Non-additive effect of the DNA methylation inhibitor, 5-Aza-dC, and glass as a culture surface on osteogenic differentiation

Alghfeli, Latifa; Parambath, Divyasree; Eldeen, Loaa A. Tag; El-Serafi, Ibrahim; El‐Serafi, Ahmed T.

doi:10.1016/j.heliyon.2022.e12433

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…More importantly, the expression pattern of MSCs-specific CD markers (CD105 and CD90) as well as the hematopoietic markers (CD45 and CD34) of lightly-hypomethylated cells was quite similar to normal cells, confirming the preservation of their mesenchymal characteristic [ 37 ]. Long-term exposure of MSCs or their incubation with higher concentrations (>10 μM) of 5-Aza-dC, reported in similar studies, triggered the mesenchymal-epithelial transition (EMT) and subsequent differentiation commitments towards chondrogenic, osteogenic, or adipogenic [ 38 – 40 ]. This scenario may predict the detrimental effect of global hypomethylation on MSCs fate.…”

Section: Discussionmentioning

confidence: 99%

Conservative Hypomethylation of Mesenchymal Stem Cells and Their Secretome Restored the Follicular Development in Cisplatin-Induced Premature Ovarian Failure Mice

Nabil Salama,

Badr,

Holah

et al. 2023

Reprod. Sci.

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Premature ovarian failure (POF) is one of the main causes of infertility in women under the age of 40 years. Recently, epigenetic reprogramming, particularly DNA hypomethylation, has emerged as a promising strategy to enhance the therapeutic potential of mesenchymal stem cells (MSCs). Thus, it is crucial to elucidate how far global hypomethylation of MSCs genome can maintain their pluripotency and viability and improve their therapeutic effect in chemotherapy-induced POF mice. Herein, the genomic DNA of bone marrow-derived MSCs (BM-MSCs) was hypomethylated by the DNA methyltransferase inhibitor (5-Aza-dC), and the degree of global hypomethylation was assessed by methylation-sensitive HepII/MspI restriction analysis. Next, mildly hypomethylated cells and their secretome were independently transplanted (or infused) in POF mice, established via cisplatin-mediated gonadotoxicity. We found that conservative global hypomethylation of BM-MSCs genome with low doses of 5-Aza-dC (≤0.5 μM) has maintained cell viability and MSCs-specific clusters of differentiation (CD). Engraftment of mildly hypomethylated cells in POF mice, or infusion of their secretome, improved the concentrations of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Mullerian hormone (AMH). Furthermore, mice restored their normal body weight, ovarian size, and ovarian follicle count. This was associated with improved follicular development, where the populations of healthy primordial, primary, secondary, and tertiary follicles were significantly ameliorated, relative to mice transplanted with normally methylated cells. This observational study suggests that transplantation of mildly hypomethylated BM-MSCs cells and their secretome can restore the structural and functional integrity of the damaged ovaries in POF mice. Also, it presents conservative hypomethylation of BM-MSCs and their secretome as a promising alternative to MSCs transplantation. Graphical Abstract Transplantation of partially hypomethylated BM-MSCs improved the follicular count and integrity in the POF mouse model. Gonadotoxic drug (cisplatin) was used to establish the POF mouse model. In parallel, BM-MSCs were isolated, authenticated, and then incubated with the DNMTs inhibitor (5-Aza-dC). Partially hypomethylated cells and their secretome were independently transplanted into the POF mice, and both the follicular count, ovarian histology, and the serum levels of the fertility-related hormones (E2, AMH, and FSH) were assessed 1 week after transplantation or infusion. Hypomethylated BM-MSCs and their secretome increased the follicular count, increased the number of healthy follicles, and restricted apoptosis of the granulose cells. Also, the hormonal profile was improved compared to their corresponding level in mice transplanted with normally methylated cells.

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Section: Discussionmentioning

confidence: 99%

Conservative Hypomethylation of Mesenchymal Stem Cells and Their Secretome Restored the Follicular Development in Cisplatin-Induced Premature Ovarian Failure Mice

Nabil Salama,

Badr,

Holah

et al. 2023

Reprod. Sci.

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“…miRNA can also shuttle as a cargo in the exosomes, locally and through the systemic circulation. The ultimate effect is the alteration of gene expression and protein production in the recipient cell ( Alghfeli et al, 2022 ). miRNA are involved in the post-transcriptional regulation of protein-coding genes by interfering with messenger RNA transcript, leading to its degradation, or -at least-repression of protein production ( Collins, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-155 mediates multiple gene regulations pertinent to the role of human adipose-derived mesenchymal stem cells in skin regeneration

Shahin,

Belcastro,

Das

et al. 2024

Front. Bioeng. Biotechnol.

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Introduction: The role of Adipose-derived mesenchymal stem cells (AD-MSCs) in skin wound healing remains to be fully characterized. This study aims to evaluate the regenerative potential of autologous AD-MSCs in a non-healing porcine wound model, in addition to elucidate key miRNA-mediated epigenetic regulations that underlie the regenerative potential of AD-MSCs in wounds.Methods: The regenerative potential of autologous AD-MSCs was evaluated in porcine model using histopathology and spatial frequency domain imaging. Then, the correlations between miRNAs and proteins of AD-MSCs were evaluated using an integration analysis in primary human AD-MSCs in comparison to primary human keratinocytes. Transfection study of AD-MSCs was conducted to validate the bioinformatics data.Results: Autologous porcine AD-MSCs improved wound epithelialization and skin properties in comparison to control wounds. We identified 26 proteins upregulated in human AD-MSCs, including growth and angiogenic factors, chemokines and inflammatory cytokines. Pathway enrichment analysis highlighted cell signalling-associated pathways and immunomodulatory pathways. miRNA-target modelling revealed regulations related to genes encoding for 16 upregulated proteins. miR-155-5p was predicted to regulate Fibroblast growth factor 2 and 7, C-C motif chemokine ligand 2 and Vascular cell adhesion molecule 1. Transfecting human AD-MSCs cell line with anti-miR-155 showed transient gene silencing of the four proteins at 24 h post-transfection.Discussion: This study proposes a positive miR-155-mediated gene regulation of key factors involved in wound healing. The study represents a promising approach for miRNA-based and cell-free regenerative treatment for difficult-to-heal wounds. The therapeutic potential of miR-155 and its identified targets should be further explored in-vivo.

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Nutrition, Epigenetics, and Stem Cells

El-Serafi,

El-Serafi

2024

Epigenetics and Human Health

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Non-additive effect of the DNA methylation inhibitor, 5-Aza-dC, and glass as a culture surface on osteogenic differentiation

Cited by 6 publications

References 73 publications

Conservative Hypomethylation of Mesenchymal Stem Cells and Their Secretome Restored the Follicular Development in Cisplatin-Induced Premature Ovarian Failure Mice

Conservative Hypomethylation of Mesenchymal Stem Cells and Their Secretome Restored the Follicular Development in Cisplatin-Induced Premature Ovarian Failure Mice

MicroRNA-155 mediates multiple gene regulations pertinent to the role of human adipose-derived mesenchymal stem cells in skin regeneration

Nutrition, Epigenetics, and Stem Cells

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