JADICELL -Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

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JADICELL -Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm

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Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm


https://biomarkerres.biomedcentral.com/ ... 019-0159-x

Abstract
Mesenchymal stem/stromal cells (MSCs) have been demonstrated to hold great potential for the treatment of several diseases. Their therapeutic effects are largely mediated by paracrine factors including exosomes, which are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication. MSC-derived exosomes contain cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. Increasing evidence suggests that MSC-derived exosomes might represent a novel cell-free therapy with compelling advantages over parent MSCs such as no risk of tumor formation and lower immunogenicity. This paper reviews the characteristics of MSC exosomes and their fate after in vivo administration, and highlights the therapeutic potential of MSC-derived exosomes in liver, kidney, cardiovascular and neurological disease. Particularly, we summarize the recent clinical trials performed to evaluate the safety and efficacy of MSC exosomes. Overall, this paper provides a general overview of MSC-exosomes as a new cell-free therapeutic paradigm.

Background
Mesenchymal stem/stromal cells (MSCs) are one of the most commonly employed cell types as a cell-based therapy for treating human diseases. Recently, several mechanisms have been put forward regarding the therapeutic potential of MSCs, including (1) paracrine factors involving proteins/peptides and hormones and (2) the transfer of exosomes/microvesicles packaging various molecules [1]. The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in vesicles [2]. Extracellular vesicles (EVs) from many cell sources have now been recognized as important messengers in intercellular communication via transfer of bioactive lipids, proteins, and RNAs. EVs are generally divided into 3 subgroups depending on their biogenesis; (a) exosomes, with a diameter of 40–150 nm, which are released into the extracellular when multivesicular bodies fuse with the cell membrane, (b) microvesicles, with a diameter of 150–1000 nm, originating from direct budding of the plasma membrane and finally (c) apoptotic bodies, which display a broad size distribution (50–2000 nm) [3]. Exosomes are crucial messengers that present in biological fluids and are involved in multiple physiological and pathological processes [4]. Today, there are hundreds of clinics and hundreds of clinical trials using human MSCs with very few, if any, focusing on the in vitro multipotential capacities of these cells, these cells home in on sites of injury or disease and secrete bioactive factors that are immunomodulatory and trophic (regenerative) [5]. One advantage of using exosomes is to get around MSCs’ side effects, exosomes are nanoparticles that can penetrate blood brain barrier and avoid potential pulmonary embolism related to transplantation of MSCs [6]. Knowledge of exosomes is essential to shed light on the functions of these vesicles on clinical applications. In this review, we focus on the mechanisms of exosomes covering the current knowledge on their potential cell-free therapeutic applications for MSC-derived exosomes.

Exosomes
Exosomes are a family of nanoparticles with a diameter in the range of 40–150 nm that are generated inside multivesicular bodies (MVBs) and are secreted when these compartments fuse with the plasma membrane [7]. Upon the fusion of MVBs with the plasma membrane, exosomes are released into the extracellular and can be either taken up by target cells residing in the microenvironment or carried to distant sites via biological fluids [8]. Exosomes are enriched in many bioactive molecules such as lipids, proteins, mRNAs, transfer RNA (tRNA), long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and mitochondrial DNA (mtDNA) [9]. Most exosomes have an evolutionarily conserved set of proteins including tetraspanins (CD81, CD63, and CD9), heat-shock proteins (HSP60, HSP70 and HSP90), ALIX and tumor susceptibility gene 101 (TSG101); however, they also have unique tissue type-specific proteins that reflect their cellular sources [10]. It has been reported that exosomes may be released from multiple cell types, including immunocytes [11], tumor cells [12], and mesenchymal stem/stromal cells (MSCs) [13]. Exosomes have received the most attention and have been implicated in physiological functions and in pathological conditions. Exosomes released by malignant cells play an important role in cancer cell communication with their microenvironment. HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes [14]. Exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression [15].

Characteristics of MSC-derived exosomes
The abundance of cargos identified from MSC-derived exosomes function largely via the constant transfer of miRNAs and proteins, > 150 miRNAs [16] and > 850 unique protein [17] have been identified in the cargo of MSC-derived exosomes, resulting in the alteration of a variety of activities in target cells via different pathways. Many miRNAs have been found in MSC-derived exosomes and are reportedly involved in both physiological and pathological processes such as organism development, epigenetic regulation, immunoregulation (miR-155 and miR-146) [18], tumorigenesis and tumor progression (miR-23b, miR-451, miR-223, miR-24, miR-125b, miR-31, miR-214, and miR-122) [19]. Over 900 species of proteins have been collected from MSC-derived exosomes according to ExoCarta. Several studies have also shown that exosomes derived from MSCs harbor cytokines and growth factors, such as TGFβ1, interleukin-6 (IL-6), IL-10, and hepatocyte growth factor (HGF), which have been proven to contribute to immunoregulation [20]. Comparable levels of VEGF, extracellular matrix metalloproteinase inducer (EMMPRIN), and MMP-9 have been reported in MSC-derived exosomes, these three proteins play a vital role in stimulating angiogenesis, which could be fundamental for tissue repair [21].

The fate of injected MSC-derived exosomes
Current knowledge of the biodistribution of EVs upon administration in animal models is limited. Do MSC-derived exosomes have a favorable biodistribution and pharmacokinetic profile? Several strategies have been employed for in vivo tracking to determine EVs biodistribution upon systemic delivery in different animal models [22, 23]. Near-infrared (NIR) dyes are ideal for in vivo applications due to their high signal/noise ratio [24]. EVs with superparamagnetic iron oxide nanoparticles for high resolution and sensitive magnetic resonance analysis provide for accurate detection also in deep organs [25]. In an intracerebral hemorrhage rat model, DiI-labeled MSC-derived exosomes reached brain, liver, lung, and spleen after intravenous injection [26]. Exosomes appear to be able to home to the injury site. In the mouse model of acute kidney injury (AKI), DiD-labeled EVs were accumulated specifically in the kidneys of mice with AKI compared with healthy controls [27]. Intranasal administration led to better brain accumulation of exosomes at the injured brain site, compared to i.v. injection [28]. Biodistribution of systemically administered EVs is a dynamic process: a rapid phase of distribution in liver, spleen, and lungs within approximately 30 min upon administration is followed by an elimination phase via hepatic and renal processing, removing EVs in 1 to 6 h after administration [29].

Therapeutic effects of MSC-derived exosomes
Liver diseases
The application of MSCs in animal models of liver fibrosis/cirrhosis and acute liver injury, eventually, in patients ameliorates the progress of the disease. Li et al. found that the exosomes derived from human umbilical cord MSCs (hucMSC) ameliorate liver fibrosis by inhibiting both the epithelial-mesenchymal transition of hepatocytes and collagen production, significantly restore the serum aspartate aminotransferase activity and inactivate the TGF-β1/Smad2 signaling pathway by decreasing collagen type I/III and TGF-β1 and the phosphorylation of Smad2 [30]. Tan et al. found that HuES9.E1 MSC-derived exosomes elicit hepatoprotective effects through an increase in hepatocyte proliferation, as demonstrated by high expression of proliferation proteins (proliferating cell nuclear antigen and Cyclin D1), the anti-apoptotic gene Bcl-xL and the signal transducer and activator of transcription 3 (STAT3) [31]. Liver regeneration was significantly stimulated by MSCs culture medium (MSC-CM) as shown by an increase in liver to body weight ratio and hepatocyte proliferation. MSC-CM upregulated hepatic gene expression of cytokines and growth factors relevant for cell proliferation, angiogenesis, and anti-inflammatory responses, treatment with MSC-derived factors can promote hepatocyte proliferation and regenerative responses in the early phase after surgical resection [32]. Transplantation of exosomes released from adipose derived-MSCs (AD-MSC) can significantly reduce the elevated serum levels of alanine aminotransferase and aspartate aminotransferase, liver inflammation and necrosis in concanavalin A (Con A)-induced hepatitis in C57BL/6 mice as well as the serum levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6, IL-18 and IL-1β, and the inflammasome activation in mouse liver [33].

Kidney disease
Mesenchymal stem/stromal cells (MSCs) have shown promising results in experimental acute kidney injury (AKI) and chronic kidney disease (CKD). Systemic administration of human umbilical cord-derived MSCs (huMSCs)-derived EVs in rats with renal Ischemia-reperfusion injury (IRI) increased renal capillary density and reduced fibrosis by direct transfer of the proangiogenic factor vascular endothelial growth factor (VEGF) and mRNAs involved in this process [34]. A single intrarenal administration of adipose tissue-derived autologous MSCs-derived EVs in pigs with renal artery stenosis attenuated renal inflammation, disclosed by decreased renal vein levels of several pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1-β. Contrarily, renal vein levels of IL-10 increased in EV-treated pigs, associated with a shift from pro-inflammatory to reparative macrophages populating the stenotic kidney, underscoring the immunomodulatory potential of EVs [35]. Microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced acute kidney injury (AKI) in SCID mice by inducing proliferation of tubular cells. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation [36]. The effects of bone marrow MSCs-derived MVs in SCID mice survival in lethal cisplatin-induced acute renal injury (AKI) was to exert a pro-survival effect on renal cells in vitro and in vivo mainly ascribed to an anti-apoptotic effect of MVs. MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA [37]. Intravenous injection of EVs isolated from the conditioned medium of human umbilical cord MSCs after unilateral renal ischemia preserved kidney function and decreased serum levels of the AKI marker neutrophil gelatinase-associated lipocalin [38]. Human bone marrow MSCs-derived exosomes contain insulin-like growth factor-1 receptor (IGF-1R) mRNA. Exosomal transfer of IGF-1R mRNA to damaged renal tubular cells promoted their proliferation and repair and this effect was significantly reduced when IGF-1R transcription in donor cells was silenced [39].

Cardiovascular disease
There are preclinical studies in which MSC-derived exosomes are used for treating cardiovascular diseases (CVDs) such as AMI, stroke, pulmonary hypertension, and septic cardiomyopathy [40]. Cui et al. demonstrated adipose-derived MSC (AdMSC)-derived exosomes led to a markedly increase in cell viability of H9C2 cells under hypoxia/reoxygenation (H/R) in vitro, and administration of AdMSC-derived exosomes protected ischemic myocardium from myocardial ischemia-reperfusion (MI/R) injury via activation of Wnt/β-catenin signaling in vivo [41]. Furthermore, Wang et al. showed superior cardioprotective effects of endometrium-derived MSCs (EmMSC) in a rat myocardial infarction (MI) model as compared to BMSCs and AdMSCs. These differences may be caused by certain miRNAs particularly miR-21 enrichment in exosomes secreted from EmMSCs, which exerted effects on cell survival and angiogenesis by targeting PTEN [42]. HuES9.E1 derived MSCs-derived exosomes treatment increased levels of ATP and NADH, decreased oxidative stress, increased phosphorylated-Akt and phosphorylated-GSK-3β, reduced phosphorylated-c-JNK in ischemic/reperfused hearts to enhance myocardial viability and prevented adverse remodeling after myocardial ischemia/reperfusion injury [43]. Feng et al. determined that miR-22 is highly enriched in exosomes secreted by mouse bone marrow-derived MSCs after ischemic preconditioning, and administration of these exosomes significantly reduced infarct size and cardiac fibrosis by targeting methyl-CpG-binding protein 2 (Mecp2) in a mouse myocardial infarction (MI) model [44]. Both bone marrow MSCs and their derived exosomes are cardioprotective against myocardial infarction in animal models. However, anti-miR-125b treatment of exosomes significantly attenuated their protective effect [45]. MiR-21-5p plays a key role in hMSC-exo–mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling [46]. In a rat myocardial ischaemia reperfusion injury model, injection of bone marrow-derived MSCs-derived exosomes reduced apoptosis and myocardial infarct size and subsequently improved heart functions by inducing cardiomyocyte autophagy via AMPK/mTOR and Akt/mTOR pathways [47].

Neurological disease
MSC-Exosomes have shown potential therapeutic benefit in the treatment of neurological and neurodegenerative diseases. One of the most outstanding results in the field is the fact that systemically injected exosomes are able to cross the blood-brain barrier (BBB) and achieve the brain parenchyma. Systemic delivery of targeted exosomes containing a siRNA against α-synuclein reduced the mRNA and protein levels of α-synuclein in the brain [48, 49]. Xin et al. also reported that rat bone marrow derived MSCs derived EVs enriched with the miR-17-92 cluster enhanced oligodendrogenesis neurogenesis neural plasticity and functional recovery after stroke possibly by suppressing PTEN and subsequently by increasing the phosphorylation of proteins downstream of PTEN including of the protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3β signaling pathway [50]. Katsuda et al. used exosomes secreted from human adipose tissue-derived MSCs that contain large amounts of neprilysin, the most prominent enzyme that degrades β-amyloid peptide in the brain. Transfer of exosomes into neuroblastoma N2a cells led to reductions in both secreted and intracellular β-amyloid peptide levels, which might be a therapeutic approach to Alzheimer’s disease [51]. The results of migration assay and capillary network formation assay showed that exosomes secreted by adipose-derived stem cells (ADSCs-Exos) promoted the mobility and angiogenesis of brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD) via miR-181b-5p/TRPM7 axis [52]. Injection of exosomes from mouse bone marrow MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1β); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB in APP/PS1 double transgenic mice [53].

Immune disease
Potent immunomodulatory properties of MSCs-exo has been evaluated. Exosomes have been observed to play crucial roles in carrying and presenting functional MHC-peptide complexes to modulate tumor-specific T cell activation [54]. Exosomes released from Bone marrow (BM)-derived MSCs can effectively ameliorate chronic graft-versus-host disease (cGVHD) in mice by inhibiting the activation and infiltration of CD4 T cells, reducing pro-inflammatory cytokine production, as well as improving the generation of IL-10-expressing Treg and inhibiting Th17 cells [55]. Human multipotent stromal cells-derived EVs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells, they also increased expression of the immunosuppressive cytokine IL-10 and suppressed Th17 cell development [56]. Human bone-marrow derived MSCs exosomes promote Tregs proliferation and immunosuppression capacity by upregulating suppressive cytokines IL-10 and TGF-β1 in PBMCs of asthmatic patient [57]. MiR-181c in human umbilical cord MSCs-derived exosomes is key to anti-inflammatory effects in burned rat inflammation model by downregulating the TLR4 signaling pathway [58] Fig. 1.
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JADICELL -The effect of mesenchymal stem cells and exosomes to treat idiopathic pulmonary fibrosis

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The effect of mesenchymal stem cells and exosomes to treat idiopathic pulmonary fibrosis

https://medcraveonline.com/JSRT/the-eff ... rosis.html

Daina M Chase, Vincent S Gallicchio
Department of Biological Sciences, USA

Correspondence: Vincent S Gallicchio, Department of Biological Sciences, College of Science, Clemson University, Clemson, SC 29637, USA

Received: April 23, 2019 | Published: April 30, 2019

Citation: Chase DM, Gallicchio VS. The effect of mesenchymal stem cells and exosomes to treat idiopathic pulmonary fibrosis. J Stem Cell Res Ther. 2019;5(2):48-59 DOI: 10.15406/jsrt.2019.05.00134

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Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a disease that consists of the scarring of the lungs. It is the most common type of pulmonary fibrosis. This disease is irreversible and becomes worse over time. In patients with IPF, treatment relies mostly on the clinical application of new drugs. Unfortunately, these drugs do not repair damaged lung tissue; therefore, these medications only have the ability to slow down disease progression. With this dilemma, stem cell treatment has become a popular alternative in the treatment of IPF, specifically mesenchymal stem cells (MSCs). MSC therapy would repair damaged lung tissue, thus not delaying the progression of the disease, but instead repairing the lungs of the patient. In addition, the application of exosomes has also gained popularity because of their functionality in intracellular communication. There is a need for regenerating the damaged lung tissue of patients with IPF, which can be accomplished with stem cell therapy. The clinical application of MSCs has been proven safe in patients with this degenerative disease, thus this finding has justified more research for the application of stem cell therapy in patients with IPF.

Key words: idiopathic, pulmonary, fibrosis, exosomes, stem cells, irreversible

Abbreviations and symbols
IPF, Idiopathic Pulmonary Fibrosis; AECs, Alveolar Epithelial Stem Cells; IIP, Idiopathic Interstitial Pneumonias; FVC, Forced Vital Capacity; MSC, Mesenchymal Stem Cells; HLA, Human Leukocyte Antigen; BLM, Bleomycin; hMSCs, Human Mesenchymal Stem Cells; BMSCs, Bone Marrow Mesenchymal Stem Cells; BMP-7, Bone Morphogenetic Protein-7; STC1, Stanniocalcin-1; ADSCs, Adipose-Derived Stem Cells; HGF, Hepatocyte Growth Factor; FDA, Food and Drug Administration; HUC-MSC, Umbilical Cord-Derived Mesenchymal Stem Cell; LTOT, Long-Term Oxygen Therapy; ATII, Alveolar Type II; miRs, MicroRNA; BALF, Bronchoalveolar Lavage Fluid; EVs, Extracellular Vesicles; hAEC Exo, Human Amnion Epithelial Cell-Derived Exosomes; HLF, Human Lung Fibroblasts; MEx, Mesenchymal Stem Cell Exosomes; hAECs, Human Placental Amniotic Epithelial Stem Cells

Introduction
Idiopathic pulmonary fibrosis (IPF) is a progressive type of lung disease that involves lung tissue becoming scarred thus inhibiting the lung’s ability to function properly.1 The scarring’s location normally progresses from the edge of the lungs toward the center as well as increasing in the amount of scarring.2 Over time the closer the scarring gets to the center of the lungs as well as the amount of scarring in the lungs reduces pulmonary function more difficult to breathe and deliver necessary oxygen throughout the body in patients with IPF.2

IPF is a debilitating condition that is irreversible and unfortunately has few treatment options.3 The cause of this debilitating disease is unknown; however, exacerbating the clinical condition is the fact that the lungs are the only internal organs with direct exposure to the external environment. Thus, the lungs are exposed to a variety of elements, which could be possible risk factors.2 Therefore, the cause of IPF could involve genetic, environmental or toxic components, but it remains unclear what is the main cause of the disease.4

Because IPF has limited treatment options, stem cell therapy has begun to be a potential option for lung tissue regeneration. Throughout life, animals depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. This is because stem cells have the capacity to self-renew and give rise to differentiated cell types. Stem cells possess the necessary properties required to address the needs for tissue replacement to maintain normal lung homeostasis as well as organ tissue regeneration after lung injury. The capacity of organ tissue regeneration of the lung epithelial stem cells involves communication with their immediate microenvironment. Thus, it is this local tissue environment that influences stem cell behavior of in part because the tissue environment is comprised of other cell types and the extracellular matrix. To have a regenerative response after lung injury, cross-talk needs to occur between the epithelial-mesenchymal stem cells as well as the signaling from fibroblast growth factor. When these communications and interactions are disrupted, cellular dysfunction can occur and may result in chronic lung diseases such as IPF. Furthermore, current research indicates that the fibrotic response of patients with IPF may be due to abnormally activated alveolar epithelial stem cells (AECs). Patients with IPF have an increase in epithelial stem cells despite the lung tissue damage.5 AECs produce mediators that bring about the formation of fibroblasts and myofibroblasts through the proliferation of resident mesenchymal cells and the attraction of circulating fibroblasts. It is the fibroblast and myofibroblast that secrete excessive amounts of extracellular matrix that results in the scarring and destruction of the lungs.6 This dysfunction leads to abnormal stem cell activation with stem cell loss which prevents proper regeneration and leads to permanent tissue damage. Therefore, stem cells are vital during normal cellular homeostasis and regeneration. A better understanding of stem cells microenvironments and their regulatory pathways involved will lead ways to recreate the microenvironments and develop cell replacement therapies.5

IPF affects about 50,000 people in the United States and about 3 million people worldwide. It is estimated that there are 15,000 new cases of IPF developing annually in the United States.2 IPF occurs in mainly older adults with the median age being at 66 years with a range of 55-75 years.4 This pathological lung condition is the most common and severe type of idiopathic interstitial pneumonias (IIP). IPF mortality rates remain high with a 50% mortality rate three years after diagnosis.3 The average survival of patients with IPF being 2–5 years from the onset of symptoms.7

As stated before, IPF is a degenerative disease of pulmonary tissue having little to no effective treatment. Pirfenidone was the first medication used in Japan to treat patients with IPF. However, it could not regenerate damaged tissue and only suppressed the disease.3 In addition, nintedanib is another antifibrotic drug that has also been shown to reduce the decline in forced vital capacity (FVC), decrease exacerbation, and improve mortality rates in several studies.4 According to Barczyk et al.8 despite these drug benefits, the medication did not improve the patients’ quality of life and survival. Drugs such as these only slow down the progression of IPF, unfortunately they do not reverse the fibrosis process.4 Thus, the only practical way to regenerate damaged pulmonary tissue would be with stem cell therapy.3 With this goal in mind, there is new evidence that the administration of mesenchymal stem cells (MSCs) could be an effective treatment for IPF patients based on the rationale that MSCs are known for their ability to differentiate into a variety of cell types, thus, they can migrate to and repair damaged tissue in anatomical locations, which would make stem cell therapy an effective use for reversing IPF.7 Stem cells have the high capacity to differentiate into special tissues which makes stem cell therapy a popular candidate for degenerative diseases.3 In this review, new evidence regarding the use of mesenchymal stem cells and exosomes will be discussed as an effective treatment to patients with IPF.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are self-renewing, multipotent progenitors that can be isolated from a variety of tissues.9 They are also easily accessible and can be simply collected from a variety of tissues such as adipose tissue, umbilical cord blood, liver, amniotic fluid, placenta, and other tissue sources. MSCs have the capability to differentiate, promote tissue-repair, immunosuppression, etc., thus they are an ever growing clinical therapeutic option for potential testing in clinical trials.9 MSCs are among the best investigated stem cell populations. Bone marrow derived MSCs are the most frequently studied of this type.10 As shown in Figure 1, MSCs are characterized by a variety of properties. Additional properties present to allow for the potential therapeutic effects of MSCs include low immunogenicity and transplantation in vitro, immunomodulation and tissue repair, and self-proliferation.11 Based on their anti-inflammatory, antifibrotic, antiapoptotic, and regenerative properties, MSCs are widely considered for the treatment of lung diseases such as IPF.12
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JADICELL -Lung Inflammatory Environments Differentially Alter Mesenchymal Stromal Cell Behavior

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Lung Inflammatory Environments Differentially Alter Mesenchymal Stromal Cell Behavior

https://journals.physiology.org/doi/pre ... 00263.2019
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