International Journal of Molecular Sciences

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5 pages, 196 KiB

Open AccessEditorial

Fundamental and Practical Perspectives in Regenerative Medicine

by Pavel I. Makarevich and Vsevolod A. Tkachuk

Int. J. Mol. Sci. 2024, 25(21), 11508; https://doi.org/10.3390/ijms252111508 - 26 Oct 2024

Viewed by 581

Abstract

As regenerative medicine continues to advance as a growing field in modern biology and the healthcare industry, it attracts enormous interest from the general public and scientists [...] Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

Research

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20 pages, 6852 KiB

Open AccessArticle

Cartilage-Specific Gene Expression and Extracellular Matrix Deposition in the Course of Mesenchymal Stromal Cell Chondrogenic Differentiation in 3D Spheroid Culture

by Igor V. Vakhrushev, Yulia B. Basok, Konstantin K. Baskaev, Victoria D. Novikova, Georgy E. Leonov, Alexey M. Grigoriev, Aleksandra D. Belova, Ludmila A. Kirsanova, Alexey Y. Lupatov, Veronika V. Burunova, Alexey V. Kovalev, Pavel I. Makarevich, Victor I. Sevastianov and Konstantin N. Yarygin

Int. J. Mol. Sci. 2024, 25(11), 5695; https://doi.org/10.3390/ijms25115695 - 23 May 2024

Viewed by 1179

Abstract

Articular cartilage damage still remains a major problem in orthopedical surgery. The development of tissue engineering techniques such as autologous chondrocyte implantation is a promising way to improve clinical outcomes. On the other hand, the clinical application of autologous chondrocytes has considerable limitations. [...] Read more.

Articular cartilage damage still remains a major problem in orthopedical surgery. The development of tissue engineering techniques such as autologous chondrocyte implantation is a promising way to improve clinical outcomes. On the other hand, the clinical application of autologous chondrocytes has considerable limitations. Mesenchymal stromal cells (MSCs) from various tissues have been shown to possess chondrogenic differentiation potential, although to different degrees. In the present study, we assessed the alterations in chondrogenesis-related gene transcription rates and extracellular matrix deposition levels before and after the chondrogenic differentiation of MSCs in a 3D spheroid culture. MSCs were obtained from three different tissues: umbilical cord Wharton’s jelly (WJMSC—Wharton’s jelly mesenchymal stromal cells), adipose tissue (ATMSC—adipose tissue mesenchymal stromal cells), and the dental pulp of deciduous teeth (SHEDs—stem cells from human exfoliated deciduous teeth). Monolayer MSC cultures served as baseline controls. Newly formed 3D spheroids composed of MSCs previously grown in 2D cultures were precultured for 2 days in growth medium, and then, chondrogenic differentiation was induced by maintaining them in the TGF-β1-containing medium for 21 days. Among the MSC types studied, WJMSCs showed the most similarities with primary chondrocytes in terms of the upregulation of cartilage-specific gene expression. Interestingly, such upregulation occurred to some extent in all 3D spheroids, even prior to the addition of TGF-β1. These results confirm that the potential of Wharton’s jelly is on par with adipose tissue as a valuable cell source for cartilage engineering applications as well as for the treatment of osteoarthritis. The 3D spheroid environment on its own acts as a trigger for the chondrogenic differentiation of MSCs. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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27 pages, 15618 KiB

Open AccessArticle

Polyploidy Promotes Hypertranscription, Apoptosis Resistance, and Ciliogenesis in Cancer Cells and Mesenchymal Stem Cells of Various Origins: Comparative Transcriptome In Silico Study

by Olga V. Anatskaya and Alexander E. Vinogradov

Int. J. Mol. Sci. 2024, 25(8), 4185; https://doi.org/10.3390/ijms25084185 - 10 Apr 2024

Viewed by 3534

Abstract

Mesenchymal stem cells (MSC) attract an increasing amount of attention due to their unique therapeutic properties. Yet, MSC can undergo undesirable genetic and epigenetic changes during their propagation in vitro. In this study, we investigated whether polyploidy can compromise MSC oncological safety and [...] Read more.

Mesenchymal stem cells (MSC) attract an increasing amount of attention due to their unique therapeutic properties. Yet, MSC can undergo undesirable genetic and epigenetic changes during their propagation in vitro. In this study, we investigated whether polyploidy can compromise MSC oncological safety and therapeutic properties. For this purpose, we compared the impact of polyploidy on the transcriptome of cancer cells and MSC of various origins (bone marrow, placenta, and heart). First, we identified genes that are consistently ploidy-induced or ploidy-repressed through all comparisons. Then, we selected the master regulators using the protein interaction enrichment analysis (PIEA). The obtained ploidy-related gene signatures were verified using the data gained from polyploid and diploid populations of early cardiomyocytes (CARD) originating from iPSC. The multistep bioinformatic analysis applied to the cancer cells, MSC, and CARD indicated that polyploidy plays a pivotal role in driving the cell into hypertranscription. It was evident from the upregulation of gene modules implicated in housekeeping functions, stemness, unicellularity, DNA repair, and chromatin opening by means of histone acetylation operating via DNA damage associated with the NUA4/TIP60 complex. These features were complemented by the activation of the pathways implicated in centrosome maintenance and ciliogenesis and by the impairment of the pathways related to apoptosis, the circadian clock, and immunity. Overall, our findings suggest that, although polyploidy does not induce oncologic transformation of MSC, it might compromise their therapeutic properties because of global epigenetic changes and alterations in fundamental biological processes. The obtained results can contribute to the development and implementation of approaches enhancing the therapeutic properties of MSC by removing polyploid cells from the cell population. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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15 pages, 1756 KiB

Open AccessArticle

Balance between Pro- and Antifibrotic Proteins in Mesenchymal Stromal Cell Secretome Fractions Revealed by Proteome and Cell Subpopulation Analysis

by Maria Kulebyakina, Nataliya Basalova, Daria Butuzova, Mikhail Arbatsky, Vadim Chechekhin, Natalia Kalinina, Pyotr Tyurin-Kuzmin, Konstantin Kulebyakin, Oleg Klychnikov and Anastasia Efimenko

Int. J. Mol. Sci. 2024, 25(1), 290; https://doi.org/10.3390/ijms25010290 - 25 Dec 2023

Cited by 2 | Viewed by 1758

Abstract

Multipotent mesenchymal stromal cells (MSCs) regulate tissue repair through paracrine activity, with secreted proteins being significant contributors. Human tissue repair commonly results in fibrosis, where fibroblast differentiation into myofibroblasts is a major cellular mechanism. MSCs’ paracrine activity can inhibit fibrosis development. We previously [...] Read more.

Multipotent mesenchymal stromal cells (MSCs) regulate tissue repair through paracrine activity, with secreted proteins being significant contributors. Human tissue repair commonly results in fibrosis, where fibroblast differentiation into myofibroblasts is a major cellular mechanism. MSCs’ paracrine activity can inhibit fibrosis development. We previously demonstrated that the separation of MSC secretome, represented by conditioned medium (CM), into subfractions enriched with extracellular vesicles (EV) or soluble factors (SF) boosts EV and SF antifibrotic effect. This effect is realized through the inhibition of fibroblast-to-myofibroblast differentiation in vitro. To unravel the mechanisms of MSC paracrine effects on fibroblast differentiation, we performed a comparative proteomic analysis of MSC secretome fractions. We found that CM was enriched in NF-κB activators and confirmed via qPCR that CM, but not EV or SF, upregulated NF-κB target genes (COX2, IL6, etc.) in human dermal fibroblasts. Furthermore, we revealed that EV and SF were enriched in TGF-β, Notch, IGF, and Wnt pathway regulators. According to scRNAseq, 11 out of 13 corresponding genes were upregulated in a minor MSC subpopulation disappearing in profibrotic conditions. Thus, protein enrichment of MSC secretome fractions and cellular subpopulation patterns shift the balance in fibroblast-to-myofibroblast differentiation, which should be considered in studies of MSC paracrine effects and the therapeutic use of MSC secretome. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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13 pages, 1928 KiB

Open AccessCommunication

M2-Macrophage-Induced Chronic Inflammation Promotes Reversible Mesenchymal Stromal Cell Senescence and Reduces Their Anti-Fibrotic Properties

by Uliana Dyachkova, Maksim Vigovskiy, Nataliya Basalova, Anastasia Efimenko and Olga Grigorieva

Int. J. Mol. Sci. 2023, 24(23), 17089; https://doi.org/10.3390/ijms242317089 - 4 Dec 2023

Cited by 3 | Viewed by 2283

Abstract

Fibrosis and the associated decline in organ functionality lead to an almost 50% mortality rate in developed countries. Multipotent mesenchymal stromal cells (MSC) were shown to suppress the development and progression of fibrosis through secreted factors including specific non-coding RNAs transferred within extracellular [...] Read more.

Fibrosis and the associated decline in organ functionality lead to an almost 50% mortality rate in developed countries. Multipotent mesenchymal stromal cells (MSC) were shown to suppress the development and progression of fibrosis through secreted factors including specific non-coding RNAs transferred within extracellular vesicles (EV). However, age-associated chronic inflammation can provoke MSC senescence and change secretome composition, thereby affecting their antifibrotic properties. Alternatively activated macrophages (M2-type) are key players in chronic inflammation that may interact with MSC through paracrine mechanisms and decrease their antifibrotic functions. To confirm this hypothesis, we evaluated the M2-macrophage conditioned medium (CM-M2) effect on human adipose-tissue-derived MSC senescence in vitro. We found that CM-M2, as well as a pro-senescence agent, hydrogen peroxide (H₂O₂), increased p21+–MSC number and secretion of IL-6 and MCP-1, which are considered main senescence-associated secretory phenotype (SASP) components. Thus, both exposures led to the senescent phenotype acquisition of MSC. EV from both CM-M2 and H₂O₂-exposed MSC, which showed a decreased effect on the suppression of TGFβ-induced fibroblast-to-myofibroblast differentiation compared to EV from control MSC according to αSMA level and the αSMA+–stress fiber reduction. After two weeks of subsequent cultivation under standard conditions, MSC demonstrated a decrease in senescence hallmarks and fibroblast differentiation suppression via EV. These results suggest that M2-macrophage-induced chronic inflammation can reversibly induce MSC senescence, which reduces the MSC’s ability to inhibit fibroblast-to-myofibroblast differentiation. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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13 pages, 4286 KiB

Open AccessArticle

Extracellular Matrix Deposition Defines the Duration of Cell Sheet Assembly from Human Adipose-Derived MSC

by Valentina S. Glazieva, Natalya A. Alexandrushkina, Peter P. Nimiritsky, Maria A. Kulebyakina, Roman Yu. Eremichev and Pavel I. Makarevich

Int. J. Mol. Sci. 2023, 24(23), 17050; https://doi.org/10.3390/ijms242317050 - 1 Dec 2023

Viewed by 1678

Abstract

Cell sheet (CS) engineering using mesenchymal stromal cells (MSC) draws significant interest for regenerative medicine and this approach translates to clinical use for numerous indications. However, little is known of factors that define the timing of CS assembly from primary cultures. This aspect [...] Read more.

Cell sheet (CS) engineering using mesenchymal stromal cells (MSC) draws significant interest for regenerative medicine and this approach translates to clinical use for numerous indications. However, little is known of factors that define the timing of CS assembly from primary cultures. This aspect is important for planning CS delivery in autologous and allogeneic modes of use. We used a comparative in vitro approach with primary donors’ (n = 14) adipose-derived MSCs and evaluated the impact of healthy subject’s sex, MSC culture features (population doubling time and lag-phase), and extracellular matrix (ECM) composition along with factors related to connective tissue formations (α-SMA and FAP-α) on CS assembly duration. Using qualitative and quantitative analysis methods, we found that, in seeded MSCs, high contents of collagen I and collagen IV had a direct correlation with longer CS assembly duration. We found that short lag-phase cultures faster turned to a ready-to-use CS, while age, sex, fibronectin, laminin, α-SMA, and FAP-α failed to provide a significant correlation with the timing of assembly. In detachable CSs, FAP-α was negatively correlated with the duration of assembly, suggesting that its concentration rose over time and contributed to MSC activation, transitioning to α-SMA-positive myofibroblasts and ECM turnover. Preliminary data on cell density and collagen I deposition suggested that the TGF-β1 signaling axis is of pivotal importance for ECM composition and construct maturation. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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16 pages, 4742 KiB

Open AccessArticle

Post-Implantation Inflammatory Responses to Xenogeneic Tissue-Engineered Cartilage Implanted in Rabbit Trachea: The Role of Cultured Chondrocytes in the Modification of Inflammation

by Ilya Klabukov, Dmitri Atiakshin, Evgenia Kogan, Michael Ignatyuk, Mikhail Krasheninnikov, Nickolay Zharkov, Anna Yakimova, Vyacheslav Grinevich, Pavel Pryanikov, Vladimir Parshin, Dmitry Sosin, Andrey A. Kostin, Peter Shegay, Andrey D. Kaprin and Denis Baranovskii

Int. J. Mol. Sci. 2023, 24(23), 16783; https://doi.org/10.3390/ijms242316783 - 26 Nov 2023

Cited by 7 | Viewed by 2023

Abstract

Immune responses to tissue-engineered grafts made of xenogeneic materials remain poorly studied. The scope of current investigations is limited by the lack of information on orthotopically implanted grafts. A deeper understanding of these processes is of great importance since innovative surgical approaches include [...] Read more.

Immune responses to tissue-engineered grafts made of xenogeneic materials remain poorly studied. The scope of current investigations is limited by the lack of information on orthotopically implanted grafts. A deeper understanding of these processes is of great importance since innovative surgical approaches include the implantation of xenogeneic decellularized scaffolds seeded by cells. The purpose of our work is to study the immunological features of tracheal repair during the implantation of tissue-engineered constructs based on human xenogeneic scaffolds modified via laser radiation in rabbits. The samples were stained with hematoxylin and Safranin O, and they were immunostained with antibodies against tryptase, collagen II, vimentin, and CD34. Immunological and inflammatory responses were studied by counting immune cells and evaluating blood vessels and collagen. Leukocyte-based inflammation prevailed during the implantation of decellularized unseeded scaffolds; meanwhile, plasma cells were significantly more abundant in tissue-engineered constructs. Mast cells were insignificantly more abundant in tissue-engineered construct samples. Conclusions: The seeding of decellularized xenogeneic cartilage with chondrocytes resulted in a change in immunological reactions upon implantation, and it was associated with plasma cell infiltration. Tissue-engineered grafts widely differed in design, including the type of used cells. The question of immunological response depending on the tissue-engineered graft composition requires further investigation. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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12 pages, 4973 KiB

Open AccessArticle

Tumor Necrosis Factor-Alpha Induces Proangiogenic Profiling of Cardiosphere-Derived Cell Secretome and Increases Its Ability to Stimulate Angiogenic Properties of Endothelial Cells

by Konstantin Dergilev, Ekaterina Zubkova, Alika Guseva, Zoya Tsokolaeva, Yulia Goltseva, Irina Beloglazova, Elizaveta Ratner, Alexander Andreev, Stanislav Partigulov, Mikhail Lepilin, Mikhail Menshikov and Yelena Parfyonova

Int. J. Mol. Sci. 2023, 24(23), 16575; https://doi.org/10.3390/ijms242316575 - 21 Nov 2023

Viewed by 1430

Abstract

Ischemic heart disease and its complications, such as myocardial infarction and heart failure, are the leading causes of death in modern society. The adult heart innately lacks the capacity to regenerate the damaged myocardium after ischemic injury. Multiple lines of evidence indicated that [...] Read more.

Ischemic heart disease and its complications, such as myocardial infarction and heart failure, are the leading causes of death in modern society. The adult heart innately lacks the capacity to regenerate the damaged myocardium after ischemic injury. Multiple lines of evidence indicated that stem-cell-based transplantation is one of the most promising treatments for damaged myocardial tissue. Different kinds of stem cells have their advantages for treating ischemic heart disease. One facet of their mechanism is the paracrine effect of the transplanted cells. Particularly promising are stem cells derived from cardiac tissue per se, referred to as cardiosphere-derived cells (CDCs), whose therapeutic effect is mediated by the paracrine mechanism through secretion of multiple bioactive molecules providing immunomodulatory, angiogenic, anti-fibrotic, and anti-inflammatory effects. Although secretome-based therapies are increasingly being used to treat various cardiac pathologies, many obstacles remain because of population heterogeneity, insufficient understanding of potential modulating compounds, and the principles of secretome regulation, which greatly limit the feasibility of this technology. In addition, components of the inflammatory microenvironment in ischemic myocardium may influence the secretome content of transplanted CDCs, thus altering the efficacy of cell therapy. In this work, we studied how Tumor necrosis factor alpha (TNFa), as a key component of the pro-inflammatory microenvironment in damaged myocardium from ischemic injury and heart failure, may affect the secretome content of CDCs and their angiogenic properties. We have shown for the first time that TNFa may act as a promising compound modulating the CDC secretome, which induces its profiling to enhance proangiogenic effects on endothelial cells. These results allow us to elucidate the underlying mechanisms of the impact of the inflammatory microenvironment on transplanted CDCs and may contribute to the optimization of CDC efficiency and the development of the technology for producing the CDC secretome with enhanced proangiogenic properties for cell-free therapy. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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20 pages, 7649 KiB

Open AccessArticle

Adipocytes in the Uterine Wall during Experimental Healing and in Cesarean Scars during Pregnancy

by Natalia Tikhonova, Andrey P. Milovanov, Valentina V. Aleksankina, Ilyas A. Kulikov, Tatiana V. Fokina, Andrey P. Aleksankin, Tamara N. Belousova, Ludmila M. Mikhaleva and Natalya V. Niziaeva

Int. J. Mol. Sci. 2023, 24(20), 15255; https://doi.org/10.3390/ijms242015255 - 17 Oct 2023

Viewed by 2196

Abstract

We have suggested that adipocytes in uterine scars may affect the development of the placenta accrete spectrum (PAS). In the experimental part, we explored adipocytes in the uterine wall by the twelfth sexual cycle after surgery. In the clinical part, we investigated adipocyte [...] Read more.

We have suggested that adipocytes in uterine scars may affect the development of the placenta accrete spectrum (PAS). In the experimental part, we explored adipocytes in the uterine wall by the twelfth sexual cycle after surgery. In the clinical part, we investigated adipocyte clusters in the cesarean scar of pregnant women with and without PAS. The uterine wall was evaluated in gross and histological sections using morphometry, histochemistry (hematoxylin and eosin stain, Mallory stain), and immunohistochemistry for FABP4 (adipocyte markers), CD68, CD163, CD206 (macrophages), CD 34 (endothelium), cytokeratin 8 (epithelium), aSMA (smooth muscle cells). The design included an experimental study on Sprague–Dawley rats (n = 18) after a full-thickness surgical incision on the seventh (n = 6), 30th (n = 6), and 60th day (n = 6). The clinical groups include pregnant women without uterine scars (n = 10), pregnant women with a uterine scar after previous cesarean sections (n = 10), and women with PAS (n = 11). Statistical processing was carried out using nonparametric methods. Comparisons were conducted using the Mann–Whitney U-test and Kruskal–Wallis test. Statistical significance was considered at p < 0.05. On the seventh day, the rat uterine horn was enveloped by adipose tissue, which contained crown-like structures with FABP4+, CD68+, CD206+, and CD163+ cells. FABP4+ cells in the uterine wall were absent by the 30th day. The number of CD206+ and CD163+ cells in the adipose tissue decreased by the 30th day. On the 60th day, the attachment of fat tissue was revealed in the form of single strands. The serous layer around the damaged area totally recovered on the 60th day. FABP4+ cells were not detected in the uterine wall samples from pregnant women without a previous cesarean section. Adipocytes were found in the scar during non-complicated pregnancy and with PAS. Reducing the number of CD68+ cells in adipocyte clusters, there were in myometrium with PAS. Increased CD206+ and CD163+ cells were revealed in uterine adipocyte clusters of the group. According to the experimental finding, adipocytes should be absent in the uterine wall by the 12th sexual cycle after a full-thickness surgical incision. The presence of adipocyte clusters in cesarean scar indicated the disturbance of cell interaction. Differences in the numbers of CD206 and CD163 cells in adipocyte clusters between groups with and without PAS may be indirect evidence that uterine adipocytes affect the development of PAS. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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11 pages, 2692 KiB

Open AccessArticle

The Influence of Combined Sterilization Factors on the Structural and Functional Characteristics of Bone Implants

by Nadezhda Nikolaeva, Vladimir Rozanov, Alexander Chernyaev, Igor Matveychuk and Milena Makarova

Int. J. Mol. Sci. 2023, 24(19), 14426; https://doi.org/10.3390/ijms241914426 - 22 Sep 2023

Viewed by 1047

Abstract

The results of a comprehensive study of the patterns of structural and functional changes in bone tissue samples after combined (ozone + radiation) sterilization are presented. The study used a different approach to the sterilization process with selective ozone or radiation exposure and [...] Read more.

The results of a comprehensive study of the patterns of structural and functional changes in bone tissue samples after combined (ozone + radiation) sterilization are presented. The study used a different approach to the sterilization process with selective ozone or radiation exposure and an integral, combined one, based on a combined ozone–oxygen treatment of bone samples at the first stage and radiation at the second. The methods of IR spectroscopy, scanning electron microscopy with a prefix for elemental analysis, atomic force microscopy, and mechanical analysis with determination of elastic-plastic properties (Vickers microhardness index) were used in the work. It is shown that the ozone exposure used at the first stage of the combined sterilization process of bone implants does not lead to negative consequences with respect to their properties and characteristics. The results obtained serve as a scientific and methodological basis for the further improvement and optimization of sterilization technologies (including combined). They also offer a comprehensive justification of the parameters of sterilization regimes to ensure the safety of using bone implants during reconstructive operations, minimizing structural and functional changes in bone matter, and creating effective health-saving technologies and the possibility of using them for various biomedical applications. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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12 pages, 3119 KiB

Open AccessArticle

T-Cadherin Deficiency Is Associated with Increased Blood Pressure after Physical Activity

by Vladimir S. Popov, Ilya B. Brodsky, Maria N. Balatskaya, Alexander V. Balatskiy, Ilia D. Ozhimalov, Maria A. Kulebyakina, Ekaterina V. Semina, Mikhail S. Arbatskiy, Viktoria S. Isakova, Polina S. Klimovich, Veronika Y. Sysoeva, Natalia I. Kalinina, Vsevolod A. Tkachuk and Kseniya A. Rubina

Int. J. Mol. Sci. 2023, 24(18), 14204; https://doi.org/10.3390/ijms241814204 - 17 Sep 2023

Viewed by 1714

Abstract

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the Cdh13 gene to be associated with hypertension. However, the role of [...] Read more.

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the Cdh13 gene to be associated with hypertension. However, the role of T-cadherin in regulating blood pressure has not been experimentally elucidated. Herein, we generated Cdh13^∆Exon3 mice lacking exon 3 in the Cdh13 gene and described their phenotype. Cdh13^∆Exon3 mice exhibited normal gross morphology, life expectancy, and breeding capacity. Meanwhile, their body weight was considerably lower than of WT mice. When running on a treadmill, the time spent running and the distance covered by Cdh13^∆Exon3 mice was similar to that of WT. The resting blood pressure in Cdh13^∆Exon3 mice was slightly higher than in WT, however, upon intensive physical training their systolic blood pressure was significantly elevated. While adiponectin content in the myocardium of Cdh13^∆Exon3 and WT mice was within the same range, adiponectin plasma level was 4.37-fold higher in Cdh13^∆Exon3 mice. Moreover, intensive physical training augmented the AMPK phosphorylation in the skeletal muscles and myocardium of Cdh13^∆Exon3 mice as compared to WT. Our data highlight a critically important role of T-cadherin in regulation of blood pressure and stamina in mice, and may shed light on the pathogenesis of hypertension. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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15 pages, 5770 KiB

Open AccessArticle

Dual Adeno-Associated Virus 9 with Codon-Optimized DYSF Gene Promotes In Vivo Muscle Regeneration and May Decrease Inflammatory Response in Limb Girdle Muscular Dystrophy Type R2

by Ivan A. Yakovlev, Aleksei M. Emelin, Yana S. Slesarenko, Igor S. Limaev, Iuliia A. Vetrova, Liliya D. Belikova, Ekaterina N. Grafskaia, Pavel A. Bobrovsky, Mikhail V. Pokrovsky, Elena V. Kuzubova, Vladimir M. Pokrovsky, Pyotr A. Lebedev, Sergei N. Bardakov, Artur A. Isaev and Roman V. Deev

Int. J. Mol. Sci. 2023, 24(17), 13551; https://doi.org/10.3390/ijms241713551 - 31 Aug 2023

Cited by 5 | Viewed by 2101

Abstract

Dysferlinopathy treatment is an active area of investigation. Gene therapy is one potential approach. We studied muscle regeneration and inflammatory response after injection of an AAV-9 with a codon-optimized DYSF gene. A dual-vector system AAV.DYSF.OVERLAP with overlapping DYSF cDNA sequences was generated. Two [...] Read more.

Dysferlinopathy treatment is an active area of investigation. Gene therapy is one potential approach. We studied muscle regeneration and inflammatory response after injection of an AAV-9 with a codon-optimized DYSF gene. A dual-vector system AAV.DYSF.OVERLAP with overlapping DYSF cDNA sequences was generated. Two AAV vectors were separately assembled by a standard triple-transfection protocol from plasmids carrying parts of the DYSF gene. Artificial myoblasts from dysferlin-deficient fibroblasts were obtained by MyoD overexpression. RT-PCR and Western blot were used for RNA and protein detection in vitro. A dysferlinopathy murine model (Bla/J) was used for in vivo studies. Histological assay, morphometry, and IHC were used for the muscle tissue analysis. Dysferlin was detected in vitro and in vivo at subphysiological levels. RT-PCR and Western Blot detected dysferlin mRNA and protein in AAV.DYSF.OVERLAP-transduced cells, and mRNA reached a 7-fold elevated level compared to the reference gene (GAPDH). In vivo, the experimental group showed intermediate median values for the proportion of necrotic muscle fibers, muscle fibers with internalized nuclei, and cross-sectional area of muscle fibers compared to the same parameters in the control groups of WT and Bla/J mice, although the differences were not statistically significant. The inverse relationship between the dosage and the severity of inflammatory changes in the muscles may be attributed to the decrease in the number of necrotic fibers. The share of transduced myofibers reached almost 35% in the group with the highest dose. The use of two-vector systems based on AAV is justified in terms of therapeutic efficacy. The expression of dysferlin at a subphysiological level, within a short observation period, is capable of inducing the restoration of muscle tissue structure, reducing inflammatory activity, and mitigating necrotic processes. Further research is needed to provide a more detailed assessment of the impact of the transgene and viral vector on the inflammatory component, including longer observation periods. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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34 pages, 15942 KiB

Open AccessArticle

Functionalization of Octacalcium Phosphate Bone Graft with Cisplatin and Zoledronic Acid: Physicochemical and Bioactive Properties

by Ekaterina A. Kuvshinova, Nataliya V. Petrakova, Yulia O. Nikitina, Irina K. Sviridova, Suraja A. Akhmedova, Valentina A. Kirsanova, Pavel A. Karalkin, Vladimir S. Komlev, Natalia S. Sergeeva and Andrey D. Kaprin

Int. J. Mol. Sci. 2023, 24(14), 11633; https://doi.org/10.3390/ijms241411633 - 19 Jul 2023

Cited by 4 | Viewed by 1992

Abstract

Bones are the fourth most frequent site of metastasis from malignant tumors, including breast cancer, prostate cancer, melanoma, etc. The bioavailability of bone tissue for chemotherapy drugs is extremely low. This requires a search for new approaches of targeted drug delivery to the [...] Read more.

Bones are the fourth most frequent site of metastasis from malignant tumors, including breast cancer, prostate cancer, melanoma, etc. The bioavailability of bone tissue for chemotherapy drugs is extremely low. This requires a search for new approaches of targeted drug delivery to the tumor growth zone after surgery treatment. The aim of this work was to develop a method for octacalcium phosphate (OCP) bone graft functionalization with the cytostatic drug cisplatin to provide the local release of its therapeutic concentrations into the bone defect. OCP porous ceramic granules (OCP ceramics) were used as a platform for functionalization, and bisphosphonate zoledronic acid was used to mediate the interaction between cisplatin and OCP and enhance their binding strength. The obtained OCP materials were studied using scanning electron and light microscopy, high-performance liquid chromatography, atomic emission spectroscopy, and real-time PCR. In vitro and in vivo studies were performed on normal and tumor cell lines and small laboratory animals. The bioactivity of initial OCP ceramics was explored and the efficiency of OCP functionalization with cisplatin, zoledronic acid, and their combination was evaluated. The kinetics of drug release and changes in ceramics properties after functionalization were studied. It was established that zoledronic acid changed the physicochemical and bioactive properties of OCP ceramics and prolonged cisplatin release from the ceramics. In vitro and in vivo experiments confirmed the biocompatibility, osteoconductivity, and osteoinductivity, as well as cytostatic and antitumor properties of the obtained materials. The use of OCP ceramics functionalized with a cytostatic via the described method seems to be promising in clinics when primary or metastatic tumors of the bone tissue are removed. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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18 pages, 2682 KiB

Open AccessArticle

Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs

by Aysilu Mullagulova, Alisa Shaimardanova, Valeriya Solovyeva, Yana Mukhamedshina, Daria Chulpanova, Alexander Kostennikov, Shaza Issa and Albert Rizvanov

Int. J. Mol. Sci. 2023, 24(11), 9204; https://doi.org/10.3390/ijms24119204 - 24 May 2023

Cited by 3 | Viewed by 2565

Abstract

Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demyelination and motor and cognitive impairments due to deficiencies of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus [...] Read more.

Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demyelination and motor and cognitive impairments due to deficiencies of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus (AAV) vectors for ARSA delivery has shown promising results. The main challenges for MLD gene therapy include optimizing the AAV dosage, selecting the most effective serotype, and determining the best route of administration for ARSA delivery into the central nervous system. This study aims to evaluate the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intravenously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans. By comparing these two administration methods, this study contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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18 pages, 3312 KiB

Open AccessArticle

Label-Free Imaging Techniques to Evaluate Metabolic Changes Caused by Toxic Liver Injury in PCLS

by Svetlana Rodimova, Artem Mozherov, Vadim Elagin, Maria Karabut, Ilya Shchechkin, Dmitry Kozlov, Dmitry Krylov, Alena Gavrina, Nikolai Bobrov, Vladimir Zagainov, Elena Zagaynova and Daria Kuznetsova

Int. J. Mol. Sci. 2023, 24(11), 9195; https://doi.org/10.3390/ijms24119195 - 24 May 2023

Cited by 3 | Viewed by 1884

Abstract

Abuse with hepatotoxic agents is a major cause of acute liver failure. The search for new criteria indicating the acute or chronic pathological processes is still a challenging issue that requires the selection of effective tools and research models. Multiphoton microscopy with second [...] Read more.

Abuse with hepatotoxic agents is a major cause of acute liver failure. The search for new criteria indicating the acute or chronic pathological processes is still a challenging issue that requires the selection of effective tools and research models. Multiphoton microscopy with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) are modern label-free methods of optical biomedical imaging for assessing the metabolic state of hepatocytes, therefore reflecting the functional state of the liver tissue. The aim of this work was to identify characteristic changes in the metabolic state of hepatocytes in precision-cut liver slices (PCLSs) under toxic damage by some of the most common toxins: ethanol, carbon tetrachloride (CCl4) and acetaminophen (APAP), commonly known as paracetamol. We have determined characteristic optical criteria for toxic liver damage, and these turn out to be specific for each toxic agent, reflecting the underlying pathological mechanisms of toxicity. The results obtained are consistent with standard methods of molecular and morphological analysis. Thus, our approach, based on optical biomedical imaging, is effective for intravital monitoring of the state of liver tissue in the case of toxic damage or even in cases of acute liver injury. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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19 pages, 1780 KiB

Open AccessArticle

Acute Myeloid Leukemia Causes Serious and Partially Irreversible Changes in Secretomes of Bone Marrow Multipotent Mesenchymal Stromal Cells

by Aleksandra Sadovskaya, Nataliya Petinati, Nina Drize, Igor Smirnov, Olga Pobeguts, Georgiy Arapidi, Maria Lagarkova, Alexander Belyavsky, Anastasia Vasilieva, Olga Aleshina and Elena Parovichnikova

Int. J. Mol. Sci. 2023, 24(10), 8953; https://doi.org/10.3390/ijms24108953 - 18 May 2023

Cited by 1 | Viewed by 1894

Abstract

In patients with acute myeloid leukemia (AML), malignant cells modify the properties of multipotent mesenchymal stromal cells (MSCs), reducing their ability to maintain normal hematopoiesis. The aim of this work was to elucidate the role of MSCs in supporting leukemia cells and the [...] Read more.

In patients with acute myeloid leukemia (AML), malignant cells modify the properties of multipotent mesenchymal stromal cells (MSCs), reducing their ability to maintain normal hematopoiesis. The aim of this work was to elucidate the role of MSCs in supporting leukemia cells and the restoration of normal hematopoiesis by analyzing ex vivo MSC secretomes at the onset of AML and in remission. The study included MSCs obtained from the bone marrow of 13 AML patients and 21 healthy donors. The analysis of proteins contained in the MSCs-conditioned medium demonstrated that secretomes of patient MSCs differed little between the onset of AML and remission; pronounced differences were observed between MSC secretomes of AML patients and healthy donors. The onset of AML was accompanied by a decrease in the secretion of proteins related to ossification, transport, and immune response. In remission, but not at the onset, secretion of proteins responsible for cell adhesion, immune response, and complement was reduced compared to donors. We conclude that AML causes crucial and, to a large extent, irreversible changes in the secretome of bone marrow MSCs ex vivo. In remission, functions of MSCs remain impaired despite the absence of tumor cells and the formation of benign hematopoietic cells. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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17 pages, 3064 KiB

Open AccessArticle

Derivation of Human Corneal Keratocytes from ReLEx SMILE Lenticules for Cell Therapy and Tissue Engineering

by Maria A. Surovtseva, Irina I. Kim, Natalia A. Bondarenko, Alexander P. Lykov, Kristina Yu. Krasner, Elena V. Chepeleva, Nataliya P. Bgatova, Alexander N. Trunov, Valery V. Chernykh and Olga V. Poveshchenko

Int. J. Mol. Sci. 2023, 24(10), 8828; https://doi.org/10.3390/ijms24108828 - 16 May 2023

Cited by 3 | Viewed by 1818

Abstract

Fibroblasts isolated and expanded from ReLEx SMILE lenticules can be a source of human keratocytes. Since corneal keratocytes are quiescent cells, it is difficult to expand them in vitro in suitable numbers for clinical and experimental use. In the present study, this problem [...] Read more.

Fibroblasts isolated and expanded from ReLEx SMILE lenticules can be a source of human keratocytes. Since corneal keratocytes are quiescent cells, it is difficult to expand them in vitro in suitable numbers for clinical and experimental use. In the present study, this problem was solved by isolating and growing corneal fibroblasts (CFs) with a high proliferative potential and their reversion to keratocytes in a selective serum-free medium. Fibroblasts reversed into keratocytes (rCFs) had a dendritic morphology and ultrastructural signs of activation of protein synthesis and metabolism. The cultivation of CFs in a medium with 10% FCS and their reversion into keratocytes was not accompanied by the induction of myofibroblasts. After reversion, the cells spontaneously formed spheroids and expressed keratocan and lumican markers, but not mesenchymal ones. The rCFs had low proliferative and migratory activity, and their conditioned medium contained a low level of VEGF. CF reversion was not accompanied by a change with the levels of IGF-1, TNF-alpha, SDF-1a, and sICAM-1. In the present study, it has been demonstrated that fibroblasts from ReLEx SMILE lenticules reverse into keratocytes in serum-free KGM, maintaining the morphology and functional properties of primary keratocytes. These keratocytes have a potential for tissue engineering and cell therapy of various corneal pathologies. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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13 pages, 1601 KiB

Open AccessArticle

Protocol Optimization for Direct Reprogramming of Primary Human Fibroblast into Induced Striatal Neurons

by Nina Kraskovskaya, Anastasia Bolshakova, Mikhail Khotin, Ilya Bezprozvanny and Natalia Mikhailova

Int. J. Mol. Sci. 2023, 24(7), 6799; https://doi.org/10.3390/ijms24076799 - 5 Apr 2023

Cited by 7 | Viewed by 3387

Abstract

The modeling of neuropathology on induced neurons obtained by cell reprogramming technologies can fill a gap between clinical trials and studies on model organisms for the development of treatment strategies for neurodegenerative diseases. Patient-specific models based on patients’ cells play an important role [...] Read more.

The modeling of neuropathology on induced neurons obtained by cell reprogramming technologies can fill a gap between clinical trials and studies on model organisms for the development of treatment strategies for neurodegenerative diseases. Patient-specific models based on patients’ cells play an important role in such studies. There are two ways to obtain induced neuronal cells. One is based on induced pluripotent stem cells. The other is based on direct reprogramming, which allows us to obtain mature neuronal cells from adult somatic cells, such as dermal fibroblasts. Moreover, the latter method makes it possible to better preserve the age-related aspects of neuropathology, which is valuable for diseases that occur with age. However, direct methods of reprogramming have a significant drawback associated with low cell viability during procedures. Furthermore, the number of reprogrammable neurons available for morphological and functional studies is limited by the initial number of somatic cells. In this article, we propose modifications of a previously developed direct reprogramming method, based on the combination of microRNA and transcription factors, which allowed us to obtain a population of functionally active induced striatal neurons (iSNs) with a high efficiency. We also overcame the problem of the presence of multinucleated neurons associated with the cellular division of starting fibroblasts. Synchronization cells in the G1 phase increased the homogeneity of the fibroblast population, increased the survival rate of induced neurons, and eliminated the presence of multinucleated cells at the end of the reprogramming procedure. We have demonstrated that iSNs are functionally active and able to form synaptic connections in co-cultures with mouse cortical neurons. The proposed modifications can also be used to obtain a population of other induced neuronal types, such as motor and dopaminergic ones, by selecting transcription factors that determine differentiation into a region-specific neuron. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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13 pages, 2278 KiB

Open AccessArticle

Corneal Reconstruction with EGFP-Labelled Limbal Mesenchymal Stem Cells in a Rabbit Model of Limbal Stem Cell Deficiency

by Julia I. Khorolskaya, Daria A. Perepletchikova, Kirill E. Zhurenkov, Daniel V. Kachkin, Aleksandr A. Rubel, Miralda I. Blinova and Natalia A. Mikhailova

Int. J. Mol. Sci. 2023, 24(6), 5431; https://doi.org/10.3390/ijms24065431 - 12 Mar 2023

Cited by 1 | Viewed by 2497

Abstract

Ocular surface reconstruction is essential for treating corneal epithelial defects and vision recovery. Stem cell-based therapy demonstrates promising results but requires further research to elucidate stem cell survival, growth, and differentiation after transplantation in vivo. This study examined the corneal reconstruction promoted by [...] Read more.

Ocular surface reconstruction is essential for treating corneal epithelial defects and vision recovery. Stem cell-based therapy demonstrates promising results but requires further research to elucidate stem cell survival, growth, and differentiation after transplantation in vivo. This study examined the corneal reconstruction promoted by EGFP-labeled limbal mesenchymal stem cells (L-MSCs-EGFP) and their fate after transplantation. EGFP labeling allowed us to evaluate the migration and survival rates of the transferred cells. L-MSCs-EGFP seeded onto decellularized human amniotic membrane (dHAM) were transplanted into rabbits with a modeled limbal stem cell deficiency. The localization and viability of the transplanted cells in animal tissue were analyzed using histology, immunohistochemistry, and confocal microscopy up to 3 months after transplantation. EGFP-labeled cells remained viable for the first 14 days after transplantation. By the 90th day, epithelialization of the rabbit corneas reached 90%, but the presence of viable labeled cells was not observed within the newly formed epithelium. Although labeled cells demonstrated low survivability in host tissue, the squamous corneal-like epithelium was partially restored by the 30th day after transplantation of the tissue-engineered graft. Overall, this study paves the way for further optimization of transplantation conditions and studying the mechanisms of corneal tissue restoration. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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Review

Jump to: Editorial, Research, Other

17 pages, 800 KiB

Open AccessReview

Gene-Activated Materials in Regenerative Dentistry: Narrative Review of Technology and Study Results

by Olga Krasilnikova, Anna Yakimova, Sergey Ivanov, Dmitri Atiakshin, Andrey A. Kostin, Dmitry Sosin, Peter Shegay, Andrey D. Kaprin and Ilya Klabukov

Int. J. Mol. Sci. 2023, 24(22), 16250; https://doi.org/10.3390/ijms242216250 - 13 Nov 2023

Cited by 3 | Viewed by 1990

Abstract

Treatment of a wide variety of defects in the oral and maxillofacial regions requires the use of innovative approaches to achieve best outcomes. One of the promising directions is the use of gene-activated materials (GAMs) that represent a combination of tissue engineering and [...] Read more.

Treatment of a wide variety of defects in the oral and maxillofacial regions requires the use of innovative approaches to achieve best outcomes. One of the promising directions is the use of gene-activated materials (GAMs) that represent a combination of tissue engineering and gene therapy. This approach implies that biocompatible materials will be enriched with gene-carrying vectors and implanted into the defect site resulting in transfection of the recipient’s cells and secretion of encoded therapeutic protein in situ. GAMs may be presented in various designs depending on the type of material, encoded protein, vector, and way of connecting the vector and the material. Thus, it is possible to choose the most suitable GAM design for the treatment of a particular pathology. The use of plasmids for delivery of therapeutic genes is of particular interest. In the present review, we aimed to delineate the principle of work and various designs of plasmid-based GAMs and to highlight results of experimental and clinical studies devoted to the treatment of periodontitis, jaw bone defects, teeth avulsion, and other pathologies in the oral and maxillofacial regions. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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32 pages, 736 KiB

Open AccessReview

Clinical Potential of Cellular Material Sources in the Generation of iPSC-Based Products for the Regeneration of Articular Cartilage

by Artem Eremeev, Arina Pikina, Yevgeny Ruchko and Alexandra Bogomazova

Int. J. Mol. Sci. 2023, 24(19), 14408; https://doi.org/10.3390/ijms241914408 - 22 Sep 2023

Cited by 4 | Viewed by 1823

Abstract

Inflammatory joint diseases, among which osteoarthritis and rheumatoid arthritis are the most common, are characterized by progressive degeneration of the cartilage tissue, resulting in the threat of limited or lost joint functionality in the absence of treatment. Currently, treating these diseases is difficult, [...] Read more.

Inflammatory joint diseases, among which osteoarthritis and rheumatoid arthritis are the most common, are characterized by progressive degeneration of the cartilage tissue, resulting in the threat of limited or lost joint functionality in the absence of treatment. Currently, treating these diseases is difficult, and a number of existing treatment and prevention measures are not entirely effective and are complicated by the patients’ conditions, the multifactorial nature of the pathology, and an incomplete understanding of the etiology. Cellular technologies based on induced pluripotent stem cells (iPSCs) can provide a vast cellular resource for the production of artificial cartilage tissue for replacement therapy and allow the possibility of a personalized approach. However, the question remains whether a number of etiological abnormalities associated with joint disease are transmitted from the source cell to iPSCs and their chondrocyte derivatives. Some data state that there is no difference between the iPSCs and their derivatives from healthy and sick donors; however, there are other data indicating a dissimilarity. Therefore, this topic requires a thorough study of the differentiation potential of iPSCs and the factors influencing it, the risk factors associated with joint diseases, and a comparative analysis of the characteristics of cells obtained from patients. Together with cultivation optimization methods, these measures can increase the efficiency of obtaining cell technology products and make their wide practical application possible. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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20 pages, 1019 KiB

Open AccessReview

Blank Spots in the Map of Human Skin: The Challenge for Xenotransplantation

by Olga L. Cherkashina, Elena I. Morgun, Alexandra L. Rippa, Anastasiya V. Kosykh, Alexander V. Alekhnovich, Aleksey B. Stoliarzh, Vasiliy V. Terskikh, Ekaterina A. Vorotelyak and Ekaterina P. Kalabusheva

Int. J. Mol. Sci. 2023, 24(16), 12769; https://doi.org/10.3390/ijms241612769 - 14 Aug 2023

Cited by 1 | Viewed by 1790

Abstract

Most of the knowledge about human skin homeostasis, development, wound healing, and diseases has been accumulated from human skin biopsy analysis by transferring from animal models and using different culture systems. Human-to-mouse xenografting is one of the fundamental approaches that allows the skin [...] Read more.

Most of the knowledge about human skin homeostasis, development, wound healing, and diseases has been accumulated from human skin biopsy analysis by transferring from animal models and using different culture systems. Human-to-mouse xenografting is one of the fundamental approaches that allows the skin to be studied in vivo and evaluate the ongoing physiological processes in real time. Humanized animals permit the actual techniques for tracing cell fate, clonal analysis, genetic modifications, and drug discovery that could never be employed in humans. This review recapitulates the novel facts about mouse skin self-renewing, regeneration, and pathology, raises issues regarding the gaps in our understanding of the same options in human skin, and postulates the challenges for human skin xenografting. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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22 pages, 1880 KiB

Open AccessReview

Practical Use of Immortalized Cells in Medicine: Current Advances and Future Perspectives

by Nikita Voloshin, Pyotr Tyurin-Kuzmin, Maxim Karagyaur, Zhanna Akopyan and Konstantin Kulebyakin

Int. J. Mol. Sci. 2023, 24(16), 12716; https://doi.org/10.3390/ijms241612716 - 12 Aug 2023

Cited by 9 | Viewed by 4215

Abstract

In modern science, immortalized cells are not only a convenient tool in fundamental research, but they are also increasingly used in practical medicine. This happens due to their advantages compared to the primary cells, such as the possibility to produce larger amounts of [...] Read more.

In modern science, immortalized cells are not only a convenient tool in fundamental research, but they are also increasingly used in practical medicine. This happens due to their advantages compared to the primary cells, such as the possibility to produce larger amounts of cells and to use them for longer periods of time, the convenience of genetic modification, the absence of donor-to-donor variability when comparing the results of different experiments, etc. On the other hand, immortalization comes with drawbacks: possibilities of malignant transformation and/or major phenotype change due to genetic modification itself or upon long-term cultivation appear. At first glance, such issues are huge hurdles in the way of immortalized cells translation into medicine. However, there are certain ways to overcome such barriers that we describe in this review. We determined four major areas of usage of immortalized cells for practical medicinal purposes, and each has its own means to negate the drawbacks associated with immortalization. Moreover, here we describe specific fields of application of immortalized cells in which these problems are of much lesser concern, for example, in some cases where the possibility of malignant growth is not there at all. In general, we can conclude that immortalized cells have their niches in certain areas of practical medicine where they can successfully compete with other therapeutic approaches, and more preclinical and clinical trials with them should be expected. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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19 pages, 2535 KiB

Open AccessReview

Effect of Hepatic Pathology on Liver Regeneration: The Main Metabolic Mechanisms Causing Impaired Hepatic Regeneration

by Svetlana Rodimova, Artem Mozherov, Vadim Elagin, Maria Karabut, Ilya Shchechkin, Dmitry Kozlov, Dmitry Krylov, Alena Gavrina, Nikolai Bobrov, Vladimir Zagainov, Elena Zagaynova and Daria Kuznetsova

Int. J. Mol. Sci. 2023, 24(11), 9112; https://doi.org/10.3390/ijms24119112 - 23 May 2023

Cited by 7 | Viewed by 5402

Abstract

Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of [...] Read more.

Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of liver regeneration can occur in the presence of concomitant hepatic pathology, which is a key factor reducing the liver’s regenerative potential. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or to directly stimulate liver regeneration. This review describes the known mechanisms of normal liver regeneration and factors that reduce its regenerative potential, primarily at the level of hepatocyte metabolism, in the presence of concomitant hepatic pathology. We also briefly discuss promising strategies for stimulating liver regeneration and those concerning methods for assessing the regenerative potential of the liver, especially intraoperatively. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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Other

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12 pages, 5775 KiB

Open AccessBrief Report

IPSC-Derived Astrocytes Contribute to In Vitro Modeling of Parkinson’s Disease Caused by the GBA1 N370S Mutation

by Elena S. Yarkova, Elena V. Grigor’eva, Sergey P. Medvedev, Sophia V. Pavlova, Suren M. Zakian and Anastasia A. Malakhova

Int. J. Mol. Sci. 2024, 25(1), 327; https://doi.org/10.3390/ijms25010327 - 26 Dec 2023

Cited by 3 | Viewed by 1658

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that ranks second in prevalence after Alzheimer’s disease. The number of PD diagnoses increases annually. Nevertheless, modern PD treatments merely mitigate symptoms rather than preventing neurodegeneration progression. The creation of an appropriate model to thoroughly study [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder that ranks second in prevalence after Alzheimer’s disease. The number of PD diagnoses increases annually. Nevertheless, modern PD treatments merely mitigate symptoms rather than preventing neurodegeneration progression. The creation of an appropriate model to thoroughly study the mechanisms of PD pathogenesis remains a current challenge in biomedicine. Recently, there has been an increase in data regarding the involvement of not only dopaminergic neurons of the substantia nigra but also astrocytes in the pathogenesis of PD. Cell models based on induced pluripotent stem cells (iPSCs) and their differentiated derivatives are a useful tool for studying the contribution and interaction of these two cell types in PD. Here, we generated two iPSC lines, ICGi034-B and ICGi034-C, by reprogramming peripheral blood mononuclear cells of a patient with a heterozygous mutation c.1226A>G (p.N370S) in the GBA1 gene by non-integrating episomal vectors encoding OCT4, KLF4, L-MYC, SOX2, LIN28, and mp53DD. The iPSC lines demonstrate the expression of pluripotency markers and are capable of differentiating into three germ layers. We differentiated the ICGi034-B and ICGi034-C iPSC lines into astrocytes. This resulting cell model can be used to study the involvement of astrocytes in the pathogenesis of GBA-associated PD. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the V National Congress of Regenerative Medicine (2022))

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