Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies

Xu, Ji-Hong; Liang, Jia-Ping; Zhu, Chu-Jun; Lian, Yu-Jun

doi:https://doi.org/10.1155/2022/5451947

Journal of Interventional Cardiology

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Abstract Introduction Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 5451947 | https://doi.org/10.1155/2022/5451947

Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies

Ji-Hong Xu,¹Jia-Ping Liang,²Chu-Jun Zhu,²and Yu-Jun Lian²

Academic Editor: Yuli Huang

Received20 May 2022

Revised09 Oct 2022

Accepted20 Oct 2022

Published04 Nov 2022

Abstract

Pulmonary hypertension (PH) is a type of clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance and subsequent progressive failure of the right heart function, and is a common complication of many diseases. Mesenchymal stem cells (MSCs) autonomously home to sites damaged by disease, repair damaged tissues, and participate in the regulation of systemic inflammation and immune responses, which have good clinical application prospects. Extracellular vesicles (EVs), such as exosomes and microvesicles, participate in various biological activities by regulating intercellular communication. Exosomes secreted into the extracellular environment also affect the host immune system. MSC-derived extracellular vesicles (MSC-EVs), as a mediator in the paracrine processes of MSCs, carry biologically active substances such as proteins, lipids, mRNA, and micro-RNA. MSC-EVs therapies, safer than cell-based treatments, have been shown to be effective in modulating macrophages to support anti-inflammatory phenotypes, which are strongly related to histological and functional benefits in preclinical models of pulmonary hypertension. The main effects of active substances and their potential medical value have attracted wide attention from researchers. This article reviews the role and relevant mechanisms of MSC-EVs in the treatment of pulmonary hypertension in recent studies and provides a basis for their future clinical applications.

1. Introduction

Pulmonary hypertension (PH) is a chronic severe cardiopulmonary disease caused by pulmonary vascular remodeling, characterized by progressive narrowing of blood vessels and elevated mean pulmonary arterial pressure, ultimately leading to heart failure and death. The main pathological change of PH is pulmonary vascular remodeling, which includes antiapoptosis and proliferation of pulmonary artery endothelial and smooth muscle cells, muscularization of the distal pulmonary artery, production and deposition of proinflammatory cytokines and chemotactic cytokines, and accumulation and infiltration of leukocytes around the pulmonary blood vessels [1–4]. PH is also a life-threatening condition of bronchopulmonary dysplasia (BPD) in premature infants [5]. Statistics show that more than 40,000 people worldwide suffer from PH each year and the fatality rate is as high as 15% [6]. Even if patients with PH undergo treatment, the 3-year survival rate is only 55%–65%. The current drugs on the market are not very effective in treating pulmonary hypertension. Most patients have a poor prognosis and little improvement in their quality of life. Furthermore, the drugs are expensive and often accompanied by obvious side effects [7]. Therefore, a new drug that cures or controls the development of PH is urgently needed in the clinic. Extracellular vesicles (EVs) are released by various types of cells, mediating intercellular communication, transmitting specific information from their origin cells to target cells, and thus, participating in physiological and pathophysiological processes. Due to these properties, EVs from specific types of cells can be used as new agents to treat various diseases, including antitumor treatment, immunomodulation, regenerative therapy, pathogen vaccination, and drug delivery. Translating EVs into clinical treatments requires the classification of EV-based therapies according to existing regulatory frameworks [8]. Mesenchymal stromal cells (MSCs) and EVs have been evaluated in patients with PH through a series of Phase I/II trials. The efficacy and safety of adipose-derived mesenchymal stem cells for PH are being assessed [9]. Preclinical studies have shown that MSC-EVs improve pulmonary hypertension [10, 11], and the emergence of exosomes has brought hope down to patients with pulmonary hypertension.

2. Biological Characteristics of Extracellular Vesicles

Extracellular vesicles (EVs) are membrane structures that are naturally released from cells. They are delimited by lipid bilayers and cannot be replicated, i.e., do not contain functional nuclei. EVs include exosomes (Exos), microvesicles (MV), microparticles (MP), exosomes, tumor bodies, and apoptosomes [12]. The term “exosome” is most commonly used to specify any type of EVs [13]. The International Society for Extracellular Vesicles (ISEV) supports “extracellular vesicle” (EV) as a generic term for particles. Because of overlapping size ranges and lack of specific markers, current extracellular vesicle preparations, including exosome preparations are heterogenous with undefined biogenesis origins and undetermined purity. The separation of EVs from other non-EV components of the matrix (conditioned media, biological fluids, and tissues) and between different types of EVs (commonly known as purification or isolation) is achieved through the different techniques available. Characterization of EVs through multiple complementary techniques is important to evaluate the effectiveness of isolation techniques and to determine the similarity of biomarkers or functions. To characterize a single EV, as a general rule, at least two techniques should be used [12].

Extracellular vesicles, especially exosomes, have been well documented as carriers of biomarkers in the extracellular space [14]. It was first discovered in 1983 that mature reticulocytes in sheep released a membrane vesicle that was originally thought to excrete excess transferrin receptors, known as exosomes [15]. Exosomes are single membrane vesicles approximately 30–100 nm in size that are widely distributed in saliva, plasma, and milk [16–18]. Exosomes have a bimolecular phospholipid structure. The surface is rich in lipids such as cholesterol, sphingomyelin, and ceramide. It contains protein, mRNA, and micro-RNA and plays a vital role in the cellular microenvironment [19, 20]. When EVs circulate, they are absorbed by adjacent or distant cells through membrane fusion, endocytosis, and ligand-receptor binding, directly affecting gene expression and cellular phenotype of recipient cells, which are considered to be major players in many biological processes under normal and pathological backgrounds [21, 22].

2.1. Origin of EVs/Exosomes

Exosomes originate from late endosomes of the endocytic system. The formation process consists of two parts. First, exosomal membrane buds form inward vesicles by reverse budding, and part of the cytoplasm becomes multivesicular cells. Then, the multicarrier endosomes fuse with the cell membrane, and the internal vesicle structure is released outside the cell to form exosomes [23–25]. Exosomes express CD55 and CD59 on the surface, thus, avoiding activation of opsonins, complement, and coagulation factors [26]. They have phagocytosis, are able to pass relatively freely through the vascular wall and extracellular matrix and are widely and stably distributed in body fluids. Exosomes eventually undergo membrane fusion with surrounding cells, enabling the circulation of biofilms.

2.2. Structure of EVs

Glioblastoma tumor cells release microvesicles containing 41,860 kinds of proteins, more than 7,540 kinds of RNA, and 1,116 kinds of lipid molecules, as well as specific glycoconjugates and membrane-related advanced oligomeric protein complexes [27]. However, ISEV noted that the described and characterized proteins should be present in the EVs of the target as expected and have transmembrane functions (e.g., transmembrane proteins) and membrane binding capabilities (e.g., cytosolic proteins) [13].

EVs vary in shape, size, and even content in different biological states and stages of formation. Generally, the content of EVs from different sources varies.

Proteins include membrane transport proteins, fusion proteins (e.g., GTPases, Annexins, and Flotillin), transmembrane proteins (e.g., CD9, CD63, CD81, and CD82), heat shock proteins (e.g., HSP70 and HSP90), and proteins involved in vesicle biosynthesis (e.g., ALG-2, ALG-2-interacting protein X (Alix), tumor susceptibility gene 101 (TSG101), and lipid-related proteins) [28–32].

Exosomes contain some nucleic acids, such as noncoding RNA, mRNA, and siRNA. After these RNAs are absorbed by the target cells, they express proteins corresponding to the mRNAs. They also degrade target RNA or interfere with its translation to mediate the silencing of target genes, thereby influencing the physiological activity of cells in vivo. Exosomes with rich RNA content are mainly involved in the transmission of genetic information between tissues. Exosomes with low RNA content those from immune cells; mainly play a major role in antigen presentation and immune co-stimulation [31]. Studies have shown that exosomes from mast cells contain mature miRNAs that can be transferred to other cells and function in new cells [33]. Therefore, these nucleic acid molecules can also serve as biomarkers for tumor diagnosis and detection, enabling relevant targeted therapies, some of which have been identified as serum markers for cancer [34].

MVs also contain antigens, such as major histocompatibility complex (MHC) I and MHCII molecules, which activate T lymphocytes, natural killer cells, and dendritic cells, stimulating biological effects on immunity [35].

In addition to protein and nucleic acids, exosomes are also rich in lipids, such as cholesterol (mainly secreted by B lymphocytes), sphingolipids containing ceramide, and phosphoglycerides with long saturated fatty acyl chains [36]. Lipids in exosomes may be associated with lipid transport and membrane fusion in target cells where the membrane surface is rich in sugars such as mannose, polylactosamine, α-2,6 sialic acid, and complex N-linked sugar chains. These substances play an important role in protein sorting [37].

2.3. Mode-of-Action of EVs

EVs/exosomes have been used as a tool for directed communication between stem cells and parenchymal cells, enabling them to act as biomarkers [38]. Currently, exosomes are thought to transfer information between cells through four main mechanisms. (1) Exosomes recognize and fuse with target cells via their own membrane proteins [39]. (2) After the lipids in exosomes are transported to recipient cells, they promote apoptosis through the Notch signaling pathway [40]. (3) Transcription factor receptors from exosomes regulate transcription in target cells [41]. (4) Exosome-derived microRNAs bind to silencing complexes and play a role in post-transcriptional regulation of recipient cells [42]. Once EVs are absorbed by the recipient cell, lipids, proteins, mRNA, micro-RNA, and other components contained therein influence protein modification and localization by altering transcription and translation procedures, and regulating signaling cascades and important enzymatic reactions. Methods such as self-regulation affect the cellular phenotype and state of target cells, while the types of source and recipient cells and their physiological and pathological states determine which mechanism plays a major role [43].

However, it should be noted that increasing studies indicate that miRNAs are not present in functional supervisor states or concentrations and are rarely delivered to cells. Authors should clarify the facts and proceed with caution to avoid confusion [44]. Most exosomes derived from standard formulations do not contain many copies of miRNA molecules. Therefore, reassessment of current exosome-mediated miRNA communication mechanisms and associated chemometric analysis is necessary to study other extracellular vesicles and their associated RNAs [45].

2.4. Role of EVs in PH

Because EVs contain many molecules, such as miRNAs, mRNAs, and proteins, these intercellular communicators act as biomarkers of lung disease, providing critical information about the health and disease status of donor cells [46]. An earlier study published in 2008 showed that endothelial cell-derived CD105 microparticles increased in the pulmonary artery blood of patients with pulmonary arterial hypertension (PAH) [47]. Furthermore, another study reported elevated levels of endothelial PECAM and VE-cadherin in plasma samples of patients with PH compared to the control group, but no increase in E-selective proteins. An increase in endothelial cell-derived MPs is associated with an increase in mean pulmonary arterial pressure, pulmonary vascular resistance, and mean right arterial pressure [48]. Subsequent studies have shown that patients with PH have a higher number of CD62e + endothelial cell-derived MPs in their plasma [49].

Both proteins and RNAs in the EV content are thought to be critical in the pathogenesis of PH. It was found that translation-controlled tumor proteins were highly expressed in exosomes released by blood-grown endothelial cells with BMPR-2 mutations, which was associated with heritable PH [50].

3. EVs Derived from Stem Cells

3.1. Classification and Characteristics of Stem Cells

Stem cells are cells that self-renew and differentiate into cells with specific functions under certain signaling conditions [51]. Stem cells are not only progenitor cells but also candidate cells. There are a large number of various stem cell types. When tissues age or are damaged, resting stem cells receive signals, perform physiological functions, proliferate, differentiate, repair, and replenish aging and damaged tissues, thereby maintaining the normal tissue structure and physiological functions. The properties of stem cells in repair and regeneration have opened up new ideas for the treatment of many diseases and have become research hotspots. There are many types of stem cells and their functions are also different. At present, there are two main classification methods. (1) In accordance with their development process, they are divided into three types: embryonic stem cells, germ cells, and adult stem cells. (2) In accordance with their differentiation potential, they are divided into four types: totipotent stem cells, subpotent stem cells, pluripotent stem cells and unipotent stem cells [52–54].

Embryonic stem cells have unique miRNAs and proteins that promote the proliferation and differentiation of endogenous progenitor cells, and embryonic stem cells are promising sources of exosomes. Adult stem cells are slow-circulating cells that respond to specific environmental signals. They are widely distributed and sourced, and the material is relatively readily available. They can also be autologously transplanted. The above advantages make them the first choice for stem cell therapy. Mesenchymal stem cells are adult pluripotent cells with self-renewing and differentiated mesenchymal plasma lineages, namely osteoblasts, fat cells, and chondrocytes, and are widely used in the field of regenerative medicine [55, 56]. The cells have the characteristics of easy isolation, high proliferation, easy in vitro, amplification, and genetic stability [57].

3.2. Effect of EVs/Exosomes on Mesenchymal Stem Cell Therapy

In 2009, researchers discovered that mesenchymal stem cells exerted their therapeutic effects through extracellular vesicles. Specifically, they found that extracellular vesicles, called microvesicles, which were 80–1000 nm in size, might prevent acute tubular injury [58]. Subsequent studies showed that 50–200 nm extracellular vesicles (i.e., exosomes) were effective in preventing myocardial reperfusion injury. This is the first time that mesenchymal stem cell-derived exosomes (MSC-Exos) have been confirmed [59]. Additionally, the term MSC-Exos is often used to describe 50–200 nm EVs prepared from MSC-conditioned media, as these EVs collectively contain exosome-associated proteins including TSG101, Alix, and tetramer transmembrane proteins CD9, CD63, and CD81. They also carry a rich variety of RNAs. MSC-Exos are increasing recognized as effective mediators for increasing number of MSC-related therapies [60].

Theoretically, exosomes are paracrine effectors of mesenchymal stem cells, which have important activities of their origin cells in a range of different disease models, including differentiation into polylines, cytokine secretion, promotion of cell proliferation, and immunomodulation. MSC-Exos have functional characteristics similar to those of stem cells. The immune potency of MSCs resides in their secreted small extracellular vesicles (sEVs). These sEVs have a large number of proteins with potent immunomodulatory activity [61]. In in vitro and in vivo models, MSC-EVs suppressed proinflammatory processes and oxidative stress in humoral and cellular components of the immune system, creating a proregenerative environment [62]. They are immunocompetent nanoparticles that mediate immune activity by stimulating T cell proliferation and IFN-γ secretion, thereby inhibiting the production of anti-CD3 and anti-CD28 antibody [63]. Additionally, MSC-Exos freely cross the blood-brain barrier and manipulate a large number of physiological and pathological processes by influencing the survival, proliferation, migration, and gene expression of recipient cells [64]. The content of exosomes derived from MSCs has its own characteristics. MSCs and their environments transmit feedback information to each other through MSC-Exos. Thus, changes in the environment of MSCs alter the amount of exosomes they secrete, which affects and alters the tissue environment. Mesenchymal stem cells produce more exosomes than myoblasts, human acute monocyte leukemia cell lines, and human embryonic renal cell lines [65]. Therefore, MSCs are considered to have the strongest exosome secretory capacity. By passing information, such as proteins, genetic material, and lipids, between cells, exosomes are important players in cell-to-cell communication [66]. MSC-Exos and exosomes from other sources do not differ significantly in morphology, isolation, or storage. MSC-Exos express common surface markers of exosomes, such as CD9, CD63, and CD81, as well as some adhesion molecules of the MSCs membrane, such as CD29, CD44, and CD73, among others [67, 68]. They are a simple and fast approach to administration, which improves the safety of treatment and reduces storage and transportation problems as well as many of the risks related to cell transplantation. Therefore, exosomes from mesenchymal stem cells are attractive as potential therapeutic agents.

Extensive research has been conducted on the application of MSC-Exos in the field of lung diseases, mainly focusing on pneumonia, lung dysplasia, lung tissue damage, and their terminal states. Other than that, MSC-Exos has been applied to bronchopulmonary diseases such as pulmonary dysplasia and radiation damage. Bronchopulmonary dysplasia is more common in children with perinatal acute respiratory failure. Bone marrow mesenchymal stem cells significantly resist oxygen radical-induced bronchopulmonary dysplasia. This mechanism may be associated with upregulation of the antioxidant stanniocalcin-1 in MSC-Exos. They are also associated with antiapoptotic effects [69]. MSCs are considered to be promising drugs for the treatment of radiation-induced lung damage. MSC-Exos mitigates radiation damage. Their mechanisms may be related to immunomodulatory, antifibrotic, regenerative, and restorative functions of exosomes [70].

Small extracellular vesicles derived from the mesenchymal matrix/stem cells (MSCs-sEV) are rapidly being applied in the clinical practice phase. However, there is still controversy about the biology, function, and potency of MSCs-sEVs. To resolve these controversies, four societies (SOCRATES, ISEV, ISCT, and ISBT) have proposed standards for MSC-sEVs to facilitate data sharing and comparison, which will propel the field toward clinical applications [71].

4. EVs Derived from MSCs Treat PH

4.1. MSC-Derived EVs Attenuate Experimental PH

MSC-EVs carry genetic information and proteinaceous material to modulate interactions between MSCs and recipient cells. Recently, more and more researchers have begun to focus on the medical role of MSC-EVs in chronic respiratory diseases. MSC-EVs are derived from the umbilical cord, bone marrow, adipose tissue, and induced pluripotent stem cells. Alternative modes of administration are intratracheal and intravenous injection. Treatments include chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and PH [72].

In animal studies, injection of MSC-EVs before or after induction of PH reversed the increase of right ventricular (RV) systolic pressure and RV hypertrophy, as well as decreased peripheral pulmonary vascular muscularization [9, 73, 74] (Table 1). The MSC-MVs exhibited general morphological characteristics of MVs, rapid annexin V and CD29 markers under TEM, with sizes ranging from 40 to 300 nm. Intravenous MSC-MVs or MSCs significantly improved mean pulmonary arterial pressure and mean RV pressure in PH rats. In addition, intravenous administration of MSC-MVs or MSCs significantly reduced RV hypertrophy, the pulmonary arteriole area index, and the thickness index in rats with PH [75, 76] (Table 1). The MSC-MVs also relieved the inflammation score and collagen fiber volume fraction [76] (Table 1). MSC-EVs attenuated monocrotaline-induced pulmonary vascular remodeling in mice with PH, an effect mediated directly by EVs on the pulmonary vascular system or through differentiation of myeloid cells into endothelial progenitor cells [77] (Table 1), [82]. These studies have revealed that MSC-Exos treatment could significantly suppress pulmonary vascular remodeling and EndMT. In another experiment, EVs from bone marrow, lungs, and plasma inhibited apoptosis of pulmonary vascular endothelial cells [46].

In cell culture experiments, MSC-Exos significantly inhibited hypoxia-induced apoptosis of pulmonary artery endothelial cells and proliferation of pulmonary artery smooth muscle cells [9] (Table 1). These data support that MSC-EVs can be a new treatment for PH [74, 83].

The use of MSC-EV at lower doses and with longer dosing intervals than previously reported can also be effective in reversing SuHx pulmonary hypertension. Hypoxic stress did not enhance this effect. These findings provide a basis for the feasibility of MSC-EV as a long-term treatment for pulmonary hypertension [78] (Table 1).

Adipose mesenchymal stem cells-derived Exos (ASC-Exos) prevented PH. Experimental results of coculture of human pulmonary artery endothelial cells (HPAECs) and ASCs-Exos showed that ASCs-Exos promoted proliferation of HPAECs treated with monochloride pyrrole [79] (Table 1).

MSC-EVs therapy had the potential to reverse CDH-related changes, particularly by rapidly inhibiting ECM-remodeling enzymes (LOX and MMP-9). Besides that, MSC-EVs therapy enhanced the structural aspects of the pulmonary arterial extracellular matrix and mitigated pathological disorders such as increased medial wall thickness and stiffness [80] (Table 1).

Early and late MSC-derived small extracellular vesicles (MEx) effectively improved the core features of hyperoxia-induced neonatal lung injury, alveolar simplification, pulmonary fibrosis, vascular remodeling, and vascular loss. Motor ability tests and PH studies have shown some improvement in function after early and late MEx treatments [81] (Table 1).

4.2. Effect of MSC-EVs on Inflammation in PH

Inflammation plays a major role in the occurrence of PH, and both innate and adaptive immune cells are related to PH [84, 85]. It destroys pulmonary vascular endothelial cells mainly through the accumulation of immune cells in pulmonary blood vessels and the release of a large number of cytokines and chemokines, which promote the proliferation of smooth muscle cells and ultimately lead to pulmonary vascular remodeling.

Immunological disorders are the basis for the development of PH. Macrophages coordinates the onset and resolution of inflammation in the lungs. Thus, manipulating lung macrophage function is a promising strategy for emerging immunomodulatory therapies including cell-based approaches [86, 87]. Under hypoxia, macrophages are activated in a lung, which induces the release of inflammatory factors, creates an inflammatory response in the lungs, and eventually causes hypoxic pulmonary hypertension. In an animal model of PH, MSC-Exos inhibited macrophage infiltration under hypoxic pulmonary hypertension, reduced the release of inflammatory factors in vivo, and reduced hypoxic/ischemic damage [88] (Table 2). MSC-Exos inhibited the influx of macrophages, proinflammatory and proliferative mediators (including monocyte chemoattractant protein-1), and hypoxia-induced mitotic factors into the hypoxic lung. MSC-Exos therapy inhibited hyperoxia-associated inflammation and changed the hyperoxic lung transcriptome. This alleviated hyperoxia-induced bronchopulmonary dysplasia, improved lung function, reduced fibrosis, and pulmonary vascular remodeling. The mechanism by which MSC-Exos works was related to regulation of the pulmonary macrophage phenotype [89] (Table 2). This effect was manifested by a low number of lung macrophages, a high proportion of alternative macrophages (M2/M1), and an increased number of peripheral blood vessels [74] (Table 2). These studies have shown that exosomes improve PH by modulating levels of immune and inflammatory factors. In fact, MSC-based therapies effectively modulate macrophages by promoting anti-inflammatory and proregressive phenotypes that correlate with histological and functional benefits in preclinical models of PH.

4.3. Effect of MSC-EVs on miRNAs in PH

Cells secrete miRNAs into body fluids through exosomes. Exosomal miRNAs establish connections between cells and regulate various important physiological processes by regulating the expression of target genes. More and more research is investigating the major role of exosomal miRNAs in the pathogenesis of PH [93].

MSC-EVs were divided into Exo and MV fractions and injected into MCT-treated mice. MSC-Exos, but not MV, reversed any increase in RV/LV + S. Exos derived from MCT-injured mice and patients with idiopathic PH contained elevated levels of miRs-19b, −20a, −20b, and −145, whereas miRs isolated from MSC-Exos, including miRs-34a, −122, −124, and −127, had anti-inflammatory and antiproliferative effects [77] (Table 2). Microarray analysis of miRNAs in MSC-Exos revealed 65 upregulated miRNAs, suggesting that MSC-Exos regulate pulmonary hypertension through their miRNAs. MiR-124 in MSC-Exos increased, while the downregulation of miR-124 contributed to pulmonary vascular remodeling in PH. It has been speculated that reversal of pulmonary vascular remodeling in mice treated with MSC-Exos may be due to upregulation of miR-124 expression. Intravenous injection of MSC-Exos into hypoxia-induced pulmonary hypertension mice inhibited activation of STAT3 signaling and the miR-17 family caused by hypoxia and increased expression of the miR-204 family. This broke the STAT3-miR-204-STAT3 feed-forward cycle, shifted the balance to an antiproliferative state, and improved PH, right ventricular hypertrophy, and pulmonary vascular remodeling [90] (Table 2).

By transfecting ASCs with antagomirs, low exosomal miR-191 expression inhibited HPAEC proliferation, while the agomir improved their proliferation. Similar results have been obtained in a single monocrotaline pyrrole (MCTP)-induced PH rat model after ASCs injection. MiR-191 inhibited the expression of bone morphogenesis protein receptor 2 (BMPR2) in HPAECs and PH rats. Therefore, miR-191 in ASCs and ASC-Exos plays a major role in PH by modulating BMPR2 [79] (Table 2).

Through endothelial cell (EC)-derived exosomes, miR-195 was delivered from ECs to SMCs, and that inhibited the proliferation and migration of SMCs by inhibiting the expression of serotonin transporters (5-HTT), and therefore micro-RNA may play a protective role in PH [91].

4.4. Effects of MSC-EVs on Genes in PH

BMPR2 is a member of the transforming growth factor β (TGF-β) receptor superfamily. It has serine and threonine protein kinase activity. The TGF-β/BMPR/BMP signaling pathway is active in pulmonary endothelial cells and pulmonary arteries. In patients with PH, mutations in the BMPR2 gene or abnormal signal transduction pathways have been identified, leading to abnormal expression of growth factors and inflammatory responses in vascular cells. Decreased or dysfunctional BMPR2 expression increased high mobility group AT-hook 1 (HMGA1) expression, leading to EndMT in PAEC and promoting occlusive remodeling of idiopathic pulmonary hypertension [94]. More exosomes can be isolated from growing endothelial cells of BMPR2 mutation carriers than from non-BMPR2 mutation carriers, which contain more translation-modulating tumor proteins involved in pulmonary hypertension. These transformative-regulated tumor proteins may be potential diagnostic markers of pulmonary hypertension [50] (Table 2).

MSC-Exos significantly upregulated the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Additionally, by silencing the Wnt5a gene, the therapeutic effect of MSC-Exos on hypoxic injury was suppressed [9] (Table 2). These illustrate that the mechanism by which MSC-Exos acts on pulmonary hypertension is related to the upregulation of Wnt5a expression.

The PAH and RV hypertrophy in hyperoxia-exposed bronchopulmonary dysplasia (BPD) mice have been corrected by MSC-CM/EXO treatment. Brain cell death was reduced and myelin sagging was reversed. Importantly, TSG-6, an immunomodulatory glycoprotein, has been detected in Exos. The knockdown of TSG-6 by NAb or by siRNA negated the obvious effect of Exos, indicating that TSG-6 is an important therapeutic molecule [10] (Table 2).

ACE2 and plasma Ang-(1–7) mRNA levels in the lung tissue of the MV group were upregulated compared with those of the PAH group. Conversely, ACE and Ang-II were decreased. However, this enhanced protection was attenuated by A-779, a Mas receptor inhibitor of the ACE2-Ang-(1–7)-Mas axis. BMMSCs-MVs changed the balance from the ACE-Ang-II-AT1R axis to the ACE2-Ang-(1–7)-Mas axis and produced positive results on MCT-induced PH in vivo, which may be a possible therapeutic mechanism for subcellular therapy with MVs [76] (Table 2).

4.5. MSC-Exos Improve Mitochondrial Health of PH

Although chronic hypoxia leads to glycolytic metastasis of PASMC, exosomes restore the energy balance and improve O₂ depletion. Exosome exposure increased the expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1) in PASMC. Additionally, exosomes reduced the expression of sirtuin 4, an upstream inhibitor of GLUD1 and PDH, despite prolonged hypoxia. These data provide first-hand material for exosomes to improve mitochondrial function and provide new insights into the therapeutic prospects of exosomes in PAH [92] (Table 2).

In conclusion, MSC-Exos therapy opens up a promising field in the treatment of PH, proposes a new concept, and attracts increasing attention. A growing number of preclinical studies have demonstrated that cell therapy is a promising therapeutic strategy for treating refractory and uncontrollable lung diseases. The complex interplay between immune system homeostasis and mesenchymal stem cells remains not fully understood. To ensure quality control and reproducible production of functional EVs, MSC-EVs clinical translation still faces many challenges, including scalable manufacturing and identity and potency assays [95]. The Association for Clinical Research and Translation of Extracellular Vesicles discussed opportunities and challenges for developing EV-based therapeutics at preclinical and clinical levels [96]. Using MSC-EVs may have considerable advantages over using live MSCs, such as reduced side effects due to the absence of infusion toxicity [97]. Although there are still significant challenges in treating PH with stem cells-EVs, we believe these issues will be addressed in further research.

Data Availability

Citations appear in the body of the article with a corresponding reference in the reference list. And the citations data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by the Basic Research Project of Shenzhen Science and Technology Innovation Commission (JCYJ20190808111216714).

References

Y. Cao, X. Zhang, L. Wang et al., “PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension,” Proceedings of the National Academy of Sciences, vol. 116, no. 27, pp. 13394–13403, 2019.
View at: Publisher Site | Google Scholar
M. Rabinovitch, C. Guignabert, M. Humbert, and M. R. Nicolls, “Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension,” Circulation Research, vol. 115, no. 1, pp. 165–175, 2014.
View at: Publisher Site | Google Scholar
T. Thenappan, M. L. Ormiston, J. J. Ryan, and S. L. Archer, “Pulmonary arterial hypertension: pathogenesis and clinical management,” BMJ, vol. 360, Article ID j5492, 2018.
View at: Publisher Site | Google Scholar
E. M. T. Lau, M. Humbert, and D. S. Celermajer, “Early detection of pulmonary arterial hypertension,” Nature Reviews Cardiology, vol. 12, no. 3, pp. 143–155, 2015.
View at: Publisher Site | Google Scholar
G. Hansmann, H. Sallmon, C. C. Roehr, S. Kourembanas, E. D. Austin, and M. Koestenberger, “Pulmonary hypertension in bronchopulmonary dysplasia,” Pediatric Research, vol. 89, no. 3, pp. 446–455, 2021.
View at: Publisher Site | Google Scholar
M. D. Mcgoon, R. L Benza, P. Escribano-Subias et al., “Pulmonary arterial hypertension: epidemiology and registries,” Journal of the American College of Cardiology, vol. 62, no. 25, pp. D51–D59, 2013.
View at: Google Scholar
T. Lener, M. Gimona, L. Aigner et al., “Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper,” Journal of Extracellular Vesicles, vol. 4, no. 1, Article ID 30087, 2015.
View at: Publisher Site | Google Scholar
H. L. Ji, C. Liu, and R. Z. Zhao, “Stem cell therapy for COVID-19 and other respiratory diseases: global trends of clinical trials,” World Journal of Stem Cells, vol. 12, no. 6, pp. 471–480, 2020.
View at: Publisher Site | Google Scholar
S. Zhang, X. Liu, L. L. Ge et al., “Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling,” Respiratory Research, vol. 21, no. 1, p. 71, 2020.
View at: Publisher Site | Google Scholar
S. Chaubey, S. Thueson, D. Ponnalagu et al., “Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 173, 2018.
View at: Publisher Site | Google Scholar
C. Théry, K. Witwer, E. Aikawa et al., “Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines,” Journal of Extracellular Vesicles, vol. 7, no. 1, Article ID 1461450, 2018.
View at: Publisher Site | Google Scholar
J. Lotvall, A. F. Hill, F. Hochberg et al., “Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the international society for extracellular vesicles,” Journal of Extracellular Vesicles, vol. 3, no. 1, Article ID 26913, 2014.
View at: Publisher Site | Google Scholar
L. M. Doyle and M. Z. Wang, “Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis,” Cells, vol. 8, no. 7, p. 727, 2019.
View at: Publisher Site | Google Scholar
R. M. Johnstone, A. Bianchini, and K. Teng, “Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions,” Blood, vol. 74, no. 5, pp. 1844–1851, 1989.
View at: Publisher Site | Google Scholar
N. P. Hessvik and A. Llorente, “Current knowledge on exosome biogenesis and release,” Cellular and Molecular Life Sciences, vol. 75, no. 2, pp. 193–208, 2018.
View at: Publisher Site | Google Scholar
C. Lasser, V. Seyed Alikhani, K. Ekstrom et al., “Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages,” Journal of Translational Medicine, vol. 9, no. 1, 2011.
View at: Publisher Site | Google Scholar
L. Barile, T. Moccetti, E. Marbán, and G. Vassalli, “Roles of exosomes in cardioprotection,” European Heart Journal, vol. 38, no. 18, pp. 1372–1379, 2017.
View at: Publisher Site | Google Scholar
D. M. Pegtel and S. J. Gould, “Exosomes,” Annual Review of Biochemistry, vol. 88, no. 1, pp. 487–514, 2019.
View at: Publisher Site | Google Scholar
Y. Zhang, M. Yu, and W. Tian, “Physiological and pathological impact of exosomes of adipose tissue,” Cell Proliferation, vol. 49, no. 1, pp. 3–13, 2016.
View at: Publisher Site | Google Scholar
P. D. Robbins, A. Dorronsoro, and C. N. Booker, “Regulation of chronic inflammatory and immune processes by extracellular vesicles,” Journal of Clinical Investigation, vol. 126, no. 4, pp. 1173–1180, 2016.
View at: Publisher Site | Google Scholar
J. M. Pitt, G. Kroemer, and L. Zitvogel, “Extracellular vesicles: masters of intercellular communication and potential clinical interventions,” Journal of Clinical Investigation, vol. 126, no. 4, pp. 1139–1143, 2016.
View at: Publisher Site | Google Scholar
Z. E. Arellano-Anaya, A. Huor, P. Leblanc et al., “Prion strains are differentially released through the exosomal pathway,” Cellular and Molecular Life Sciences, vol. 72, no. 6, pp. 1185–1196, 2015.
View at: Publisher Site | Google Scholar
B. Février and G. Raposo, “Exosomes: endosomal-derived vesicles shipping extracellular messages,” Current Opinion in Cell Biology, vol. 16, no. 4, pp. 415–421, 2004.
View at: Publisher Site | Google Scholar
B. T. Pan, K. Teng, C. Wu, M. Adam, and R. M. Johnstone, “Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes,” The Journal of Cell Biology, vol. 101, no. 3, pp. 942–948, 1985.
View at: Publisher Site | Google Scholar
A. Clayton, C. Harris, J. Court, M. D. Mason, and B. Morgan, “Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59,” European Journal of Immunology, vol. 33, no. 2, pp. 522–531, 2003.
View at: Publisher Site | Google Scholar
J. Skog, T. Würdinger, S. van Rijn et al., “Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers,” Nature Cell Biology, vol. 10, no. 12, pp. 1470–1476, 2008.
View at: Publisher Site | Google Scholar
R. J. Simpson, S. S. Jensen, and J. W. E. Lim, “Proteomic profiling of exosomes: current perspectives,” Proteomics, vol. 8, no. 19, pp. 4083–4099, 2008.
View at: Publisher Site | Google Scholar
D. A. Harris, S. H. Patel, M. Gucek, A. Hendrix, W. Westbroek, and J. W. Taraska, “Exosomes released from breast cancer carcinomas stimulate cell movement,” PLoS One, vol. 10, no. 3, Article ID e0117495, 2015.
View at: Publisher Site | Google Scholar
C. Théry, A. Regnault, J. Garin et al., “Molecular characterization of dendritic cell-derived exosomes: selective accumulation of the heat,” Journal of Cell Biology, vol. 147, no. 3, pp. 599–610, 1999.
View at: Publisher Site | Google Scholar
K. Oshima, N. Aoki, T. Kato, K. Kitajima, and T. Matsuda, “Secretion of a peripheral membrane protein, MFG-E8, as a complex with membrane vesicles,” European Journal of Biochemistry, vol. 269, no. 4, pp. 1209–1218, 2002.
View at: Publisher Site | Google Scholar
H. Valadi, K. Ekström, A. Bossios, M. Sjostrand, J. J. Lee, and J. O. Lotvall, “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells,” Nature Cell Biology, vol. 9, no. 6, pp. 654–659, 2007.
View at: Publisher Site | Google Scholar
C. Roma-Rodrigues, A. R. Fernandes, and P. V. Baptista, “Exosome in tumour microenvironment: overview of the crosstalk between normal and cancer cells,” BioMed Research International, vol. 2014, Article ID 179486, 10 pages, 2014.
View at: Publisher Site | Google Scholar
G. Di Leva and C. M. Croce, “miRNA profiling of cancer,” Current Opinion in Genetics & Development, vol. 23, no. 1, pp. 3–11, 2013.
View at: Publisher Site | Google Scholar
C. Théry, M. Ostrowski, and E. Segura, “Membrane vesicles as conveyors of immune responses,” Nature Reviews Immunology, vol. 9, no. 8, pp. 581–593, 2009.
View at: Publisher Site | Google Scholar
J. C. Caruana and S. A. Walper, “Bacterial membrane vesicles as mediators of microbe-microbe and microbe-host community interactions,” Frontiers in Microbiology, vol. 11, p. 432, 2020.
View at: Publisher Site | Google Scholar
W. Zhao, X. L. Zheng, and S. P. Zhao, “Exosome and its roles in cardiovascular diseases,” Heart Failure Reviews, vol. 20, no. 3, pp. 337–348, 2014.
View at: Publisher Site | Google Scholar
A. Kalani, A. Tyagi, and N. Tyagi, “Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics,” Molecular Neurobiology, vol. 49, no. 1, pp. 590–600, 2014.
View at: Publisher Site | Google Scholar
R. Jeske, J. Bejoy, M. Marzano, and Y. Li, “Human pluripotent stem cell-derived extracellular vesicles: characteristics and applications,” Tissue Engineering Part B Reviews, vol. 26, no. 2, pp. 129–144, 2020.
View at: Publisher Site | Google Scholar
J. C. Gross, V. Chaudhary, K. Bartscherer, and M. Boutros, “Active Wnt proteins are secreted on exosomes,” Nature Cell Biology, vol. 14, no. 10, pp. 1036–1045, 2012.
View at: Publisher Site | Google Scholar
S. Beloribi, E. Ristorcelli, G. Breuzard et al., “Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells,” PLoS One, vol. 7, no. 10, Article ID e47480, 2012.
View at: Publisher Site | Google Scholar
S. Wang, F. Cesca, G. Loers et al., “Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes,” Journal of Neuroscience, vol. 31, no. 20, pp. 7275–7290, 2011.
View at: Publisher Site | Google Scholar
H. Dweep, N. Gretz, and C. Sticht, “miRWalk database for miRNA-target interactions,” Methods in Molecular Biology, vol. 1182, pp. 289–305, 2014.
View at: Publisher Site | Google Scholar
S. EL Andaloussi, I. Mager, X. O. Breakefield, and M. J. A. Wood, “Extracellular vesicles: biology and emerging therapeutic opportunities,” Nature Reviews Drug Discovery, vol. 12, no. 5, pp. 347–357, 2013.
View at: Publisher Site | Google Scholar
M. Albanese, Y. F. A. Chen, C. Hüls et al., “MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells,” PLoS Genetics, vol. 17, no. 12, Article ID e1009951, 2021.
View at: Publisher Site | Google Scholar
J. R. Chevillet, Q. Kang, I. K. Ruf et al., “Quantitative and stoichiometric analysis of the microRNA content of exosomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 41, pp. 14888–14893, 2014.
View at: Publisher Site | Google Scholar
A. Mohan, S. Agarwal, M. Clauss, N. S. Britt, and N. K. Dhillon, “Extracellular vesicles: novel communicators in lung diseases,” Respiratory Research, vol. 21, no. 1, p. 175, 2020.
View at: Publisher Site | Google Scholar
B. Bakouboula, O. Morel, A. Faure et al., “Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 5, pp. 536–543, 2008.
View at: Publisher Site | Google Scholar
N. Amabile, C. Heiss, W. M. Real et al., “Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 11, pp. 1268–1275, 2008.
View at: Publisher Site | Google Scholar
N. Amabile, C. Heiss, V. Chang et al., “Increased CD62e (+) endothelial microparticle levels predict poor outcome in pulmonary hypertension patients,” The Journal of Heart and Lung Transplantation, vol. 28, no. 10, pp. 1081–1086, 2009.
View at: Publisher Site | Google Scholar
E. Ferrer, B. J. Dunmore, D. Hassan et al., “A potential role for exosomal translationally controlled tumor protein export in vascular remodeling in pulmonary arterial hypertension,” American Journal of Respiratory Cell and Molecular Biology, vol. 59, no. 4, pp. 467–478, 2018.
View at: Publisher Site | Google Scholar
H. Balla, “Stem cells,” Journal of Craniofacial Surgery, vol. 31, no. 1, pp. 4-5, 2020.
View at: Google Scholar
D. G. Drubin and A. A. Hyman, “Stem cells: the new “model organism”,” Molecular Biology of the Cell, vol. 28, no. 11, pp. 1409–1411, 2017.
View at: Publisher Site | Google Scholar
D. Dambournet, K. A. Sochacki, A. T. Cheng et al., “Genome-edited human stem cells expressing fluorescently labeled endocytic markers allow quantitative analysis of clathrin-mediated endocytosis during differentiation,” Journal of Cell Biology, vol. 217, no. 9, pp. 3301–3311, 2018.
View at: Publisher Site | Google Scholar
T. Narita and K. Suzuki, “Bone marrow-derived mesenchymal stem cells for the treatment of heart failure,” Heart Failure Reviews, vol. 20, no. 1, pp. 53–68, 2015.
View at: Publisher Site | Google Scholar
H. Saeed, M. Ahsan, Z. Saleem et al., “Mesenchymal stem cells (MSCs) as skeletal therapeutics-an update,” Journal of Biomedical Science, vol. 23, no. 1, p. 41, 2016.
View at: Publisher Site | Google Scholar
A. Mohammadalipour, S. P. Dumbali, and P. L. Wenzel, “Mitochondrial transfer and regulators of mesenchymal stromal cell function and therapeutic efficacy,” Frontiers in Cell and Developmental Biology, vol. 8, no. 8, Article ID 603292, 2020.
View at: Publisher Site | Google Scholar
K. L. Lankford, E. J. Arroyo, K. Nazimek, K. Bryniarski, P. W. Askenase, and J. D. Kocsis, “Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord,” PLoS One, vol. 13, no. 1, Article ID e0190358, 2018.
View at: Publisher Site | Google Scholar
S. Bruno, C. Grange, M. C. Deregibus et al., “Mesenchymal stem cell-derived microvesicles protect against acute tubular injury,” Journal of the American Society of Nephrology, vol. 20, no. 5, pp. 1053–1067, 2009.
View at: Publisher Site | Google Scholar
R. C. Lai, F. Arslan, M. M. Lee et al., “Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury,” Stem Cell Research, vol. 4, no. 3, pp. 214–222, 2010.
View at: Publisher Site | Google Scholar
W. S. Toh, R. C. Lai, B. Zhang, and S. K. Lim, “MSC exosome works through a protein-based mechanism of action,” Biochemical Society Transactions, vol. 46, no. 4, pp. 843–853, 2018.
View at: Publisher Site | Google Scholar
W. S. Toh, B. Zhang, R. C. Lai, and S. K. Lim, “Immune regulatory targets of mesenchymal stromal cell exosomes/small extracellular vesicles in tissue regeneration,” Cytotherapy, vol. 20, no. 12, pp. 1419–1426, 2018.
View at: Publisher Site | Google Scholar
V. Börger, M. Bremer, R. Ferrer-Tur et al., “Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents,” International Journal of Molecular Sciences, vol. 18, no. 7, p. 1450, 2017.
View at: Publisher Site | Google Scholar
R. Blazquez, F. M. Sanchez-Margallo, O. de la Rosa et al., “Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells,” Frontiers in Immunology, vol. 5, p. 556, 2014.
View at: Publisher Site | Google Scholar
X. Li, Y. N. Wang, Q. Wang, Y. Liu, W. Bao, and S. Wu, “Exosomes in cancer: small transporters with big functions,” Cancer Letters, vol. 435, pp. 55–65, 2018.
View at: Publisher Site | Google Scholar
S. Shojaei, S. M. Hashemi, H. Ghanbarian, K. Sharifi, M. Salehi, and S. Mohammadi-Yeganeh, “Delivery of miR-381-3p mimic by mesenchymal stem cell-derived exosomes inhibits triple negative breast cancer aggressiveness; an in vitro study,” Stem Cell Reviews and Reports, vol. 17, no. 3, pp. 1027–1038, 2021.
View at: Publisher Site | Google Scholar
J. Maia, S. Caja, M. C. Strano Moraes, N. Couto, and B. Costa-Silva, “Exosome-based cell-cell communication in the tumor microenvironment,” Frontiers in Cell and Developmental Biology, vol. 6, p. 18, 2018.
View at: Publisher Site | Google Scholar
B. Yu, X. Zhang, and X. Li, “Exosomes derived from mesenchymal stem cells,” International Journal of Molecular Sciences, vol. 15, no. 3, pp. 4142–4157, 2014.
View at: Publisher Site | Google Scholar
J. Ma, Y. Zhao, L. Sun et al., “Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D,” Stem Cells Translational Medicine, vol. 6, no. 1, pp. 51–59, 2017.
View at: Publisher Site | Google Scholar
P. Waszak, R. Alphonse, A. Vadivel, L. Ionescu, F. Eaton, and B. Thebaud, “Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats,” Stem Cells and Development, vol. 21, no. 15, pp. 2789–2797, 2012.
View at: Publisher Site | Google Scholar
J. Xue, X. Li, Y. Lu et al., “Gene-modified mesenchymal stem cells protect against radiation-induced lung injury,” Molecular Therapy, vol. 21, no. 2, pp. 456–465, 2013.
View at: Publisher Site | Google Scholar
K. W. Witwer, B. W. M. Van Balkom, S. Bruno et al., “Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications,” Journal of Extracellular Vesicles, vol. 8, no. 1, Article ID 1609206, 2019.
View at: Publisher Site | Google Scholar
Y. M. Ma, X. M. Liu, Y. J. Long, and Y. Chen, “Emerging therapeutic potential of mesenchymal stem cell-derived extracellular vesicles in chronic respiratory diseases: an overview of recent progress,” Frontiers in Bioengineering and Biotechnology, vol. 10, Article ID 845042, 2022.
View at: Publisher Site | Google Scholar
L. Ge, W. Jiang, S. Zhang et al., “Mesenchymal stromal cell-derived exosomes attenuate experimental pulmonary arterial hypertension,” Current Pharmaceutical Biotechnology, vol. 22, no. 12, pp. 1654–1662, 2021.
View at: Publisher Site | Google Scholar
J. R. Klinger, M. Pereira, M. Del Tatto et al., “Mesenchymal stem cell extracellular vesicles reverse sugen/hypoxia pulmonary hypertension in Rats,” American Journal of Respiratory Cell and Molecular Biology, vol. 62, no. 5, pp. 577–587, 2020.
View at: Publisher Site | Google Scholar
J. Y. Chen, R. An, Z. J. Liu et al., “Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats,” Acta Pharmacologica Sinica, vol. 35, no. 9, pp. 1121–1128, 2014.
View at: Publisher Site | Google Scholar
Z. J. Liu, J. H. Liu, M. Y. Xiao et al., “Mesenchymal stem cell-derived microvesicles alleviate pulmonary arterial hypertension by regulating renin-angiotensin system,” Journal of the American Society of Hypertension, vol. 12, no. 6, pp. 470–478, 2018.
View at: Publisher Site | Google Scholar
J. M. Aliotta, M. Pereira, S. Wen et al., “Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice,” Cardiovascular Research, vol. 110, no. 3, pp. 319–330, 2016.
View at: Publisher Site | Google Scholar
J. R. Klinger, M. Pereira, M. Del Tatto et al., “Effect of dose, dosing intervals, and hypoxic stress on the reversal of pulmonary hypertension by mesenchymal stem cell extracellular vesicles,” Pulmonary Circulation, vol. 11, no. 4, pp. 1–11, 2021.
View at: Publisher Site | Google Scholar
C. Zhang, P. Wang, A. Mohammed et al., “Function of adipose-derived mesenchymal stem cells in monocrotaline-induced pulmonary arterial hypertension through miR-191 via regulation of BMPR2,” BioMed Research International, vol. 2019, Article ID 2858750, 12 pages, 2019.
View at: Publisher Site | Google Scholar
M. N. Monroe, S. Zhaorigetu, V. S. Gupta et al., “Extracellular vesicles influence the pulmonary arterial extracellular matrix in congenital diaphragmatic hernia,” Pediatric Pulmonology, vol. 55, no. 9, pp. 2402–2411, 2020.
View at: Publisher Site | Google Scholar
G. R. Willis, A. Fernandez-Gonzalez, M. Reis et al., “Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury,” Journal of Extracellular Vesicles, vol. 9, no. 1, Article ID 1790874, 2020.
View at: Publisher Site | Google Scholar
S. C. Abreu, D. J. Weiss, and P. R. M. Rocco, “Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?” Stem Cell Research & Therapy, vol. 7, no. 1, p. 53, 2016.
View at: Publisher Site | Google Scholar
A. Tieu, K. Hu, C. Gnyra et al., “Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: a meta-analysis,” Journal of Extracellular Vesicles, vol. 10, no. 12, Article ID e12141, 2021.
View at: Publisher Site | Google Scholar
E. Soon, A. M. Holmes, C. M. Treacy et al., “Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension,” Circulation, vol. 122, no. 9, pp. 920–927, 2010.
View at: Publisher Site | Google Scholar
A. Zimmer, R. B. Teixeira, J. H. P. Bonetto et al., “Role of inflammation, oxidative stress, and autonomic nervous system activation during the development of right and left cardiac remodeling in experimental pulmonary arterial hypertension,” Molecular and Cellular Biochemistry, vol. 464, no. 1-2, pp. 93–109, 2020.
View at: Publisher Site | Google Scholar
G. R. Willis, A. Fernandez-Gonzalez, M. Reis, S. Mitsialis, and S. Kourembanas, “Macrophage immunomodulation: the gatekeeper for mesenchymal stem cell derived-exosomes in pulmonary arterial hypertension?” International Journal of Molecular Sciences, vol. 19, no. 9, p. 2534, 2018.
View at: Publisher Site | Google Scholar
S. Zeng, Y. B. Zhong, J. Xiao et al., “Kappa opioid receptor on pulmonary macrophages and immune function,” Translational Perioperative and Pain Medicine, vol. 7, no. 3, pp. 225–233, 2020.
View at: Publisher Site | Google Scholar
H. Kubo, “Extracellular vesicles in lung disease,” Chest, vol. 153, no. 1, pp. 210–216, 2018.
View at: Publisher Site | Google Scholar
G. R. Willis, A. Fernandez-Gonzalez, J. Anastas et al., “Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation,” American Journal of Respiratory and Critical Care Medicine, vol. 197, no. 1, pp. 104–116, 2018.
View at: Publisher Site | Google Scholar
C. Lee, S. A. Mitsialis, M. Aslam et al., “Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension,” Circulation, vol. 126, no. 22, pp. 2601–2611, 2012.
View at: Publisher Site | Google Scholar
J. Gu, H. Zhang, B. Ji et al., “Vesicle miR-195 derived from endothelial cells inhibits expression of serotonin transporter in vessel smooth muscle cells,” Scientific Reports, vol. 7, no. 1, Article ID 43546, 2017.
View at: Publisher Site | Google Scholar
S. E. Hogan, M. P. Rodriguez Salazar, J. Cheadle et al., “Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 316, no. 5, pp. L723–L737, 2019.
View at: Publisher Site | Google Scholar
Z. Zhu, Z. Fang, X. Hu, and S. Zhou, “MicroRNAs and mesenchymal stem cells: hope for pulmonary hypertension,” Revista Brasileira de Cirurgia Cardiovascular, vol. 30, no. 3, pp. 380–385, 2015.
View at: Publisher Site | Google Scholar
R. K. Hopper, J. R. A. Moonen, I. Diebold et al., “In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to- mesenchymal transition via HMGA1 and its target slug,” Circulation, vol. 133, no. 18, pp. 1783–1794, 2016.
View at: Publisher Site | Google Scholar
M. Gimona, M. F. Brizzi, A. B. H. Choo et al., “Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles,” Cytotherapy, vol. 23, no. 5, pp. 373–380, 2021.
View at: Publisher Site | Google Scholar
A. T. Reiner, K. W. Witwer, B. W. M. van Balkom et al., “Concise review: developing best-practice models for the therapeutic use of extracellular vesicles,” Stem Cells Translational Medicine, vol. 6, no. 8, pp. 1730–1739, 2017.
View at: Publisher Site | Google Scholar
M. Mendt, K. Rezvani, and E. Shpall, “Mesenchymal stem cell-derived exosomes for clinical use,” Bone Marrow Transplantation, vol. 54, no. 2, pp. 789–792, 2019.
View at: Publisher Site | Google Scholar

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