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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 28303

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Special Issue Editor

Dr. Paulina Borkowska

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Guest Editor

Department of Medical Genetics, Medical University of Silesia, 41-200 Sosnowiec, Poland
Interests: MSC differentiation; lentiviral transduction; genes’ expression; genes’ overexpression; neuronal pathway; regenerative medicine

Special Issue Information

Dear Colleagues,

Mesenchymal stem cells (MSC) have great potential when it comes to using them in regenerative medicine, specifically in cell therapy. A big advantage of MSC is the fact that they are easily isolated from various tissues; they have a low tumorigenic potential and are characterized by a high degree of plasticity. Their low expression of MHC molecules makes it possible to use them in allogeneic transplants. MSC easily differentiate into the different cell types from all three germ layers. Experimental studies have shown that both naive—undifferentiated MSC and in vitro differentiated MSC, e.g., into neural progenitors, are sensitive to the “stress” that is associated with the transplant procedure. In addition, their basic nature does not spontaneously transform into functional specialized cells. As a result, transplant cells that have been weakened by the transplant procedure die in the foreign brain environment. This Special Issue will present state-of-the-art studies on the differentiation protocol of MSC and/or their derivatives in the context of improving post-transplant survival and the efficiency of differentiation into specialized cells of a particular type. The potential topics to be covered include (1) optimization of the in vitro MSC differentiation process, (2) genetic modification of MSC and (3) properties’ investigation of the in vitro differentiated MSC and/or genetically modified MSC.

Dr. Paulina Borkowska
Guest Editor

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Keywords

MSC differentiation
lentiviral transduction
genetically modified MSC
regenerative potential of MSC
MSC therapy

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Published Papers (11 papers)

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Research

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18 pages, 4582 KiB

Open AccessArticle

Derivation of Limbal Stem Cells from Human Adult Mesenchymal Stem Cells for the Treatment of Limbal Stem Cell Deficiency

by Marta Cadenas-Martin, Francisco Arnalich-Montiel and Maria P De Miguel

Int. J. Mol. Sci. 2023, 24(3), 2350; https://doi.org/10.3390/ijms24032350 - 25 Jan 2023

Cited by 2 | Viewed by 2596

Abstract

Approximately 10 million individuals have blindness due to limbal stem cell (LSCs) deficiency, one of the most challenging problems in ophthalmology. To replenish the LSC pool, an autologous extraocular cell source is appropriate, thereby avoiding the risk of immune rejection, the need for immunosuppression and the risk of damaging the contralateral eye. In recent years, adipose-derived mesenchymal stem cells (ADSCs) have been a key element in ocular regenerative medicine. In this study, we developed a protocol for deriving human LSCs from ADSCs compatible with the standard carrier human amniotic membrane, helping provide a stem cell pool capable of maintaining proper corneal epithelial homeostasis. The best protocol included an ectodermal induction step by culturing ADSCs with media containing fetal bovine serum, transforming growth factor-β inhibitor SB-505124, Wnt inhibitor IWP-2 and FGF2 for 7 days, followed by an LSC induction step of culture in modified supplemental hormonal epithelial medium supplemented with pigment epithelium-derived factor and keratinocyte growth factor for 10 additional days. The optimal differentiation efficiency was achieved when cells were cultured in this manner over vitronectin coating, resulting in up to 50% double-positive αp63/BMI-1 cells. The results of this project will benefit patients with LSC deficiency, aiding the restoration of vision. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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16 pages, 1535 KiB

Open AccessArticle

Equine Muscle Derived Mesenchymal Stem Cells Loaded with Water-Soluble Curcumin: Modulation of Neutrophil Activation and Enhanced Protection against Intracellular Oxidative Attack

by Thierry Franck, Justine Ceusters, Hélène Graide, Ariane Niesten, Julien Duysens, Ange Mouithys Mickalad and Didier Serteyn

Int. J. Mol. Sci. 2023, 24(2), 1030; https://doi.org/10.3390/ijms24021030 - 5 Jan 2023

Cited by 1 | Viewed by 1653

Abstract

We investigated the antioxidant potential of equine mesenchymal stem cells derived from muscle microbiopsies (mdMSCs), loaded by a water-soluble curcumin lysinate incorporated into hydroxypropyl-β-cyclodextrin (NDS27). The cell loading was rapid and dependent on NDS27 dosage (14, 7, 3.5 and 1 µM). The immunomodulatory capacity of loaded mdMSCs was evaluated by ROS production, on active and total myeloperoxidase (MPO) degranulation and neutrophil extracellular trap (NET) formation after neutrophil stimulation. The intracellular protection of loaded cells was tested by an oxidative stress induced by cumene hydroperoxide. Results showed that 10 min of mdMSC loading with NDS27 did not affect their viability while reducing their metabolism. NDS27 loaded cells in presence of 14, 7 µM NDS27 inhibited more intensively the ROS production, the activity of the MPO released and bound to the NET after neutrophil stimulation. Furthermore, loaded cells powerfully inhibited intracellular ROS production induced by cumene as compared to control cells or cyclodextrin-loaded cells. Our results showed that the loading of mdMSCs with NDS27 significantly improved their antioxidant potential against the oxidative burst of neutrophil and protected them against intracellular ROS production. The improved antioxidant protective capacity of loaded mdMSCs could be applied to target inflammatory foci involving neutrophils. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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13 pages, 2432 KiB

Open AccessArticle

Induction of Corneal Endothelial-like Cells from Mesenchymal Stem Cells of the Umbilical Cord

by Eun Ah Ye, Ho Seok Chung, Yoonkyung Park, Jeong Hye Sunwoo, Whanseo Lee, Jin Kim, Hungwon Tchah, Hun Lee and Jae Yong Kim

Int. J. Mol. Sci. 2022, 23(23), 15408; https://doi.org/10.3390/ijms232315408 - 6 Dec 2022

Cited by 5 | Viewed by 1863

Abstract

Because of the limited differentiation capacity of human corneal endothelial cells (CECs), stem cells have emerged as a potential remedy for corneal endothelial dysfunction (CED). This study aimed to demonstrate the differentiation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) into CECs and to investigate the efficacy of MSC-induced CEC injection into the anterior chamber in a rabbit model of CED. Human UC-MSCs were differentiated into CECs using medium containing glycogen synthase kinase 3β inhibitor and two types of Rho-associated protein kinase inhibitors. In the MSC-induced CECs, CEC-specific proteins were identified through immunohistochemistry and changes in CEC-specific gene expressions over time were confirmed through quantitative RT-PCR. When MSC-induced CECs were injected into a rabbit model of CED, corneal opacity and neovascularization were improved compared with the non-transplanted control or MSC injection group. We also confirmed that MSC-induced CECs were well engrafted as evidenced by human mitochondrial DNA in the central cornea of an animal model. Therefore, we demonstrated the differentiation of UC-MSCs into CECs in vitro and demonstrated the clinical efficacy of MSC-induced CEC injection, providing in vivo evidence that MSC-induced CECs have potential as a treatment option for CED. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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14 pages, 2679 KiB

Open AccessArticle

Tiron Has Negative Effects on Osteogenic Differentiation via Mitochondrial Dysfunction in Human Periosteum-Derived Cells

by Jin-Ho Park, Eun-Byeol Koh, Young-Jin Seo, Hye-Seong Oh, Ju-Yeong Won, Sun-Chul Hwang and June-Ho Byun

Int. J. Mol. Sci. 2022, 23(22), 14040; https://doi.org/10.3390/ijms232214040 - 14 Nov 2022

Cited by 2 | Viewed by 1865

Abstract

Tiron is a potent antioxidant that counters the pathological effects of reactive oxygen species (ROS) production due to oxidative stress in various cell types. We examined the effects of tiron on mitochondrial function and osteoblastic differentiation in human periosteum-derived cells (hPDCs). Tiron increased mitochondrial activity and decreased senescence-associated β-galactosidase activity in hPDCs; however, it had a detrimental effect on osteoblastic differentiation by reducing alkaline phosphatase (ALP) activity and alizarin red-positive mineralization, regardless of H₂O₂ treatment. Osteoblast-differentiating hPDCs displayed increased ROS production compared with non-differentiating hPDCs, and treatment with tiron reduced ROS production in the differentiating cells. Antioxidants decreased the rates of oxygen consumption and ATP production, which are increased in hPDCs during osteoblastic differentiation. In addition, treatment with tiron reduced the levels of most mitochondrial proteins, which are increased in hPDCs during culture in osteogenic induction medium. These results suggest that tiron exerts negative effects on the osteoblastic differentiation of hPDCs by causing mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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14 pages, 2375 KiB

Open AccessArticle

The Structural Interactions of Molecular and Fibrillar Collagen Type I with Fibronectin and Its Role in the Regulation of Mesenchymal Stem Cell Morphology and Functional Activity

by Yuliya Nashchekina, Pavel Nikonov, Nikita Prasolov, Maksim Sulatsky, Alina Chabina and Alexey Nashchekin

Int. J. Mol. Sci. 2022, 23(20), 12577; https://doi.org/10.3390/ijms232012577 - 20 Oct 2022

Cited by 7 | Viewed by 2653

Abstract

The observed differences in the structure of native tissue and tissue formed in vitro cause the loss of functional activity of cells cultured in vitro. The lack of fundamental knowledge about the protein mechanism interactions limits the ability to effectively create in vitro native tissue. Collagen is able to spontaneously assemble into fibrils in vitro, but in vivo, other proteins, for example fibronectin, have a noticeable effect on this process. The molecular or fibrillar structure of collagen plays an equally important role. Therefore, we studied the interaction of the molecular and fibrillar structure of collagen with fibronectin. Atomic force and transmission electron microscopy showed that the presence of fibronectin does not affect the native structure and diameter of collagen fibrils. Confocal microscopy demonstrated that the collagen structure affects the cell morphology. Cells are better spread on molecular collagen compared with cells cultured on fibrillar collagen. Fibronectin promotes the formation of a large number of focal contacts, while in combination with collagen of both forms, its effect is leveled. Thus, understanding the mechanisms of the relationship between the protein structure and composition will effectively manage the creation in vitro of a new tissue with native properties. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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15 pages, 2508 KiB

Open AccessArticle

Mesenchymal Stem Cells and Formyl Peptide Receptor 2 Activity in Hyperoxia-Induced Lung Injury in Newborn Mice

by Young Eun Kim, So Yoon Ahn, Dong Kyung Sung, Yun Sil Chang and Won Soon Park

Int. J. Mol. Sci. 2022, 23(18), 10604; https://doi.org/10.3390/ijms231810604 - 13 Sep 2022

Cited by 1 | Viewed by 2056

Abstract

Formyl peptide receptor (FPR) 2 is known to play a critical role in regulating inflammation, including either the pro-inflammatory or pro-resolving effects. However, its role in neonatal hyperoxia-induced lung injury has not been delineated. In this study, we investigate whether mesenchymal stem cells (MSCs) attenuate hyperoxia-induced neonatal lung injury by regulating FPR2 activity. We observed a significant increase in FPR2 levels in alveolar macrophages (RAW264.7 cells) after H₂O₂-induced stress, which decreased after MSC treatment. In the H₂O₂-induction model, increased levels of inflammatory cytokines (IL-1α and TNF-α) were significantly reduced in RAW264.7 cells after treatment with WRW4, an inhibitor of FPR2, or MSCs. Viability of lung epithelial cells and endothelial cells was significantly improved when cultured in the conditioned media of RAW264.7 cells treated with WRW4 or MSCs, compared to when cultured in the conditioned media of control RAW265.7 cells exposed to H₂O₂. For the in vivo study, wild-type and FPR2 knockout (FPR2^−/−) C57/BL6 mouse pups were randomly exposed to 80% oxygen or room air from postnatal day (P) 1 to P14. At P5, 2 × 10⁵ MSCs were transplanted intratracheally. MSCs reduced the elevated FPR2 activity at P7 and improved the decreased FPR2 activity as well as the increased immuno-stained FPR2 activity in alveolar macrophages in hyperoxic lungs at P14. Both FPR2^−/− and MSCs similarly attenuated impaired alveolarization and angiogenesis, and increased apoptosis and inflammation of hyperoxic lungs without synergistic effects. Our findings suggest that the protective effects of MSCs in hyperoxic lung injury might be related to indirect modulation of FPR2 activity, at least of alveolar macrophages in neonatal mice. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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12 pages, 2383 KiB

Open AccessArticle

Cobalt Ferrite Magnetic Nanoparticles for Tracing Mesenchymal Stem Cells in Tissue: A Preliminary Study

by Željka Večerić-Haler, Nika Kojc, Karmen Wechtersbach, Martina Perše and Andreja Erman

Int. J. Mol. Sci. 2022, 23(15), 8738; https://doi.org/10.3390/ijms23158738 - 5 Aug 2022

Viewed by 1787

Abstract

Therapy with mesenchymal stem cells (MSCs) is promising in many diseases. Evaluation of their efficacy depends on adequate follow-up of MSCs after transplantation. Several studies have shown that MSCs can be labeled and subsequently visualized with magnetic nanoparticles (NPs). We investigated the homing of MSCs labeled with magnetic cobalt ferrite NPs in experimentally induced acute kidney injury in mice. To explore the homing of MSCs after systemic infusion into mice, we developed a pre-infusion strategy for optimal tracing and identification of MSCs with polyacrylic acid-coated cobalt ferrite (CoFe₂O₄) NPs by light and transmission electron microscopy (TEM) in various organs of mice with cisplatin-induced acute kidney injury and control mice. By correlative microscopy, we detected MSCs labeled with NPs in the lungs, spleen, kidney, and intestine of cisplatin-treated mice and in the lungs and spleen of control mice. Our results confirm that labeling MSCs with metal NPs did not affect the ultrastructure of MSCs and their ability to settle in various organs. This study demonstrates the usefulness of cobalt ferrite NPs in ex vivo visualization of MSCs and offers correlative microscopy as a useful method in routine histopathology laboratories for tracing MSCs in paraffin-embedded tissue. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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10 pages, 3868 KiB

Open AccessArticle

Anti-Arthritogenic Property of Interleukin 10-Expressing Human Amniotic MSCs Generated by Gene Editing in Collagen-Induced Arthritis

by Dong-Sik Chae, Young-Jin Park and Sung-Whan Kim

Int. J. Mol. Sci. 2022, 23(14), 7913; https://doi.org/10.3390/ijms23147913 - 18 Jul 2022

Cited by 7 | Viewed by 1948

Abstract

Although stem cells are promising tools for the treatment of arthritis, their therapeutic effects remain controversial. In this study, we investigated the therapeutic properties of interleukin (IL)-10-overexpressing human amniotic mesenchymal stem cells (AMMs) generated via gene editing in a collagen-induced mouse model. IL-10 was inserted into the genomic loci of AMMs via transcription activator-like effector nucleases. In vitro immunomodulatory effects of IL-10-overexpressing AMMs (AMM/I) were evaluated and their anti-arthritogenic properties were determined in collagen-induced arthritis (CIA) mice. Transplantation of AMM/I attenuates CIA progression. In addition, the regulatory T cell population was increased, while T helper-17 cell activation was suppressed by AMM/I administration in CIA mice. Consistently, AMM/I injection increased proteoglycan expression, while reducing inflammation and the expression levels of the pro-inflammatory factors, IL-1 β, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor- α, in joint tissues. In conclusion, use of IL-10-edited human AMM/I may be a novel therapeutic strategy for the treatment of arthritis. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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12 pages, 2047 KiB

Open AccessArticle

Intratracheal Transplantation of Mesenchymal Stem Cells Attenuates Hyperoxia-Induced Microbial Dysbiosis in the Lungs, Brain, and Gut in Newborn Rats

by So Yoon Ahn, Dong Kyung Sung, Yun Sil Chang and Won Soon Park

Int. J. Mol. Sci. 2022, 23(12), 6601; https://doi.org/10.3390/ijms23126601 - 13 Jun 2022

Cited by 4 | Viewed by 2249

Abstract

We attempted to determine whether intratracheal (IT) transplantation of mesenchymal stem cells (MSCs) could simultaneously attenuate hyperoxia-induced lung injuries and microbial dysbiosis of the lungs, brain, and gut in newborn rats. Newborn rats were exposed to hyperoxia (90% oxygen) for 14 days. Human umbilical cord blood-derived MSCs (5 × 10⁵) were transplanted via the IT route on postnatal day (P) five. At P14, the lungs were harvested for histological, biochemical, and microbiome analyses. Bacterial 16S ribosomal RNA genes from the lungs, brain, and large intestine were amplified, pyrosequenced, and analyzed. IT transplantation of MSCs simultaneously attenuated hyperoxia-induced lung inflammation and the ensuing injuries, as well as the dysbiosis of the lungs, brain, and gut. In correlation analyses, lung interleukin-6 (IL-6) levels were significantly positively correlated with the abundance of Proteobacteria in the lungs, brain, and gut, and it was significantly inversely correlated with the abundance of Firmicutes in the gut and lungs and that of Bacteroidetes in the lungs. In conclusion, microbial dysbiosis in the lungs, brain, and gut does not cause but is caused by hyperoxic lung inflammation and ensuing injuries, and IT transplantation of MSCs attenuates dysbiosis in the lungs, brain, and gut, primarily by their anti-oxidative and anti-inflammatory effects. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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Review

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22 pages, 2414 KiB

Open AccessReview

Bone Marrow-Derived Mesenchymal Stem Cell Implants for the Treatment of Focal Chondral Defects of the Knee in Animal Models: A Systematic Review and Meta-Analysis

by Ernest Lee, Ilias Ektor Epanomeritakis, Victor Lu and Wasim Khan

Int. J. Mol. Sci. 2023, 24(4), 3227; https://doi.org/10.3390/ijms24043227 - 6 Feb 2023

Cited by 12 | Viewed by 2711

Abstract

Osteoarthritis remains an unfortunate long-term consequence of focal cartilage defects of the knee. Associated with functional loss and pain, it has necessitated the exploration of new therapies to regenerate cartilage before significant deterioration and subsequent joint replacement take place. Recent studies have investigated a multitude of mesenchymal stem cell (MSC) sources and polymer scaffold compositions. It is uncertain how different combinations affect the extent of integration of native and implant cartilage and the quality of new cartilage formed. Implants seeded with bone marrow-derived MSCs (BMSCs) have demonstrated promising results in restoring these defects, largely through in vitro and animal studies. A PRISMA systematic review and meta-analysis was conducted using five databases (PubMed, MEDLINE, EMBASE, Web of Science, and CINAHL) to identify studies using BMSC-seeded implants in animal models of focal cartilage defects of the knee. Quantitative results from the histological assessment of integration quality were extracted. Repair cartilage morphology and staining characteristics were also recorded. Meta-analysis demonstrated that high-quality integration was achieved, exceeding that of cell-free comparators and control groups. This was associated with repair tissue morphology and staining properties which resembled those of native cartilage. Subgroup analysis showed better integration outcomes for studies using poly-glycolic acid-based scaffolds. In conclusion, BMSC-seeded implants represent promising strategies for the advancement of focal cartilage defect repair. While a greater number of studies treating human patients is necessary to realize the full clinical potential of BMSC therapy, high-quality integration scores suggest that these implants could generate repair cartilage of substantial longevity. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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32 pages, 2672 KiB

Open AccessReview

Skin-Derived ABCB5⁺ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine

by Elke Niebergall-Roth, Natasha Y. Frank, Christoph Ganss, Markus H. Frank and Mark A. Kluth

Int. J. Mol. Sci. 2023, 24(1), 66; https://doi.org/10.3390/ijms24010066 - 21 Dec 2022

Cited by 7 | Viewed by 5527

Abstract

The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5⁺ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5⁺ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5⁺ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5⁺ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5⁺ MSCs (AMESANAR^®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany. Full article

(This article belongs to the Special Issue Advance in Mesenchymal Stem Cells)

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