Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome

Shah, Trushil; Qin, Shanshan; Vashi, Mona; Predescu, Dan; Jeganathan, Niranjan; Bardita, Cristina; Ganesh, Balaji; DiBartolo, Salvatore; Fogg, Louis; Balk, R.A.; Predescu, Sanda

doi:10.1186/s40169-018-0197-2

Cited by 28 publications

(26 citation statements)

References 62 publications

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Section: Lung Cancermentioning

confidence: 99%

“…ALI/ARDS/pulmonary Sepsis MSC-derived EVs from ARDS patients showed the presence of transforming growth factor-beta receptor I (TβRI)/Alk5 and the Runx1 p66 and p52 transcription factor that are crucial in protecting ARDS [255]. Importantly, higher Runx1p66/p52 ratio provided a survival advantage [255]. Runx1p66 from bone marrow-derived MSC-EVs induces proliferation of LPS-treated ECs and help to improve pathology of lung in LPS induced ALI mice [255].…”

Section: Lung Cancermentioning

confidence: 99%

“…Importantly, higher Runx1p66/p52 ratio provided a survival advantage [255]. Runx1p66 from bone marrow-derived MSC-EVs induces proliferation of LPS-treated ECs and help to improve pathology of lung in LPS induced ALI mice [255]. Bone marrow-derived mesenchymal stem cell EVs induced cytoskeletal RhoA GTPase activity, leading to a significant decrease in hemorrhagic shockinduced lung vascular permeability in the hemorrhagicshock mice model of ARDS [256].…”

Section: Lung Cancermentioning

confidence: 99%

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Extracellular vesicles: novel communicators in lung diseases

et al. 2020

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The lung is the organ with the highest vascular density in the human body. It is therefore perceivable that the endothelium of the lung contributes significantly to the circulation of extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies. In addition to the endothelium, EVs may arise from alveolar macrophages, fibroblasts and epithelial cells. Because EVs harbor cargo molecules, such as miRNA, mRNA, and proteins, these intercellular communicators provide important insight into the health and disease condition of donor cells and may serve as useful biomarkers of lung disease processes. This comprehensive review focuses on what is currently known about the role of EVs as markers and mediators of lung pathologies including COPD, pulmonary hypertension, asthma, lung cancer and ALI/ARDS. We also explore the role EVs can potentially serve as therapeutics for these lung diseases when released from healthy progenitor cells, such as mesenchymal stem cells. Extracellular vesicles Cell-to-cell communication is essential for nearly all physiologic and metabolic processes. This intercellular conveyance is achieved through receptor ligands, signaling molecules, hormones, and extracellular vesicles (EVs). Historically, secretion of the cell in the form of EVs was considered as unimportant waste material, cellular "garbage bags," or dust particles [1-5]. However, in recent years, this so-called "waste" is now known to be of profound importance in various biological systems, creating a boon in their exploration across the scientific community. Lipid bilayer membrane-enclosed vesicles are secreted by both prokaryotic and eukaryotic cells [4-9]. Although, the term "extracellular vesicle" is sometimes used in reference to exosomes, it is actually a very broad term that encompasses all different types of vesicles secreted outside the cells [10]. Regardless, the function of all these vesicles appears to be all the same: communication between the cells within an organism or between species [11, 12]. In addition, it is not necessary that all vesicles secreted from cells are functional or have any role in some kind of biological process. Sometimes, they just act as "dustcart" to remove the waste from cells [13]. Of note, there have been discrepancies in the classification of these vesicles in the literature. Some studies divide EVs into two major categories: I) exosomes, defined as vesicles released by exocytosis of the multivesicular bodies; and II) ectosomes, defined as the vesicles which are assembled and released by the plasma membrane [14]. However, most recent studies categorize EVs as either exosome, microvesicles, microparticles, or apoptotic bodies based on vesicle size and how they are formed [15-21] (Fig. 1). Exosomes Exosomes are small EVs with sizes ranging between 30 and 150 nm in diameter that originate from the internal vesicles of multivesicular bodies (MVB) of nearly all cell types. Exosomes originating from different cell types have different composition; however, there are certain

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Section: Lung Cancermentioning

confidence: 99%

Section: Lung Cancermentioning

confidence: 99%

Section: Lung Cancermentioning

confidence: 99%

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Extracellular vesicles: novel communicators in lung diseases

et al. 2020

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“…This interaction could rescue the aberrant phenotype, thereby improving the overall severity of the disease; this mechanism was previously demonstrated in other types of lung disease. 43,44 Although not tested, if true, administering PHD2-containing microparticles of hematopoietic cell origin may prove efficacious in treating idiopathic PAH patients. Regardless, this is the first study, to our knowledge, to generate a severe mouse model of PAH that recapitulates almost all key pathologic features exhibited in the human PAH phenotypes.…”

Section: Egln1 Knockout Micementioning

confidence: 99%

Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension

Carman

Predescu

Machado

et al. 2019

The American Journal of Pathology

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As time progresses, our understanding of disease pathology is propelled forward by technological advancements. Much of the advancements that aid in understanding disease mechanics are based on animal studies. Unfortunately, animal models often fail to recapitulate the entirety of the human disease. This is especially true with animal models used to study pulmonary arterial hypertension (PAH), a disease with two distinct phases. The first phase is defined by nonspecific medial and adventitial thickening of the pulmonary artery and is commonly reproduced in animal models, including the classic models (ie, hypoxia-induced pulmonary hypertension and monocrotaline lung injury model). However, many animal models, including the classic models, fail to capture the progressive, or second, phase of PAH. This is a stage defined by plexogenic arteriopathy, resulting in obliteration and occlusion of the small-to mid-sized pulmonary vessels. Each of these two phases results in severe pulmonary hypertension that directly leads to right ventricular hypertrophy, decompensated right-sided heart failure, and death. Fortunately, newly developed animal models have begun to address the second, more severe, side of PAH and aid in our ability to develop new therapeutics. Moreover, p38 mitogen-activated protein kinase activation emerges as a central molecular mediator of plexiform lesions in both experimental models and human disease. Therefore, this review will focus on plexiform arteriopathy in experimental animal models of PAH.

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“…[17]. MSC-EVs have also been shown to promote recovery of patients with ARDS [22] and administration of ACE2 + MSC-sEVs, beside their decoy function for SARS-CoV-2, would likely translate into useful therapies for ARDS [23] and so COVID-19 ARDS [24]. By way of further example, the immunomodulatory capacity of MSCs, intravenously transplanted into seven patients with COVID-19, was recently assessed.…”

mentioning

confidence: 99%

Decoy ACE2-expressing extracellular vesicles that competitively bind SARS-CoV-2 as a possible COVID-19 therapy

Inal

2020

Clinical Science

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The novel strain of coronavirus that appeared in 2019, SARS-CoV-2, is the causative agent of severe respiratory disease, COVID-19, and the ongoing pandemic. As for SARS-CoV that caused the SARS 2003 epidemic, the receptor on host cells that promotes uptake, through attachment of the spike (S) protein of the virus, is angiotensin-converting enzyme 2 (ACE2). In a recent article published by Batlle et al. (Clin. Sci. (Lond.) (2020) 134, 543–545) it was suggested that soluble recombinant ACE2 could be used as a novel biological therapeutic to intercept the virus, limiting the progression of infection and reducing lung injury. Another way, discussed here, to capture SARS-CoV-2, as an adjunct or alternative, would be to use ACE2+-small extracellular vesicles (sEVs). A competitive inhibition therapy could therefore be developed, using sEVs from engineered mesenchymal stromal/stem cells (MSCs), overexpressing ACE2.

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Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome

Cited by 28 publications

References 62 publications

Extracellular vesicles: novel communicators in lung diseases

Extracellular vesicles: novel communicators in lung diseases

Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension

Decoy ACE2-expressing extracellular vesicles that competitively bind SARS-CoV-2 as a possible COVID-19 therapy

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