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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 52603

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Dr. Mujib Ullah

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Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Interests: stem cells; regenerative medicine
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Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs, including exosomes) released in multiple body fluids. EVs protect their content from degradation and are increasingly considered for the development of novel clinical applications. EVs research is complicated by the small size of EVs, lacking of tracking tools for EVs, its heterogeneity, and the lack of tools to study different populations of these nano-sized drug carrier in detail. With the emergence of new tools, bioengineering principles, and methods for EVs research, these challenges are being overcome. The purpose of this Special Issue is to examine bioengineering approaches in stem cells or EVs heterogeneity, tracking, biogenesis, and specific attributes of EVs as they play a role in cellular communication, tissue repair, tumor formation, immune activation, inflammation, proliferation, aging, and other conditions that important for progression of diseases. In providing this overview, this Special Issue will delineate the current foundations, bioengineering approaches and tools for the next steps toward determining the roles of EVs in pathogenesis and therapeutic strategies for the treatment of a wide range of diseases.

Dr. Mujib Ullah
Guest Editor

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Published Papers (9 papers)

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Research

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15 pages, 7847 KiB

Open AccessArticle

Exosomes Derived from BMMSCs Mitigate the Hepatic Fibrosis via Anti-Pyroptosis Pathway in a Cirrhosis Model

by Yichi Zhang, Hanjing Zhangdi, Xinsheng Nie, Lijuan Wang, Zhuzhi Wan, Hao Jin, Ronghui Pu, Meihui Liang, Yuan Chang, Yang Gao, Hailong Zhang and Shizhu Jin

Cells 2022, 11(24), 4004; https://doi.org/10.3390/cells11244004 - 10 Dec 2022

Cited by 8 | Viewed by 1817

Abstract

Researchers increasingly report the therapeutic effect of exosomes derived from rat bone marrow mesenchymal stem cells (Exos-rBMMSC) on liver disease, while the optimal dose of Exos-rBMMSC in liver cirrhotic treatment has not been reported. In this study, we aimed to explore the efficacy and dose of Exos-rBMMSC in a hepatic cirrhosis rat model. The therapeutic effects of a low dose, medium dose and high dose of Exos-rBMMSC were assessed by liver function tests and histopathology. After four-weeks of Exos-rBMMSC therapy, pyroptosis-related expression levels in the medium dose and the high dose Exos-rBMMSC groups were significantly decreased compared to those in the liver cirrhosis group (p < 0.05). The hepatic function assay and histopathology results showed significant improvement in the medium dose and the high dose Exos-rBMMSCs groups. The localization of PKH67-labeled Exos-rBMMSC was verified microscopically, and these particles were coexpressed with the PCNA, NLRP3, GSDMD and Caspase-1. Our results demonstrated that Exos-rBMMSC accelerated hepatocyte proliferation and relieved liver fibrosis by restraining hepatocyte pyroptosis. More importantly, we confirmed that the high dose of Exos-rBMMSC may be the optimal dose for liver cirrhosis, which is conducive to the application of Exos-rBMMSC as a promising cell-free strategy. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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20 pages, 8400 KiB

Open AccessArticle

Exosomes from Adipose Stem Cells Promote Diabetic Wound Healing through the eHSP90/LRP1/AKT Axis

by Sen Ren, Jing Chen, Jiahe Guo, Yutian Liu, Hewei Xiong, Boping Jing, Xiaofan Yang, Gongchi Li, Yu Kang, Cheng Wang, Xiang Xu, Zhenyu Liu, Maojie Zhang, Kaituo Xiang, Chengcheng Li, Qianyun Li, Hans-Günther Machens and Zhenbing Chen

Cells 2022, 11(20), 3229; https://doi.org/10.3390/cells11203229 - 14 Oct 2022

Cited by 33 | Viewed by 3418

Abstract

Oxidative damage is a critical cause of diabetic wounds. Exosomes from various stem cells could promote wound repair. Here, we investigated the potential mechanism by which exosomes from adipose-derived stem cells (ADSC-EXOs) promote diabetic wound healing through the modulation of oxidative stress. We found that ADSC-EXOs could promote proliferation, migration, and angiogenesis in keratinocytes, fibroblasts, and endothelial cells. Furthermore, ADSC-EXOs reduced the reactive oxygen species (ROS) levels in these cells and protected them against hypoxic and oxidative stress damage. Finally, the local injection of ADSC-EXOs at wound sites significantly increased collagen deposition and neovascularization while reducing ROS levels and cell death; thus, it led to accelerated diabetic wound closure. The mechanism underlying ADSC-EXO functions involved heat-shock protein 90 (HSP90) expressed on the cell surface; these functions could be inhibited by an anti-HSP90 antibody. Exosomal HSP90 could bind to the low-density lipoprotein receptor-related protein 1 (LRP1) receptor on the recipient cell membrane, leading to activation of the downstream AKT signaling pathway. Knockdown of LRP1 and inhibition of the AKT signaling pathway by LY294002 in fibroblasts was sufficient to impair the beneficial effect of ADSC-EXOs. In summary, ADSC-EXOs significantly accelerated diabetic wound closure through an exosomal HSP90/LRP1/AKT signaling pathway. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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22 pages, 7238 KiB

Open AccessArticle

Effects of Extracellular Vesicles from Osteogenic Differentiated Human BMSCs on Osteogenic and Adipogenic Differentiation Capacity of Naïve Human BMSCs

by Chenglong Wang, Sabine Stöckl, Shushan Li, Marietta Herrmann, Christoph Lukas, Yvonne Reinders, Albert Sickmann and Susanne Grässel

Cells 2022, 11(16), 2491; https://doi.org/10.3390/cells11162491 - 11 Aug 2022

Cited by 10 | Viewed by 2985

Abstract

Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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16 pages, 4560 KiB

Open AccessArticle

Adipose-Derived Mesenchymal Stromal Cells Treated with Interleukin 1 Beta Produced Chondro-Protective Vesicles Able to Fast Penetrate in Cartilage

by Alessandra Colombini, Enrico Ragni, Leonardo Mortati, Francesca Libonati, Carlotta Perucca Orfei, Marco Viganò, Marco Brayda-Bruno and Laura de Girolamo

Cells 2021, 10(5), 1180; https://doi.org/10.3390/cells10051180 - 12 May 2021

Cited by 17 | Viewed by 2938

Abstract

The study of the miRNA cargo embedded in extracellular vesicles (EVs) released from adipose-derived mesenchymal stromal cells (ASC) preconditioned with IL-1β, an inflammatory stimulus driving osteoarthritis (OA), along with EVs-cartilage dynamic interaction represent poorly explored fields and are the purpose of the present research. ASCs were isolated from subcutaneous adipose tissue and EVs collected by ultracentrifugation. Shuttled miRNAs were scored by high-throughput screening and analyzed through bioinformatics approach that predicted the potentially modulated OA-related pathways. Fluorescently labeled EVs incorporation into OA cartilage explants was followed in vitro by time-lapse coherent anti-Stokes Raman scattering; second harmonic generation and two-photon excited fluorescence. After IL-1β preconditioning, 7 miRNA were up-regulated, 4 down-regulated, 37 activated and 17 silenced. Bioinformatics allowed to identify miRNAs and target genes mainly involved in Wnt, Notch, TGFβ and Indian hedgehog (IHH) pathways, cartilage homeostasis, immune/inflammatory responses, cell senescence and autophagy. As well, ASC-EVs steadily diffuse in cartilage cells and matrix, reaching a plateau 16 h after administration. Overall, ASCs preconditioned with IL-1β allows secretion of EVs embedded with a chondro-protective miRNA cargo, able to fast penetrate in collagen-rich areas of cartilage with tissue saturation in a day. Further functional studies exploring the EVs dose-effects are needed to achieve clinical relevance. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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17 pages, 2567 KiB

Open AccessArticle

Muscle Stem Cell-Derived Extracellular Vesicles Reverse Hydrogen Peroxide-Induced Mitochondrial Dysfunction in Mouse Myotubes

by Kyle T. Shuler, Brittany E. Wilson, Eric R. Muñoz, Andrew D. Mitchell, Joshua T. Selsby and Matthew B. Hudson

Cells 2020, 9(12), 2544; https://doi.org/10.3390/cells9122544 - 26 Nov 2020

Cited by 8 | Viewed by 3372

Abstract

Muscle stem cells (MuSCs) hold great potential as a regenerative therapeutic but have met numerous challenges in treating systemic muscle diseases. Muscle stem cell-derived extracellular vesicles (MuSC-EVs) may overcome these limitations. We assessed the number and size distribution of extracellular vesicles (EVs) released by MuSCs ex vivo, determined the extent to which MuSC-EVs deliver molecular cargo to myotubes in vitro, and quantified MuSC-EV-mediated restoration of mitochondrial function following oxidative injury. MuSCs released an abundance of EVs in culture. MuSC-EVs delivered protein cargo into myotubes within 2 h of incubation. Fluorescent labeling of intracellular mitochondria showed co-localization of delivered protein and mitochondria. Oxidatively injured myotubes demonstrated a significant decline in maximal oxygen consumption rate and spare respiratory capacity relative to untreated myotubes. Remarkably, subsequent treatment with MuSC-EVs significantly improved maximal oxygen consumption rate and spare respiratory capacity relative to the myotubes that were damaged but received no subsequent treatment. Surprisingly, MuSC-EVs did not affect mitochondrial function in undamaged myotubes, suggesting the cargo delivered is able to repair but does not expand the existing mitochondrial network. These data demonstrate that MuSC-EVs rapidly deliver proteins into myotubes, a portion of which co-localizes with mitochondria, and reverses mitochondria dysfunction in oxidatively-damaged myotubes. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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Review

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20 pages, 1279 KiB

Open AccessReview

Different Sourced Extracellular Vesicles and Their Potential Applications in Clinical Treatments

by Leila Bahmani and Mujib Ullah

Cells 2022, 11(13), 1989; https://doi.org/10.3390/cells11131989 - 21 Jun 2022

Cited by 32 | Viewed by 4435

Abstract

Extracellular vesicles (EVs) include a heterogeneous group of natural cell-derived nanostructures that are increasingly regarded as promising biotherapeutic agents and drug delivery vehicles in human medicine. Desirable intrinsic properties of EVs including the ability to bypass natural membranous barriers and to deliver their unique biomolecular cargo to specific cell populations position them as fiercely competitive alternatives for currently available cell therapies and artificial drug delivery platforms. EVs with distinct characteristics can be released from various cell types into the extracellular environment as a means of transmitting bioactive components and altering the status of the target cell. Despite the existence of a large number of preclinical studies confirming the therapeutic efficacy of different originated EVs for treating several pathological conditions, in this review, we first provide a brief overview of EV biophysical properties with an emphasis on their intrinsic therapeutic benefits over cell-based therapies and synthetic delivery systems. Next, we describe in detail different EVs derived from distinct cell sources, compare their advantages and disadvantages, and recapitulate their therapeutic effects on various human disorders to highlight the progress made in harnessing EVs for clinical applications. Finally, knowledge gaps and concrete hurdles that currently hinder the clinical translation of EV therapies are debated with a futuristic perspective. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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22 pages, 1214 KiB

Open AccessEditor’s ChoiceReview

Methodologies to Isolate and Purify Clinical Grade Extracellular Vesicles for Medical Applications

by Asma Akbar, Farzaneh Malekian, Neda Baghban, Sai Priyanka Kodam and Mujib Ullah

Cells 2022, 11(2), 186; https://doi.org/10.3390/cells11020186 - 6 Jan 2022

Cited by 54 | Viewed by 6257

Abstract

The use of extracellular vesicles (EV) in nano drug delivery has been demonstrated in many previous studies. In this study, we discuss the sources of extracellular vesicles, including plant, salivary and urinary sources which are easily available but less sought after compared with blood and tissue. Extensive research in the past decade has established that the breadth of EV applications is wide. However, the efforts on standardizing the isolation and purification methods have not brought us to a point that can match the potential of extracellular vesicles for clinical use. The standardization can open doors for many researchers and clinicians alike to experiment with the proposed clinical uses with lesser concerns regarding untraceable side effects. It can make it easier to identify the mechanism of therapeutic benefits and to track the mechanism of any unforeseen effects observed. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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48 pages, 5371 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine

by Mangesh D. Hade, Caitlin N. Suire and Zucai Suo

Cells 2021, 10(8), 1959; https://doi.org/10.3390/cells10081959 - 1 Aug 2021

Cited by 222 | Viewed by 21049

Abstract

Exosomes are a type of extracellular vesicles, produced within multivesicular bodies, that are then released into the extracellular space through a merging of the multivesicular body with the plasma membrane. These vesicles are secreted by almost all cell types to aid in a vast array of cellular functions, including intercellular communication, cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. This ability to contribute to several distinct processes is due to the complexity of exosomes, as they carry a multitude of signaling moieties, including proteins, lipids, cell surface receptors, enzymes, cytokines, transcription factors, and nucleic acids. The favorable biological properties of exosomes including biocompatibility, stability, low toxicity, and proficient exchange of molecular cargos make exosomes prime candidates for tissue engineering and regenerative medicine. Exploring the functions and molecular payloads of exosomes can facilitate tissue regeneration therapies and provide mechanistic insight into paracrine modulation of cellular activities. In this review, we summarize the current knowledge of exosome biogenesis, composition, and isolation methods. We also discuss emerging healing properties of exosomes and exosomal cargos, such as microRNAs, in brain injuries, cardiovascular disease, and COVID-19 amongst others. Overall, this review highlights the burgeoning roles and potential applications of exosomes in regenerative medicine. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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21 pages, 1081 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Exosomes Exhibit Promising Potential for Treating SARS-CoV-2-Infected Patients

by Alok Raghav, Zeeshan Ahmad Khan, Viabhav Kumar Upadhayay, Prashant Tripathi, Kirti Amresh Gautam, Brijesh Kumar Mishra, Jamal Ahmad and Goo-Bo Jeong

Cells 2021, 10(3), 587; https://doi.org/10.3390/cells10030587 - 7 Mar 2021

Cited by 35 | Viewed by 5176

Abstract

The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime. Full article

(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)

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