty

Balasubramaniam

et al. 2018

Biochemical and Biophysical Research Communications

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Mesenchymal stromal cell (MSC) derived exosomes mediate tissue protection and regeneration in many injuries and diseases by modulating cell protein production, protecting from apoptosis, inhibiting inflammation, and increasing angiogenesis. In the present study, daily intraperitoneal injection of MSC-derived exosomes protected alveolarization and angiogenesis in a newborn rat model of bronchopulmonary dysplasia (BPD) induced by 14 days of neonatal hyperoxia exposure (85% O). Exosome treatment during hyperoxia prevented disruption of alveolar growth, increased small blood vessel number, and inhibited right heart hypertrophy at P14, P21, and P56. In vitro, exosomes significantly increased tube-like network formation by HUVEC, in part through a VEGF mediated mechanism. In summary, daily intraperitoneal injection of exosomes increased blood vessel number and size in the lung through pro-angiogenic mechanisms. MSC-derived exosomes therefore have both anti-inflammatory and pro-angiogenic mechanism to protect the lung from hyperoxia induced lung and heart disease associated with BPD.

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“…EVs derived from MSCs show therapeutic effects on various tissue injury in preclinical animal models by modulating immune response (65), ameliorating oxidative stress (66), and decreasing apoptosis (67), which is similar to what is achieved using the originating MSCs themselves. In recent studies using newborn animals, MSC-derived EVs protected neonatal lungs after hyperoxic injury (68), fetal brains after hypoxiaischemia (64), and the intestine from experimental necrotizing enterocolitis (69).…”

Section: Paracrine Protectionmentioning

confidence: 99%

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

et al. 2017

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Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.

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Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation

Cited by 467 publications

References 49 publications

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

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