Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review

Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.

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Sources and Clinical Applications of Mesenchymal Stem Cells: State-of-the-art review

Sultan Qaboos University Medical Journal [SQUMJ] ◽

10.18295/squmj.2018.18.03.002 ◽

2018 ◽

Vol 18 (3) ◽

pp. 264 ◽

Cited By ~ 52

Author(s):

Roberto Berebichez-Fridman ◽

Pablo R. Montero-Olvera

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Adult Stem Cells ◽

Current Knowledge ◽

Clinical Applications ◽

The Body ◽

Differentiation Potential ◽

Advantages And Disadvantages

First discovered by Friedenstein in 1976, mesenchymal stem cells (MSCs) are adult stem cells found throughout the body that share a fixed set of characteristics. Discovered initially in the bone marrow, this cell source is considered the gold standard for clinical research, although various other sources—including adipose tissue, dental pulp, mobilised peripheral blood and birth-derived tissues—have since been identified. Although similar, MSCs derived from different sources possess distinct characteristics, advantages and disadvantages, including their differentiation potential and proliferation capacity, which influence their applicability. Hence, they may be used for specific clinical applications in the fields of regenerative medicine and tissue engineering. This review article summarises current knowledge regarding the various sources, characteristics and therapeutic applications of MSCs.Keywords: Mesenchymal Stem Cells; Adult Stem Cells; Regenerative Medicine; Cell Differentiation; Tissue Engineering.

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Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190222201749 ◽

2019 ◽

Vol 14 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

Carl R. Harrell ◽

Marina Gazdic ◽

Crissy Fellabaum ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Animal Models ◽

Amniotic Fluid ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Therapeutic Effects ◽

Differentiation Potential ◽

Differentiation Capacity ◽

Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

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Impact of Graphene Derivatives as Artificial Extracellular Matrices on Mesenchymal Stem Cells

Molecules ◽

10.3390/molecules27020379 ◽

2022 ◽

Vol 27 (2) ◽

pp. 379

Author(s):

Rabia Ikram ◽

Shamsul Azlin Ahmad Shamsuddin ◽

Badrul Mohamed Jan ◽

Muhammad Abdul Qadir ◽

George Kenanakis ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Regenerative Medicine ◽

Cell Types ◽

Biological Properties ◽

Research Progress ◽

Differentiation Potential ◽

Graphene Derivatives ◽

Potential Applicability

Thanks to stem cells’ capability to differentiate into multiple cell types, damaged human tissues and organs can be rapidly well-repaired. Therefore, their applicability in the emerging field of regenerative medicine can be further expanded, serving as a promising multifunctional tool for tissue engineering, treatments for various diseases, and other biomedical applications as well. However, the differentiation and survival of the stem cells into specific lineages is crucial to be exclusively controlled. In this frame, growth factors and chemical agents are utilized to stimulate and adjust proliferation and differentiation of the stem cells, although challenges related with degradation, side effects, and high cost should be overcome. Owing to their unique physicochemical and biological properties, graphene-based nanomaterials have been widely used as scaffolds to manipulate stem cell growth and differentiation potential. Herein, we provide the most recent research progress in mesenchymal stem cells (MSCs) growth, differentiation and function utilizing graphene derivatives as extracellular scaffolds. The interaction of graphene derivatives in human and rat MSCs has been also evaluated. Graphene-based nanomaterials are biocompatible, exhibiting a great potential applicability in stem-cell-mediated regenerative medicine as they may promote the behaviour control of the stem cells. Finally, the challenges, prospects and future trends in the field are discussed.

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CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin α5 expression

Cell Death and Differentiation ◽

10.1038/s41418-020-0600-6 ◽

2020 ◽

Vol 28 (1) ◽

pp. 283-302

Author(s):

Dandan Zhang ◽

Ni Ni ◽

Yuyao Wang ◽

Zhimin Tang ◽

Huiqin Gao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Osteogenic Differentiation ◽

Progenitor Cell ◽

Bone Repair ◽

Circular Rnas ◽

Mineral Density ◽

Differentiation Potential ◽

Integrin Α5

AbstractAdipose-derived mesenchymal stem cells (ADSCs) are promising candidate for regenerative medicine to repair non-healing bone defects due to their high and easy availability. However, the limited osteogenic differentiation potential greatly hinders the clinical application of ADSCs in bone repair. Accumulating evidences demonstrate that circular RNAs (circRNAs) are involved in stem/progenitor cell fate determination, but their specific role in stem/progenitor cell osteogenesis, remains mostly undescribed. Here, we show that circRNA-vgll3 originating from the vgll3 locus markedly enhances osteogenic differentiation of ADSCs; nevertheless, silencing of circRNA-vgll3 dramatically attenuates ADSC osteogenesis. Furthermore, we validate that circRNA-vgll3 functions in ADSC osteogenesis through a circRNA-vgll3/miR-326-5p/integrin α5 (Itga5) pathway. Itga5 promotes ADSC osteogenic differentiation and miR-326-5p suppresses Itga5 translation. CircRNA-vgll3 directly sequesters miR-326-5p in the cytoplasm and inhibits its activity to promote osteogenic differentiation. Moreover, the therapeutic potential of circRNA-vgll3-modified ADSCs with calcium phosphate cement (CPC) scaffolds was systematically evaluated in a critical-sized defect model in rats. Our results demonstrate that circRNA-vgll3 markedly enhances new bone formation with upregulated bone mineral density, bone volume/tissue volume, trabeculae number, and increased new bone generation. This study reveals the important role of circRNA-vgll3 during new bone biogenesis. Thus, circRNA-vgll3 engineered ADSCs may be effective potential therapeutic targets for bone regenerative medicine.

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Application of Nanoscaffolds in Mesenchymal Stem Cell-Based Therapy

Advances in Regenerative Medicine ◽

10.1155/2014/369498 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Saman Ghoraishizadeh ◽

Afsoon Ghorishizadeh ◽

Peyman Ghoraishizadeh ◽

Nasibeh Daneshvar ◽

Mohadese Hashem Boroojerdi

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Regenerative Medicine ◽

Adult Stem Cells ◽

Cell Signalling ◽

Great Influence ◽

Source Characterization ◽

Differentiation Potential ◽

Cell Based Therapy ◽

Essential Components

Regenerative medicine is an alternative solution for organ transplantation. Stem cells and nanoscaffolds are two essential components in regenerative medicine. Mesenchymal stem cells (MSCs) are considered as primary adult stem cells with high proliferation capacity, wide differentiation potential, and immunosuppression properties which make them unique for regenerative medicine and cell therapy. Scaffolds are engineered nanofibers that provide suitable microenvironment for cell signalling which has a great influence on cell proliferation, differentiation, and biology. Recently, application of scaffolds and MSCs is being utilized in obtaining more homogenous population of MSCs with higher cell proliferation rate and greater differentiation potential, which are crucial factors in regenerative medicine. In this review, the definition, biology, source, characterization, and isolation of MSCs and current report of application of nanofibers in regenerative medicine in different lesions are discussed.

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Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis

Stem Cells International ◽

10.1155/2017/5979741 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Dixin Cui ◽

Hongyu Li ◽

Xin Xu ◽

Ling Ye ◽

Xuedong Zhou ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cartilage Regeneration ◽

Cartilage Degeneration ◽

Self Healing ◽

Condylar Cartilage ◽

Differentiation Potential ◽

Tissue Repair And Regeneration ◽

Cell Based Therapy ◽

Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease, characterized by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has raised much attention as an alternative approach towards tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ OA. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will briefly discuss the pathogenesis of cartilage degeneration in TMJ OA and emphasize the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ OA, particularly focusing on the MSC-based therapy and tissue engineering.

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Histone deacetylase inhibitor overrides the effect of soft hydrogel on the mechanoresponse of human mesenchymal stem cells

10.1101/2022.01.04.474891 ◽

2022 ◽

Author(s):

Rohit Joshi ◽

Pooja Murlidharan ◽

Puspendra Yadav ◽

Vedanshi Dharnidharka ◽

Abhijit Majumder

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitor ◽

Mapk Pathway ◽

Chromatin Condensation ◽

Chemical Stimulus ◽

Differentiation Potential ◽

Deacetylase Inhibitor

Human Mesenchymal cells (hMSCs) are promising in regenerative medicine for their multi-lineage differentiation capability. It has been demonstrated that lineage specification is governed by both chemical and mechanical cues. Among all the different mechanical cues known to control hMSCs fate, substrate stiffness is the most well-studied. It has been shown that the naive mesenchymal stem cells when cultured on soft gel, they commit towards adipogenic lineage while when cultured on stiff gel they become osteogenic. Soft substrates also cause less cell spreading, less traction, less focal adhesion assembly and stress fibre formation. Furthermore, chromatin condensation increases when cells are cultured on soft substrates. As the nucleus has been postulated to be mechanosensor and mechanotransducer, in this paper we asked the question how mechanosensing and mechanoresponse process will be influenced if we change the chromatin condensation by using an external chemical stimulus. To address this question, we treated hMSCs cultured on soft polyacrylamide (PA) gels with a histone deacetylase inhibitor (HDACi) called Valproic Acid (VA) which decondense the chromatin by hyperacetylation of histone proteins. We found that the treatment with VA overrides the effect of soft substrates on hMSCs morphology, cellular traction, nuclear localization of mechnosensory protein YAP, and differentiation. VA treated cells behaved as if they are on stiff substrates in all aspects tested here. Furthermore, we have shown that VA controls hMSCs differentiation via activation of ERK/MAPK pathway by increasing the p-ERK expression which inhibits adipogenic differentiation potential of mesenchymal stem cells. Collectively, these findings for the first time demonstrate that inhibiting histone acetylation can override the mechanoresponse of hMSCs. This work will help us to fundamentally understand the mechanosignalling process and to control the hMSCs differentiation in tissue engineering and regenerative medicine.

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Characterization and Neural Differentiation of Fetal Lung Mesenchymal Stem Cells.

Blood ◽

10.1182/blood.v104.11.4177.4177 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4177-4177

Author(s):

Zhong Chao Han ◽

Cun Gang ◽

Feng Wu ◽

Qing Jun ◽

Shi Hong ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Flow Cytometric Analysis ◽

Fetal Lung ◽

Neural Cells ◽

Alternative Source ◽

Differentiation Potential ◽

Cell Based Therapy ◽

Mesenchymal Differentiation ◽

M Phase

Abstract Mesenchymal stem cells (MSCs) have been successfully isolated from a broad range of adult, fetal and other non-embryonic tissues. Fetal lung has been identified as a rich source of MSCs capable of differentiating into multilineage cells of mesenchymal origin. However, the biological characteristics and differentiation potential of fetal lung MSCs remain to be explored. In this study, we have established a series of methods for isolation and expansion of fetal lung MSCs. These MSCs could withstand 40 passages without obvious decline in proliferation ability, significant changes in morphology and expression of cell markers. Cell cycle analysis revealed that when the MSCs reached their log phase of growth, more than 90% of the cells were in G0-G1 phase while the proportion of cells in S phase and G2-M phase were about 5.56% and 2.08% cells individually. Flow cytometric analysis showed that fetal lung MSCs expressed CD13, CD29, CD44, CD90, CD105, D117, CD166 and HLA-ABC, but not CD14, CD31, CD34, CD38, CD41a, CD42b, CD45, CD49d, CD61, CD106, CD133 and HLA-DR. These MSCs could differentiate into neural cells in addition to their mesenchymal differentiation potential. Our data suggest that the fetal lung MSC population is an alternative source of stem cells for cell-based therapy of neurological defects or mesenchymal originated diseases.

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The Effect of Blood-Derived Products on the Chondrogenic and Osteogenic Differentiation Potential of Adipose-Derived Mesenchymal Stem Cells Originated from Three Different Locations

Stem Cells International ◽

10.1155/2019/1358267 ◽

2019 ◽

Vol 2019 ◽

pp. 1-20 ◽

Cited By ~ 1

Author(s):

Markus Neubauer ◽

Olga Kuten ◽

Christoph Stotter ◽

Karina Kramer ◽

Andrea De Luna ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Regenerative Medicine ◽

Blood Product ◽

Blood Products ◽

Fat Tissue ◽

Differentiation Potential ◽

Lower Blood

Background. Adipose-derived mesenchymal stem cells (AD-MSCs) from fat tissue considered “surgical waste” during joint surgery may provide a potent source for regenerative medicine. Intra-articular, homologous fat tissue (Hoffa’s fat pad, pouch fat) might possess a superior chondrogenic and osteogenic differentiation potential in comparison to extra-articular, nonhomologous fat. Blood products might further enhance this potential. Methods. AD-MSCs were isolated from fat tissue of 3 donors from 3 locations each, during total knee replacement. Isolated cells were analyzed via flow cytometry. Cells were supplemented with blood products: two types of platelet-rich plasma (EPRP—PRP prepared in the presence of EDTA; CPRP—PRP prepared in the presence of citrate), hyperacute serum (hypACT), and standard fetal calf serum (FCS) as a positive control. The viability of the cells was determined by XTT assay, and the progress of differentiation was tested via histological staining and monitoring of specific gene expression. Results. Blood products enhance ex vivo cell metabolism. Chondrogenesis is enhanced by EDTA-PRP and osteogenesis by citrate PRP, whereas hyperacute serum enhances both differentiations comparably. This finding was consistent in histological analysis as well as in gene expression. Lower blood product concentrations and shorter differentiation periods lead to superior histological results for chondrogenesis. Both PRP types had a different biological effect depending upon concentration, whereas hyperacute serum seemed to have a more consistent effect, independent of the used concentration. Conclusion. (i) Blood product preparation method, (ii) type of anticoagulant, (iii) differentiation time, and (iv) blood product concentration have a significant influence on stem cell viability and the differentiation potential, favouring no use of anticoagulation, shorter differentiation time, and lower blood product concentrations. Cell-free blood products like hyperacute serum may be considered as an alternative supplementation in regenerative medicine, especially for stem cell therapies.

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