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23 pages, 6528 KiB

Open AccessArticle

Immunogenic Properties of MVs Containing Structural Hantaviral Proteins: An Original Study

by Layaly Shkair, Ekaterina Evgenevna Garanina, Ekaterina Vladimirovna Martynova, Alena Igorevna Kolesnikova, Svetlana Sergeevna Arkhipova, Angelina Andreevna Titova, Albert Anatolevich Rizvanov and Svetlana Francevna Khaiboullina

Pharmaceutics 2022, 14(1), 93; https://doi.org/10.3390/pharmaceutics14010093 - 01 Jan 2022

Cited by 2 | Viewed by 2270

Abstract

Hemorrhagic fever with renal syndrome (HFRS) is an emerging infectious disease that remains a global public health threat. The highest incidence rate is among zoonotic disease cases in Russia. Most cases of HFRS are reported in the Volga region of Russia, which commonly [...] Read more.

Hemorrhagic fever with renal syndrome (HFRS) is an emerging infectious disease that remains a global public health threat. The highest incidence rate is among zoonotic disease cases in Russia. Most cases of HFRS are reported in the Volga region of Russia, which commonly identifies the Puumala virus (PUUV) as a pathogen. HFRS management is especially challenging due to the lack of specific treatments and vaccines. This study aims to develop new approaches for HFRS prevention. Our goal is to test the efficacy of microvesicles (MVs) as PUUV nucleocapsid (N) and glycoproteins (Gn/Gc) delivery vehicles. Our findings show that MVs could deliver the PUUV N and Gn/Gc proteins in vitro. We have also demonstrated that MVs loaded with PUUV proteins could elicit a specific humoral and cellular immune response in vivo. These data suggest that an MV-based vaccine could control HFRS. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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20 pages, 3279 KiB

Open AccessArticle

Effective Osteogenic Priming of Mesenchymal Stem Cells through LNA-ASOs-Mediated Sfrp1 Gene Silencing

by Daniel García-Sánchez, Alberto González-González, Patricia García-García, Ricardo Reyes, María Isabel Pérez-Núñez, José A. Riancho, Carmen Évora, José Carlos Rodríguez-Rey and Flor M. Pérez-Campo

Pharmaceutics 2021, 13(8), 1277; https://doi.org/10.3390/pharmaceutics13081277 - 17 Aug 2021

Cited by 4 | Viewed by 2237

Abstract

Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that Smurf1 silencing [...] Read more.

Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that Smurf1 silencing by using Locked Nucleic Acid-Antisense Oligonucleotides, in combination with a scaffold that sustainably releases low doses of BMP-2, was able to increase the osteogenic potential of MSCs in the presence of BMP-2 doses significantly smaller than those currently used in the clinic. This would potentially allow an important reduction in this protein in MSs-based treatments, and thus of the side effects linked to its administration. We have further improved this system by specifically targeting the Wnt pathway modulator Sfrp1. This approach not only increases MSC bone regeneration efficiency, but is also able to induce osteogenic differentiation in osteoporotic human MSCs, bypassing the need for BMP-2 induction, underscoring the regenerative potential of this system. Achieving successful osteogenesis with the sole use of LNA-ASOs, without the need of administering pro-osteogenic factors such as BMP-2, would not only reduce the cost of treatments, but would also open the possibility of targeting these LNA-ASOs specifically to MSCs in the bone marrow, allowing us to treat systemic bone loss such as that associated with osteoporosis. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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13 pages, 2365 KiB

Open AccessArticle

Design and Validation of a Process Based on Cationic Niosomes for Gene Delivery into Novel Urine-Derived Mesenchymal Stem Cells

by Yerai Vado, Gustavo Puras, Melania Rosique, Cesar Martin, Jose Luis Pedraz, Shifa Jebari-Benslaiman, Marian M. de Pancorbo, Jon Zarate and Guiomar Perez de Nanclares

Pharmaceutics 2021, 13(5), 696; https://doi.org/10.3390/pharmaceutics13050696 - 11 May 2021

Cited by 3 | Viewed by 2061

Abstract

Background: Mesenchymal stem cells (MSCs) are stem cells present in adult tissues. They can be cultured, have great growth capacity, and can differentiate into several cell types. The isolation of urine-derived mesenchymal stem cells (hUSCs) was recently described. hUSCs present additional benefits in [...] Read more.

Background: Mesenchymal stem cells (MSCs) are stem cells present in adult tissues. They can be cultured, have great growth capacity, and can differentiate into several cell types. The isolation of urine-derived mesenchymal stem cells (hUSCs) was recently described. hUSCs present additional benefits in the fact that they can be easily obtained noninvasively. Regarding gene delivery, nonviral vectors based on cationic niosomes have been used and are more stable and have lower immunogenicity than viral vectors. However, their transfection efficiency is low and in need of improvement. Methods: We isolated hUSCs from urine, and the cell culture was tested and characterized. Different cationic niosomes were elaborated using reverse-phase evaporation, and they were physicochemically characterized. Then, they were screened into hUSCs for transfection efficiency, and their internalization was evaluated. Results: GPxT-CQ at a lipid/DNA ratio of 5:1 (w/w) had the best transfection efficiency. Intracellular localization studies confirmed that nioplexes entered mainly via caveolae-mediated endocytosis. Conclusions: In conclusion, we established a protocol for hUSC isolation and their transfection with cationic niosomes, which could have relevant clinical applications such as in gene therapy. This methodology could also be used for creating cellular models for studying and validating pathogenic genetic variants, and even for performing functional studies. Our study increases knowledge about the internalization of tested cationic niosomes in these previously unexplored cells. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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16 pages, 4072 KiB

Open AccessArticle

Hyaluronic Acid Supplement as a Chondrogenic Adjuvant in Promoting the Therapeutic Efficacy of Stem Cell Therapy in Cartilage Healing

by Chin-Chean Wong, Shi-Da Sheu, Pei-Chun Chung, Yi-Yen Yeh, Chih-Hwa Chen, Yen-Wei Chang and Tzong-Fu Kuo

Pharmaceutics 2021, 13(3), 432; https://doi.org/10.3390/pharmaceutics13030432 - 23 Mar 2021

Cited by 7 | Viewed by 2626

Abstract

The main aim of this study is to investigate the therapeutic efficacy of direct intra-articular injection of bone-marrow-derived stem/stromal cells (BMSCs) and the adjuvant role of hyaluronic acid (HA) in facilitating rabbit articular cartilage repair. First, rabbit BMSCs were treated with a medium [...] Read more.

The main aim of this study is to investigate the therapeutic efficacy of direct intra-articular injection of bone-marrow-derived stem/stromal cells (BMSCs) and the adjuvant role of hyaluronic acid (HA) in facilitating rabbit articular cartilage repair. First, rabbit BMSCs were treated with a medium containing different concentrations of HA. Later, HA’s influence on BMSCs’ CD44 expression, cell viability, extracellular glycosaminoglycan (GAG) synthesis, and chondrogenic gene expression was evaluated during seven-day cultivation. For the in vivo experiment, 24 rabbits were used for animal experiments and 6 rabbits were randomly allocated to each group. Briefly, chondral defects were created at the medial femoral condyle; group 1 was left untreated, group 2 was injected with HA, group 3 was transplanted with 3 × 10⁶ BMSCs, and group 4 was transplanted with 3 × 10⁶ BMSCs suspended in HA. Twelve weeks post-treatment, the repair outcome in each group was assessed and compared both macroscopically and microscopically. Results showed that HA treatment can promote cellular CD44 expression. However, the proliferation rate of BMSCs was downregulated when treated with 1 mg/mL (3.26 ± 0.03, p = 0.0002) and 2 mg/mL (2.61 ± 0.04, p = 0.0001) of HA compared to the control group (3.49 ± 0.05). In contrast, 2 mg/mL (2.86 ± 0.3) of HA treatment successfully promoted normalized GAG expression compared to the control group (1.88 ± 0.06) (p = 0.0009). The type II collagen gene expression of cultured BMSCs was significantly higher in BMSCs treated with 2 mg/mL of HA (p = 0.0077). In the in vivo experiment, chondral defects treated with combined BMSC and HA injection demonstrated better healing outcomes than BMSC or HA treatment alone in terms of gross grading and histological scores. In conclusion, this study helps delineate the role of HA as a chondrogenic adjuvant in augmenting the effectiveness of stem-cell-based injection therapy for in vivo cartilage repair. From a translational perspective, the combination of HA and BMSCs is a convenient, ready-to-use, and effective formulation that can improve the therapeutic efficacy of stem-cell-based therapies. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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Review

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42 pages, 3206 KiB

Open AccessReview

Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

by Marcella Liciani Franco, Stephany Beyerstedt and Érika Bevilaqua Rangel

Pharmaceutics 2022, 14(1), 11; https://doi.org/10.3390/pharmaceutics14010011 - 21 Dec 2021

Cited by 14 | Viewed by 6857

Abstract

Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high [...] Read more.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high financial burden for the health system. Studies have indicated Klotho as a promising therapeutic approach for these conditions. Klotho reduces inflammation, oxidative stress and fibrosis and counter-regulates the renin-angiotensin-aldosterone system. In CKD and AKI, Klotho expression is downregulated from early stages and correlates with disease progression. Therefore, the restoration of its levels, through exogenous or endogenous pathways, has renoprotective effects. An important strategy for administering Klotho is through mesenchymal stem cells (MSCs). In summary, this review comprises in vitro and in vivo studies on the therapeutic potential of Klotho for the treatment of CKD and AKI through the administration of MSCs. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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20 pages, 2310 KiB

Open AccessReview

Mesenchymal Stem Cells Engineered by Nonviral Vectors: A Powerful Tool in Cancer Gene Therapy

by Yuan Ding, Chenyang Wang, Zhongquan Sun, Yingsheng Wu, Wanlu You, Zhengwei Mao and Weilin Wang

Pharmaceutics 2021, 13(6), 913; https://doi.org/10.3390/pharmaceutics13060913 - 21 Jun 2021

Cited by 10 | Viewed by 2747

Abstract

Due to their “tumor homing” and “immune privilege” characteristics, the use of mesenchymal stem cells (MSCs) has been proposed as a novel tool against cancer. MSCs are genetically engineered in vitro and then utilized to deliver tumoricidal agents, including prodrugs and bioactive molecules, [...] Read more.

Due to their “tumor homing” and “immune privilege” characteristics, the use of mesenchymal stem cells (MSCs) has been proposed as a novel tool against cancer. MSCs are genetically engineered in vitro and then utilized to deliver tumoricidal agents, including prodrugs and bioactive molecules, to tumors. The genetic modification of MSCs can be achieved by various vectors, and in most cases viral vectors are used; however, viruses may be associated with carcinogenesis and immunogenicity, restricting their clinical translational potential. As such, nonviral vectors have emerged as a potential solution to address these limitations and have gradually attracted increasing attention. In this review, we briefly revisit the current knowledge about MSC-based cancer gene therapy. Then, we summarize the advantages and challenges of nonviral vectors for MSC transfection. Finally, we discuss recent advances in the development of new nonviral vectors, which have provided promising strategies to overcome obstacles in the gene modulation of MSCs. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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28 pages, 3217 KiB

Open AccessReview

Mesenchymal Stem Cells as a Gene Delivery Tool: Promise, Problems, and Prospects

by Noha Attia, Mohamed Mashal, Gustavo Puras and Jose Luis Pedraz

Pharmaceutics 2021, 13(6), 843; https://doi.org/10.3390/pharmaceutics13060843 - 07 Jun 2021

Cited by 16 | Viewed by 4135

Abstract

The cell-based approach in gene therapy arises as a promising strategy to provide safe, targeted, and efficient gene delivery. Owing to their unique features, as homing and tumor-tropism, mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in gene therapy. [...] Read more.

The cell-based approach in gene therapy arises as a promising strategy to provide safe, targeted, and efficient gene delivery. Owing to their unique features, as homing and tumor-tropism, mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in gene therapy. Nevertheless, non-viral transfer of nucleic acids into MSCs remains limited due to various factors related to the main stakeholders of the process (e.g., nucleic acids, carriers, or cells). In this review, we have summarized the main types of nucleic acids used to transfect MSCs, the pros and cons, and applications of each. Then, we have emphasized on the most efficient lipid-based carriers for nucleic acids to MSCs, their main features, and some of their applications. While a myriad of studies have demonstrated the therapeutic potential for engineered MSCs therapy in various illnesses, optimization for clinical use is an ongoing challenge. On the way of improvement, genetically modified MSCs have been combined with various novel techniques and tools (e.g., exosomes, spheroids, 3D-Bioprinting, etc.,) aiming for more efficient and safe applications in biomedicine. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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14 pages, 275 KiB

Open AccessReview

Considerations in the Design of Non-Clinical Development Programmes to Support Non-Viral Genetically Modified Mesenchymal Stromal Cell Therapies

by Valeria Iansante, Andrew Brooks and Lee Coney

Pharmaceutics 2021, 13(6), 823; https://doi.org/10.3390/pharmaceutics13060823 - 02 Jun 2021

Cited by 2 | Viewed by 2662

Abstract

Due to their immune suppressive pharmacology, regenerative capacity, and immune privileged status, mesenchymal stromal cells (MSCs) are an attractive cell type to treat a variety of diseases. Genetically engineered MSCs are currently in non-clinical and clinical development for a wide range of applications [...] Read more.

Due to their immune suppressive pharmacology, regenerative capacity, and immune privileged status, mesenchymal stromal cells (MSCs) are an attractive cell type to treat a variety of diseases. Genetically engineered MSCs are currently in non-clinical and clinical development for a wide range of applications including the delivery of pro-drugs and therapeutic proteins or modified to enhance their regenerative potential. Unmodified MSCs have been shown to have good safety profiles in clinical development. The introduction of exogenous transgenes introduces possible additional risks that need to be assessed in non-clinical studies prior to initiating clinical studies. The use of ex vivo non-viral genetic modification approaches potentially reduces the risks associated with viral vector transfection approaches, including the potential for cell transformation. This review provides an overview of the regulatory-compliant non-clinical proof-of-concept and safety studies required to take MSC-based gene therapy products from the bench to the clinic. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

12 pages, 3170 KiB

Open AccessReview

Induced Tissue-Specific Stem Cells (iTSCs): Their Generation and Possible Use in Regenerative Medicine

by Issei Saitoh, Masahiro Sato, Yuki Kiyokawa, Emi Inada, Yoko Iwase, Natsumi Ibano and Hirofumi Noguchi

Pharmaceutics 2021, 13(6), 780; https://doi.org/10.3390/pharmaceutics13060780 - 23 May 2021

Cited by 3 | Viewed by 2936

Abstract

Induced tissue-specific stem cells (iTSCs) are partially reprogrammed cells which have an intermediate state, such as progenitors or stem cells. They originate from the de-differentiation of differentiated somatic cells into pluripotent stem cells, such as induced pluripotent stem cells (iPSCs) and embryonic stem [...] Read more.

Induced tissue-specific stem cells (iTSCs) are partially reprogrammed cells which have an intermediate state, such as progenitors or stem cells. They originate from the de-differentiation of differentiated somatic cells into pluripotent stem cells, such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), or from the differentiation of undifferentiated cells. They show a limited capacity to differentiate and a morphology similar to that of somatic cell stem cells present in tissues, but distinct from that of iPSCs and ESCs. iTSCs can be generally obtained 7 to 10 days after reprogramming of somatic cells with Yamanaka’s factors, and their fibroblast-like morphology remains unaltered. iTSCs can also be obtained directly from iPSCs cultured under conditions allowing cellular differentiation. In this case, to effectively induce iTSCs, additional treatment is required, as exemplified by the conversion of iPSCs into naïve iPSCs. iTSCs can proliferate continuously in vitro, but when transplanted into immunocompromised mice, they fail to generate solid tumors (teratomas), implying loss of tumorigenic potential. The low tendency of iTSCs to elicit tumors is beneficial, especially considering applications for regenerative medicine in humans. Several iTSC types have been identified, including iTS-L, iTS-P, and iTS-D, obtained by reprogramming hepatocytes, pancreatic cells, and deciduous tooth-derived dental pulp cells, respectively. This review provides a brief overview of iPSCs and discusses recent advances in the establishment of iTSCs and their possible applications in regenerative medicine. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells-Based Gene Therapy Approach Mediated by Non-viral Vectors)

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