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15 pages, 4801 KiB

Open AccessArticle

Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

by Satish Kumar, Joanne E. Curran, Erica DeLeon, Ana C. Leandro, Tom E. Howard, Donna M. Lehman, Sarah Williams-Blangero, David C. Glahn and John Blangero

Int. J. Mol. Sci. 2020, 21(19), 6980; https://doi.org/10.3390/ijms21196980 - 23 Sep 2020

Cited by 9 | Viewed by 4275

Abstract

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous [...] Read more.

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10⁻¹⁵–1.44 × 10⁻⁴). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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8 pages, 2164 KiB

Open AccessArticle

The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells

by Jung Hwa Ko and Joo Youn Oh

Int. J. Mol. Sci. 2020, 21(18), 6809; https://doi.org/10.3390/ijms21186809 - 16 Sep 2020

Cited by 2 | Viewed by 2232

Abstract

Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play [...] Read more.

Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play a role in the effects of MSCs on macrophage activation. A miRNA microarray revealed that miR-146a was the most highly upregulated miRNA in MSCs upon co-culture with activated macrophages. Inhibition of miR-146a in MSCs through miR-146a inhibitor transfection had a different effect on the expression of immunoregulatory factors secreted by MSCs. Pentraxin 3, tumor necrosis factor-inducible gene 6, and cyclooxygenase-2, which are well-known mediators of the immunomodulatory functions of MSCs, were significantly upregulated in MSCs after miR-146a knockdown. By contrast, hepatocyte growth factor and stanniocalcin 1, other immunoregulatory molecules expressed by MSCs, were downregulated by miR-146a knockdown. Consequently, the inhibition of miR-146a in MSCs did not change the overall effect of MSCs on the suppression of inflammatory macrophage activation or the induction of anti-inflammatory macrophage polarization. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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13 pages, 3489 KiB

Open AccessArticle

Tuning Adipogenic Differentiation in ADSCs by Metformin and Vitamin D: Involvement of miRNAs

by Sara Cruciani, Giuseppe Garroni, Francesca Balzano, Renzo Pala, Emanuela Bellu, Maria Laura Cossu, Giorgio Carlo Ginesu, Carlo Ventura and Margherita Maioli

Int. J. Mol. Sci. 2020, 21(17), 6181; https://doi.org/10.3390/ijms21176181 - 27 Aug 2020

Cited by 13 | Viewed by 2732

Abstract

Fat tissue represents an important source of adipose-derived stem cells (ADSCs), which can differentiate towards several phenotypes under certain stimuli. Definite molecules as vitamin D are able to influence stem cell fate, acting on the expression of specific genes. In addition, miRNAs are [...] Read more.

Fat tissue represents an important source of adipose-derived stem cells (ADSCs), which can differentiate towards several phenotypes under certain stimuli. Definite molecules as vitamin D are able to influence stem cell fate, acting on the expression of specific genes. In addition, miRNAs are important modulating factors in obesity and numerous diseases. We previously identified specific conditioned media able to commit stem cells towards defined cellular phenotypes. In the present paper, we aimed at evaluating the role of metformin on ADSCs differentiation. In particular, ADSCs were cultured in a specific adipogenic conditioned medium (MD), in the presence of metformin, alone or in combination with vitamin D. Our results showed that the combination of the two compounds is able to counteract the appearance of an adipogenic phenotype, indicating a feedforward regulation on vitamin D metabolism by metformin, acting on CYP27B1 and CYP3A4. We then evaluated the role of specific epigenetic modulating genes and miRNAs in controlling stem cell adipogenesis. The combination of the two molecules was able to influence stem cell fate, by modulating the adipogenic phenotype, suggesting their possible application in clinical practice in counteracting uncontrolled lipogenesis and obesity-related diseases. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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20 pages, 5776 KiB

Open AccessArticle

MicroRNA Profiling Reveals an Abundant miR-200a-3p Promotes Skeletal Muscle Satellite Cell Development by Targeting TGF-β2 and Regulating the TGF-β2/SMAD Signaling Pathway

by Huadong Yin, Haorong He, Xiaoxu Shen, Shuyue Tang, Jing Zhao, Xinao Cao, Shunshun Han, Can Cui, Yuqi Chen, Yuanhang Wei, Yan Wang, Diyan Li and Qing Zhu

Int. J. Mol. Sci. 2020, 21(9), 3274; https://doi.org/10.3390/ijms21093274 - 5 May 2020

Cited by 14 | Viewed by 3174

Abstract

MicroRNAs (miRNAs) are evolutionarily conserved, small noncoding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. Chicken is an optimal model to study skeletal muscle formation because its developmental anatomy is similar to that of mammals. In this study, we identified [...] Read more.

MicroRNAs (miRNAs) are evolutionarily conserved, small noncoding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. Chicken is an optimal model to study skeletal muscle formation because its developmental anatomy is similar to that of mammals. In this study, we identified potential miRNAs in the breast muscle of broilers and layers at embryonic day 10 (E10), E13, E16, and E19. We detected 1836 miRNAs, 233 of which were differentially expressed between broilers and layers. In particular, miRNA-200a-3p was significantly more highly expressed in broilers than layers at three time points. In vitro experiments showed that miR-200a-3p accelerated differentiation and proliferation of chicken skeletal muscle satellite cells (SMSCs) and inhibited SMSCs apoptosis. The transforming growth factor 2 (TGF-β2) was identified as a target gene of miR-200a-3p, and which turned out to inhibit differentiation and proliferation, and promote apoptosis of SMSCs. Exogenous TGF-β2 increased the abundances of phosphorylated SMAD2 and SMAD3 proteins, and a miR-200a-3p mimic weakened this effect. The TGF-β2 inhibitor treatment reduced the promotional and inhibitory effects of miR-200a-3p on SMSC differentiation and apoptosis, respectively. Our results indicate that miRNAs are abundantly expressed during embryonic skeletal muscle development, and that miR-200a-3p promotes SMSC development by targeting TGF-β2 and regulating the TGF-β2/SMAD signaling pathway. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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14 pages, 4867 KiB

Open AccessArticle

miR-9-5p Inhibits Skeletal Muscle Satellite Cell Proliferation and Differentiation by Targeting IGF2BP3 through the IGF2-PI3K/Akt Signaling Pathway

by Huadong Yin, Haorong He, Xiaoxu Shen, Jing Zhao, Xinao Cao, Shunshun Han, Can Cui, Yuqi Chen, Yuanhang Wei, Lu Xia, Yan Wang, Diyan Li and Qing Zhu

Int. J. Mol. Sci. 2020, 21(5), 1655; https://doi.org/10.3390/ijms21051655 - 28 Feb 2020

Cited by 47 | Viewed by 4992

Abstract

MicroRNAs are evolutionarily conserved, small non-coding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. We previously found that miR-9-5p is abundantly expressed in chicken skeletal muscle. Here, we demonstrate a new role for miR-9-5p as a myogenic microRNA that regulates [...] Read more.

MicroRNAs are evolutionarily conserved, small non-coding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. We previously found that miR-9-5p is abundantly expressed in chicken skeletal muscle. Here, we demonstrate a new role for miR-9-5p as a myogenic microRNA that regulates skeletal muscle development. The overexpression of miR-9-5p significantly inhibited the proliferation and differentiation of skeletal muscle satellite cells (SMSCs), whereas miR-9-5p inhibition had the opposite effect. We show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a target gene of miR-9-5p, using dual-luciferase assays, RT-qPCR, and Western Blotting, and that it promotes proliferation and differentiation of SMSCs. In addition, we found that IGF2BP3 regulates IGF-2 expression, using overexpression and knockdown studies. We show that Akt is activated by IGF2BP3 and is essential for IGF2BP3-induced cell development. Together, our results indicate that miR-9-5p could regulate the proliferation and differentiation of myoblasts by targeting IGF2BP3 through IGF-2 and that this activity results in the activation of the PI3K/Akt signaling pathway in skeletal muscle cells. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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Review

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35 pages, 1727 KiB

Open AccessReview

Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome

by Andrea Angius, Antonio Mario Scanu, Caterina Arru, Maria Rosaria Muroni, Vincenzo Rallo, Giulia Deiana, Maria Chiara Ninniri, Ciriaco Carru, Alberto Porcu, Giovanna Pira, Paolo Uva, Paolo Cossu-Rocca and Maria Rosaria De Miglio

Int. J. Mol. Sci. 2021, 22(4), 1603; https://doi.org/10.3390/ijms22041603 - 5 Feb 2021

Cited by 17 | Viewed by 6280

Abstract

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness [...] Read more.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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38 pages, 773 KiB

Open AccessReview

MicroRNAs at the Crossroad of the Dichotomic Pathway Cell Death vs. Stemness in Neural Somatic and Cancer Stem Cells: Implications and Therapeutic Strategies

by Andrea Diana, Giuseppe Gaido, Cristina Maxia and Daniela Murtas

Int. J. Mol. Sci. 2020, 21(24), 9630; https://doi.org/10.3390/ijms21249630 - 17 Dec 2020

Cited by 1 | Viewed by 3456

Abstract

Stemness and apoptosis may highlight the dichotomy between regeneration and demise in the complex pathway proceeding from ontogenesis to the end of life. In the last few years, the concept has emerged that the same microRNAs (miRNAs) can be concurrently implicated in both [...] Read more.

Stemness and apoptosis may highlight the dichotomy between regeneration and demise in the complex pathway proceeding from ontogenesis to the end of life. In the last few years, the concept has emerged that the same microRNAs (miRNAs) can be concurrently implicated in both apoptosis-related mechanisms and cell differentiation. Whether the differentiation process gives rise to the architecture of brain areas, any long-lasting perturbation of miRNA expression can be related to the occurrence of neurodevelopmental/neuropathological conditions. Moreover, as a consequence of neural stem cell (NSC) transformation to cancer stem cells (CSCs), the fine modulation of distinct miRNAs becomes necessary. This event implies controlling the expression of pro/anti-apoptotic target genes, which is crucial for the management of neural/neural crest-derived CSCs in brain tumors, neuroblastoma, and melanoma. From a translational point of view, the current progress on the emerging miRNA-based neuropathology therapeutic applications and antitumor strategies will be disclosed and their advantages and shortcomings discussed. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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21 pages, 1548 KiB

Open AccessReview

The Key Role of MicroRNAs in Self-Renewal and Differentiation of Embryonic Stem Cells

by Giuseppina Divisato, Fabiana Passaro, Tommaso Russo and Silvia Parisi

Int. J. Mol. Sci. 2020, 21(17), 6285; https://doi.org/10.3390/ijms21176285 - 31 Aug 2020

Cited by 24 | Viewed by 4121

Abstract

Naïve pluripotent embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent distinctive developmental stages, mimicking the pre- and the post-implantation events during the embryo development, respectively. The complex molecular mechanisms governing the transition from ESCs into EpiSCs are orchestrated by fluctuating levels [...] Read more.

Naïve pluripotent embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent distinctive developmental stages, mimicking the pre- and the post-implantation events during the embryo development, respectively. The complex molecular mechanisms governing the transition from ESCs into EpiSCs are orchestrated by fluctuating levels of pluripotency transcription factors (Nanog, Oct4, etc.) and wide-ranging remodeling of the epigenetic landscape. Recent studies highlighted the pivotal role of microRNAs (miRNAs) in balancing the switch from self-renewal to differentiation of ESCs. Of note, evidence deriving from miRNA-based reprogramming strategies underscores the role of the non-coding RNAs in the induction and maintenance of the stemness properties. In this review, we revised recent studies concerning the functions mediated by miRNAs in ESCs, with the aim of giving a comprehensive view of the highly dynamic miRNA-mediated tuning, essential to guarantee cell cycle progression, pluripotency maintenance and the proper commitment of ESCs. Full article

(This article belongs to the Special Issue MicroRNAs and Stem Cells 2.0)

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