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Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (5 June 2019) | Viewed by 64851

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Dr. Krzysztof Marycz

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1. Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, 50-375 Wroclaw, Poland
2. Klinik für Pferde (Chirurgie) mit Lehrschmiede, Justus Liebig University Giessen, Frankfurter Str. 108, 35392 Gießen, Germany
Interests: regenerative medicine; ASCs; biomaterials; tissue engineering; clinical application of ASCs; regenerative endocrinology; theranostics

Special Issue Information

Dear Colleagues,

Adipose-derived mesenchymal stem cells (ASCs) and their extracellular microvesicles (ExMVs) are promising therapeutic tools in the field of regenerative medicine for both human as well as veterinary medicine. For many years, ASCs have been successfully applied in animal regenerative medicine, and, currently, few clinical trials take place with the application of ASCs. This is due to their multilineage differentiation potential, and the fact that they are easy to collect and possess abundant paracrine activity. More and more data explain the pro-regenerative potential of ASCs by their paracrine and endocrine affects, transferring cytokines and hormones, mRNA or miRNA, which target injured tissue and enhance their regeneration. However, as has been recently shown, donor age and disease limit their regenerative potential. Therefore, the search for a strategy that will improve their clinical potential seems to be reasonable. Moreover, ASCs are widely combined with various types of scaffold, including ceramics or polymers, for tissue regeneration. The aim of this Special Issue is to provide an updated point of view about clinical and pre-clinical studies with applications of ASCs or their extracellular microvesicles (ExMVs). Original research articles, short communications, as well as review articles, will be acceptable for this Special Issue.

Dr. Krzysztof Marycz
Guest Editor

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Keywords

Regenerative potential of ASCs
Therapeutic potential of ExMVs isolated from ASCs
ASCs based cellular therapy for bone and cartilage regeneration
ASCs physiological deterioration and clinical consequences

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Published Papers (11 papers)

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Editorial

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6 pages, 200 KiB

Open AccessEditorial

Stem Cells in Equine Veterinary Practice—Current Trends, Risks, and Perspectives

by Katarzyna Kornicka, Florian Geburek, Michael Röcken and Krzysztof Marycz

J. Clin. Med. 2019, 8(5), 675; https://doi.org/10.3390/jcm8050675 - 14 May 2019

Cited by 5 | Viewed by 3310

Abstract

With this Editorial, we introduce the Special Issue “Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications” to the scientific community. In this issue, we focus on regenerative medicine, stem cells, and their clinical application. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

Research

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15 pages, 19485 KiB

Open AccessArticle

Systemic Sclerosis Serum Steers the Differentiation of Adipose-Derived Stem Cells Toward Profibrotic Myofibroblasts: Pathophysiologic Implications

by Mirko Manetti, Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto, Emanuela Praino, Serena Guiducci, Florenzo Iannone, Lidia Ibba-Manneschi and Marco Matucci-Cerinic

J. Clin. Med. 2019, 8(8), 1256; https://doi.org/10.3390/jcm8081256 - 19 Aug 2019

Cited by 14 | Viewed by 5195

Abstract

Systemic sclerosis (SSc; scleroderma) is characterized by life-threatening progressive multiorgan fibrosis orchestrated by profibrotic myofibroblasts originating from different sources. Because recent data demonstrated that the majority of myofibroblasts in a murine scleroderma model arise from adipocytic progenitors through the adipocyte-myofibroblast transition process, we sought to determine whether the SSc microenvironment may affect the differentiation potential of adipose-derived stem cells (ADSC). Normal human ADSC from three donors were treated with serum from SSc patients (n = 6), serum from healthy individuals (n = 6), or recombinant human transforming growth factor-β1 (TGFβ1) as positive control of myofibroblastic phenotype induction. ADSC were subjected to in vitro adipogenic differentiation for up to 21 days in the presence of different stimuli followed by lipid content quantification. In selected experiments, adipocytic and mesenchymal/myofibroblast marker gene and protein expression levels were assessed by Real-Time PCR, immunoblotting and immunofluorescence after administration of different stimuli for 72 and 96 h, respectively. Cell contractile phenotype was assayed by collagen gel contraction assay. Likewise stimulation with TGFβ1, SSc serum was able to significantly inhibit the adipocyte differentiation of ADSC as testified by a strong decrease in red-colored lipid droplets after 21 days of adipogenic induction. Treatment of ADSC either with SSc serum or TGFβ1 resulted in the acquisition of a myofibroblast-like phenotype characterized by a reduced expression of the adipocytic markers perilipin and adiponectin, a significant upregulation of the mesenchymal/myofibroblast markers α-SMA+ stress fibers, S100A4 and type I collagen, and an ability to effectively contract collagen gels. In SSc, the pathologic environment may favor the differentiation of ADSC into profibrotic and contractile myofibroblast-like cells. These findings strengthen the notion that the generation of myofibroblasts from ADSC may be relevant in SSc pathophysiology potentially representing a new target for the prevention/treatment of multiorgan fibrosis. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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19 pages, 3135 KiB

Open AccessArticle

Adipose-Derived Mesenchymal Stem Cells Isolated from Patients with Type 2 Diabetes Show Reduced “Stemness” through an Altered Secretome Profile, Impaired Anti-Oxidative Protection, and Mitochondrial Dynamics Deterioration

by Michalina Alicka, Piotr Major, Michał Wysocki and Krzysztof Marycz

J. Clin. Med. 2019, 8(6), 765; https://doi.org/10.3390/jcm8060765 - 30 May 2019

Cited by 85 | Viewed by 6024

Abstract

The widespread epidemic of obesity and type 2 diabetes (T2D), suggests that both disorders are closely linked. Several pre-clinical and clinical studies have showed that adipose-derived mesenchymal stem cells (ASC) transplantation is efficient and safe. Moreover, scientists have already highlighted the therapeutic capacity of their secretomes. In this study, we used quantitative PCR, a flow cytometry-based system, the ELISA method, spectrophotometry, and confocal and scanning electron microscopy, to compare the differences in proliferation activity, viability, morphology, mitochondrial dynamics, mRNA and miRNA expression, as well as the secretory activity of ASCs derived from two donor groups—non-diabetic and T2D patients. We demonstrated that ASCs from T2D patients showed a reduced viability and a proliferative potential. Moreover, they exhibited mitochondrial dysfunction and senescence phenotype, due to excessive oxidative stress. Significant differences were observed in the expressions of miRNA involved in cell proliferations (miR-16-5p, miR-146a-5p, and miR-145-5p), as well as miRNA and genes responsible for glucose homeostasis and insulin sensitivity (miR-24-3p, 140-3p, miR-17-5p, SIRT1, HIF-1α, LIN28, FOXO1, and TGFβ). We have observed a similar correlation of miR-16-5p, miR-146a-5p, miR-24-3p, 140-3p, miR-17-5p, and miR-145-5p expression in extracellular vesicles fraction. Furthermore, we have shown that ASC_T2D exhibited a lower VEGF, adiponectin, and CXCL-12 secretion, but showed an overproduction of leptin. We have shown that type 2 diabetes attenuated crucial functions of ASC, like proliferation, viability, and secretory activity, which highly reduced their therapeutic efficiency. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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21 pages, 3709 KiB

Open AccessArticle

Engineered Fat Graft Enhanced with Adipose-Derived Stromal Vascular Fraction Cells for Regenerative Medicine: Clinical, Histological and Instrumental Evaluation in Breast Reconstruction

by Pietro Gentile, Donato Casella, Enza Palma and Claudio Calabrese

J. Clin. Med. 2019, 8(4), 504; https://doi.org/10.3390/jcm8040504 - 12 Apr 2019

Cited by 92 | Viewed by 4813

Abstract

The areas in which Stromal Vascular Fraction cells (SVFs) have been used include radiotherapy based tissue damage after mastectomy, breast augmentation, calvarial defects, Crohn’s fistulas, and damaged skeletal muscle. Currently, the authors present their experience using regenerative cell therapy in breast reconstruction. The goal of this study was to evaluate the safety and efficacy of the use of Engineered Fat Graft Enhanced with Adipose-derived Stromal Vascular Fraction cells (EF-e-A) in breast reconstruction. 121 patients that were affected by the outcomes of breast oncoplastic surgery were treated with EF-e-A, comparing the results with the control group (n = 50) treated with not enhanced fat graft (EF-ne-A). The preoperative evaluation included a complete clinical examination, a photographic assessment, biopsy, magnetic resonance (MRI) of the soft tissue, and ultrasound (US). Postoperative follow-up took place at two, seven, 15, 21, 36 weeks, and then annually. In 72.8% (n = 88) of breast reconstruction treated with EF-e-A, we observed a restoration of the breast contour and an increase of 12.8 mm in the three-dimensional volume after 12 weeks, which was only observed in 27.3% (n = 33) of patients in the control group that was treated with EF-ne-A. Transplanted fat tissue reabsorption was analyzed with instrumental MRI and US. Volumetric persistence in the study group was higher (70.8%) than that in the control group (41.4%) (p < 0.0001 vs. control group). The use of EF-e-A was safe and effective in this series of treated cases. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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22 pages, 4562 KiB

Open AccessArticle

Osteochondritis Dissecans (OCD)-Derived Chondrocytes Display Increased Senescence, Oxidative Stress, Chaperone-Mediated Autophagy and, in Co-Culture with Adipose-Derived Stem Cells (ASCs), Enhanced Expression of MMP-13

by Katarzyna Kornicka, Mohamad Al Naem, Michael Röcken, Marta Zmiertka and Krzysztof Marycz

J. Clin. Med. 2019, 8(3), 328; https://doi.org/10.3390/jcm8030328 - 8 Mar 2019

Cited by 7 | Viewed by 4493

Abstract

Osteochondritis dissecans (OCD) in equids, especially in sport horses, has become a growing issue as it contributes to the occurrence of lameness. Thus the aim of this study was to investigate the cytophysiological properties of OCD chondrocytes including expression of chondrogenic genes, apoptosis, mitochondria dynamics and autophagy. Horse chondrocytes were isolated from healthy (HE) and OCD cartilages. Properties of cells were evaluated using multiple assays e.g., polymerase chain reaction (PCR), immunofluorescence, Western blot. OCD chondrocytes were characterized by increased apoptosis and senescence. Expression of chondrogenic genes (vimentin, aggrecan) was decreased while mRNA levels of matrix metalloproteinase 13 significantly upregulated in comparison to HE cells. Moreover, OCD cells displayed increased mitochondrial fusion while fission events were diminished. Interestingly, chaperone mediated autophagy was triggered in those cells and it predominated over macroautophagy. Furthermore, co-culture of LPS-treated chondrocytes with adipose-derived stem cells (ASC) decreased p62/sequestosome 1 (SQSTM) and increases MMP-13 expression in OCD cells. Our results suggest that OCD affected horse chondrocytes are characterized by senescent phenotype due to endoplasmic reticulum stress and mitochondria dynamics deterioration. Expression of chondrogenic markers is decreased in those cells while expression of chaperone mediated autophagy (CMA)-related genes increased. Increased malfunctioning of cells leads to loss of their functionality and capacity to maintain tissue homeostasis. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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25 pages, 7510 KiB

Open AccessArticle

Metformin Promotes Osteogenic Differentiation of Adipose-Derived Stromal Cells and Exerts Pro-Osteogenic Effect Stimulating Bone Regeneration

by Agnieszka Śmieszek, Krzysztof A. Tomaszewski, Katarzyna Kornicka and Krzysztof Marycz

J. Clin. Med. 2018, 7(12), 482; https://doi.org/10.3390/jcm7120482 - 26 Nov 2018

Cited by 39 | Viewed by 5530

Abstract

Metformin, the gold standard in type 2 diabetes treatment, is a drug with multi-faceted effects. Currently, metformin has gained much attention as an agent that may find application in regenerative medicine. In this study, we considered its pro-osteogenic function in the course of in vitro osteogenesis of multipotent stromal cells derived from rat adipose tissue (rASCs). In addition, we evaluated the effect of metformin treatment on bone metabolism in a model of cranial defect in nondiabetic rats. In vitro study showed that metformin that is introduced to the culture medium at concentration equal 500 µM may promote the differentiation of rASCs into bone-forming cells, which express mRNA and secrets proteins that are related to the functional tissue (namely, alkaline phosphatase and osteocalcin). Osteogenic effect of metformin, as determined using in vitro model, was also manifested with the formation of mineralized extracellular matrix rich calcium and phosphorous deposits. We have also found, that in undifferentiated rASCs, metformin significantly activates a critical regulatory factor for osteogenic differentiation, i.e., AMPK. Moreover, using in vivo model we showed metformin administration at a dose of 250 mg/kg/day accelerated bone healing and the formation of mature tissue at a fracture site in rat cranial defect model. The obtained results shed promising light on metformin application in regenerative orthopedics, both as an agent improving functionality of ASCs for therapeutic transplantation, as well as a medication enhancing the bone healing process. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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18 pages, 5212 KiB

Open AccessArticle

Immunomodulatory Properties of Adipose-Derived Stem Cells Treated with 5-Azacytydine and Resveratrol on Peripheral Blood Mononuclear Cells and Macrophages in Metabolic Syndrome Animals

by Katarzyna Kornicka, Agnieszka Śmieszek, Agnieszka Sławomira Węgrzyn, Michael Röcken and Krzysztof Marycz

J. Clin. Med. 2018, 7(11), 383; https://doi.org/10.3390/jcm7110383 - 24 Oct 2018

Cited by 24 | Viewed by 4886

Abstract

Endocrine disorders, including equine metabolic syndrome (EMS), are a serious issue in veterinary medicine and horse breeding. Furthermore, EMS was shown to affect the cytophysiological properties of adipose-derived stem cells, reducing their therapeutic potential. However, it was shown that those cells can be rejuvenated while using a combination of two chemicals: 5-azacytydine (AZA) and resveratrol (RES). In the present study, we decided to evaluate the immunomodulatory properties of AZA/RES-treated adipose-derived stem cells (ASC) isolated from EMS horses (ASC_EMS). Thus, we co-cultured ASC with peripheral blood mononuclear cells (PBMC) and RAW264.7 macrophages. Most attention was placed on regulatory T lymphocytes (T_REG), as well as the messenger RNA (mRNA) and protein levels of several cytokines (tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-10, and IL-1β). Moreover, we also investigated the expression of genes related to auto- and mitophagy in both PBMCs and ASCs. PBMCs were obtained from healthy and EMS-suffering individuals and were co-cultured with ASCs that were isolated from healthy and EMS horses cultured in control conditions and with AZA/RES. We discovered that cells treated with AZA/RES increase the T_REG number while co-cultured with PBMCs. Moreover, the co-culture of PBMCs with AZA/RES-treated ASC_EMS induced mitophagy in PBMCs. Furthermore, ASC_EMS pre-treated with AZA/RES displayed anti-inflammatory properties, as decreased levels of TNF-α, nitric oxide (NO), and IL-6 were observed in those cells in comparison with their untreated counterparts in the co-culture with RAW264.7 macrophages. In summary, we demonstrated that ASC_EMS treated with AZA/RES displayed increased anti-inflammatory properties, and was able to regulate and activate the T_REG-related anti-inflammatory response. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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Review

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19 pages, 1039 KiB

Open AccessReview

Adipose Tissue Stem Cells for Therapy: An Update on the Progress of Isolation, Culture, Storage, and Clinical Application

by Dinh-Toi Chu, Thuy Nguyen Thi Phuong, Nguyen Le Bao Tien, Dang Khoa Tran, Le Bui Minh, Vo Van Thanh, Pham Gia Anh, Van Huy Pham and Vu Thi Nga

J. Clin. Med. 2019, 8(7), 917; https://doi.org/10.3390/jcm8070917 - 26 Jun 2019

Cited by 114 | Viewed by 14527

Abstract

Adipose tissue stem cells (ASCs), known as multipotent stem cells, are most commonly used in the clinical applications in recent years. Adipose tissues (AT) have the advantage in the harvesting, isolation, and expansion of ASCs, especially an abundant amount of stem cells compared to bone marrow. ASCs can be found in stromal vascular fractions (SVF) which are easily obtained from the dissociation of adipose tissue. Both SVFs and culture-expanded ASCs exhibit the stem cell characteristics such as differentiation into multiple cell types, regeneration, and immune regulators. Therefore, SVFs and ASCs have been researched to evaluate the safety and benefits for human use. In fact, the number of clinical trials on ASCs is going to increase by years; however, most trials are in phase I and II, and lack phase III and IV. This systemic review highlights and updates the process of the harvesting, characteristics, isolation, culture, storage, and application of ASCs, as well as provides further directions on the therapeutic use of ASCs. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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13 pages, 253 KiB

Open AccessReview

Concise Review: Adipose-Derived Stem Cells (ASCs) and Adipocyte-Secreted Exosomal microRNA (A-SE-miR) Modulate Cancer Growth and proMote Wound Repair

by Pietro Gentile and Simone Garcovich

J. Clin. Med. 2019, 8(6), 855; https://doi.org/10.3390/jcm8060855 - 15 Jun 2019

Cited by 110 | Viewed by 5435

Abstract

Adipose-derived stem cells (ASCs) have been routinely used from several years in regenerative surgery without any definitive statement about their potential pro-oncogenic or anti-oncogenic role. ASCs has proven to favor tumor progression in several experimental cancer models, playing a central role in regulating tumor invasiveness and metastatic potential through several mechanisms, such as the paracrine release of exosomes containing pro-oncogenic molecules and the induction of epithelial-mesenchymal transition. However, the high secretory activity and the preferential tumor-targeting make also ASCs a potentially suitable vehicle for delivery of new anti-cancer molecules in tumor microenvironment. Nanotechnologies, viral vectors, drug-loaded exosomes, and micro-RNAs (MiR) represent additional new tools that can be applied for cell-mediated drug delivery in a tumor microenvironment. Recent studies revealed that the MiR play important roles in paracrine actions on adipose-resident macrophages, and their dysregulation has been implicated in the pathogenesis of obesity, diabetes, and diabetic complications as wounds. Numerous MiR are present in adipose tissues, actively participating in the regulation of adipogenesis, adipokine secretion, inflammation, and inter-cellular communications in the local tissues. These results provide important insights into Adipocyte-secreted exosomal microRNA (A-SE-MiR) function and they suggest evaluating the potential role of A-SE-MiR in tumor progression, the mechanisms underlying ASCs-cancer cell interplay and clinical safety of ASCs-based therapies. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

28 pages, 2311 KiB

Open AccessReview

Regenerative and Transplantation Medicine: Cellular Therapy Using Adipose Tissue-Derived Mesenchymal Stromal Cells for Type 1 Diabetes Mellitus

by Hiroyuki Takahashi, Naoaki Sakata, Gumpei Yoshimatsu, Suguru Hasegawa and Shohta Kodama

J. Clin. Med. 2019, 8(2), 249; https://doi.org/10.3390/jcm8020249 - 15 Feb 2019

Cited by 29 | Viewed by 6032

Abstract

Type 1 diabetes mellitus (T1DM) is caused by the autoimmune targeting of pancreatic β-cells, and, in the advanced stage, severe hypoinsulinemia due to islet destruction. In patients with T1DM, continuous exogenous insulin therapy cannot be avoided. However, an insufficient dose of insulin easily induces extreme hyperglycemia or diabetic ketoacidosis, and intensive insulin therapy may cause hypoglycemic symptoms including hypoglycemic shock. While these insulin therapies are efficacious in most patients, some additional therapies are warranted to support the control of blood glucose levels and reduce the risk of hypoglycemia in patients who respond poorly despite receiving appropriate treatment. There has been a recent gain in the popularity of cellular therapies using mesenchymal stromal cells (MSCs) in various clinical fields, owing to their multipotentiality, capacity for self-renewal, and regenerative and immunomodulatory potential. In particular, adipose tissue-derived MSCs (ADMSCs) have become a focus in the clinical setting due to the abundance and easy isolation of these cells. In this review, we outline the possible therapeutic benefits of ADMSC for the treatment of T1DM. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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Other

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21 pages, 8035 KiB

Open AccessCase Report

Intra-Vitreal Administration of Microvesicles Derived from Human Adipose-Derived Multipotent Stromal Cells Improves Retinal Functionality in Dogs with Retinal Degeneration

by Anna Cislo-Pakuluk, Agnieszka Smieszek, Natalia Kucharczyk, Peter G.C. Bedford and Krzysztof Marycz

J. Clin. Med. 2019, 8(4), 510; https://doi.org/10.3390/jcm8040510 - 13 Apr 2019

Cited by 4 | Viewed by 3753

Abstract

This study was designed to determine the influence of microvesicles (MVs) derived from multipotent stromal cells isolated from human adipose tissue (hASCs) on retinal functionality in dogs with various types of retinal degeneration. The biological properties of hASC-MVs were first determined using an in vitro model of retinal Muller-like cells (CaMLCs). The in vitro assays included analysis of hASC-MVs influence on cell viability and metabolism. Brain-derived neurotrophic factor (BDNF) expression was also determined. Evaluation of the hASC-MVs was performed under normal and oxidative stress conditions. Preliminary clinical studies were performed on ten dogs with retinal degeneration. The clinical studies included behavioral tests, fundoscopy and electroretinography before and after hASC-MVs intra-vitreal injection. The in vitro study showed that CaMLCs treated with hASC-MVs were characterized by improved viability and mitochondrial potential, both under normal and oxidative stress conditions. Additionally, hASC-MVs under oxidative stress conditions reduced the number of senescence-associated markers, correlating with the increased expression of BDNF. The preliminary clinical study showed that the intra-vitreal administration of hASC-MVs significantly improved the dogs’ general behavior and tracking ability. Furthermore, fundoscopy demonstrated that the retinal blood vessels appeared to be less attenuated, and electroretinography using HMsERG demonstrated an increase in a- and b-wave amplitude after treatment. These results shed promising light on the application of cell-free therapies in veterinary medicine for retinal degenerative disorders treatment. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells and Their Extracellular Microvesicles (ExMVs) for Tissue Engineering and Regenerative Medicine Applications)

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