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

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 54450

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Prof. Dr. Ssang-Goo Cho

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Department of Stem Cell and Regenerative Biology, Konkuk University, Seoul, Republic of Korea
Interests: transplantation; signaling pathways in stem, cancer, and cancer stem cells; molecular mechanism of cellular reprogramming; apoptosis and autophagy; cancer stem cells; induced pluripotent stem cells; pancreatic beta-cell differentiation; pancreatic cancer cells
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Dear Colleagues,

Stem cells are defined as cells that have the capacity to perpetuate themselves through self-renewal and to generate mature cells of a specific tissue through differentiation. They are considered to be a promising tool for the treatment of patients experiencing serious degenerative and incurable diseases. Recently, there has been a significant turning point in the field of stem cells after the development of induced pluripotent stem cells (iPS cells) technology. Reprogramming of somatic cells is the hallmark of this technology, and also it can be derived for adult tissues, as well as from the patients’ tissue. Of note, iPS cells technology may overcome the hurdle of moral and ethical issues that arise from using human ES cells, as well as immune rejection. Cancer research also developed a new turn due to iPSC technology. The reprogramming of cancer cells is an interesting approach to the study of cancer-related genes and the interaction between these genes and the cellular microenvironment, before and after reprogramming, to explain the mechanisms of various stages of cancer development. Cancer cell reprogramming may be one of the ways to develop novel cancer treatments, as cancer cells may be converted into an immature or benign state. As normal stem cells and cancer cells share the capacity to self-renew, it seems reasonable to propose that newly-arising cancer cells appropriate the machinery for self-renewing cell division, which is normally expressed in stem cells. Evidence shows that many pathways that are classically associated with cancer may also regulate normal stem cell development. Signaling pathways associated with oncogenesis, metastasis, epithelial–mesenchymal transition (EMT), or mesenchymal–epithelial transition (MET), such as the Notch, Sonic hedgehog (Shh), Wnt, kinase, GPCR signaling pathways, may also regulate stem cell self-renewal.

In this Special Issue of IJMS, the focus will be on reprogramming somatic cells to stem cells or cancer stem cells, reprogramming cancer cells or malignant cancer cells to normal or benign tumor cells, or signaling pathways regulating stem cell self-renewal or oncogenesis metastasis, epithelial–mesenchymal transition (EMT), or mesenchymal–epithelial transition (MET) in relation to new treatment options or other biological and medical applications.

Prof. Dr. Ssang-Goo Cho
Guest Editor

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Cell Reprogramming in International Journal of Molecular Sciences (5 articles)

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Research

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16 pages, 3084 KiB

Open AccessArticle

The Effect of Uncoated SPIONs on hiPSC-Differentiated Endothelial Cells

by Barbara Salingova, Pavel Simara, Pavel Matula, Lenka Zajickova, Petr Synek, Ondrej Jasek, Lenka Veverkova, Miroslava Sedlackova, Zuzana Nichtova and Irena Koutna

Int. J. Mol. Sci. 2019, 20(14), 3536; https://doi.org/10.3390/ijms20143536 - 19 Jul 2019

Cited by 4 | Viewed by 4094

Abstract

Background: Endothelial progenitor cells (EPCs) were indicated in vascular repair, angiogenesis of ischemic organs, and inhibition of formation of initial hyperplasia. Differentiation of endothelial cells (ECs) from human induced pluripotent stem cells (hiPSC)-derived endothelial cells (hiPSC-ECs) provides an unlimited supply for clinical application. Furthermore, magnetic cell labelling offers an effective way of targeting and visualization of hiPSC-ECs and is the next step towards in vivo studies. Methods: ECs were differentiated from hiPSCs and labelled with uncoated superparamagnetic iron-oxide nanoparticles (uSPIONs). uSPION uptake was compared between hiPSC-ECs and mature ECs isolated from patients by software analysis of microscopy pictures after Prussian blue cell staining. The acute and long-term cytotoxic effects of uSPIONs were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) and Annexin assay. Results: We showed, for the first time, uptake of uncoated SPIONs (uSPIONs) by hiPSC-ECs. In comparison with mature ECs of identical genetic background hiPSC-ECs showed lower uSPION uptake. However, all the studied endothelial cells were effectively labelled and showed magnetic properties even with low labelling concentration of uSPIONs. uSPIONs prepared by microwave plasma synthesis did not show any cytotoxicity nor impair endothelial properties. Conclusion: We show that hiPSC-ECs labelling with low concentration of uSPIONs is feasible and does not show any toxic effects in vitro, which is an important step towards animal studies. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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12 pages, 1741 KiB

Open AccessCommunication

OCT4 Silencing Triggers Its Epigenetic Repression and Impairs the Osteogenic and Adipogenic Differentiation of Mesenchymal Stromal Cells

by Ricardo Malvicini, Diego Santa-Cruz, Natalia Pacienza and Gustavo Yannarelli

Int. J. Mol. Sci. 2019, 20(13), 3268; https://doi.org/10.3390/ijms20133268 - 3 Jul 2019

Cited by 10 | Viewed by 3488

Abstract

Mechanisms mediating mesenchymal stromal/stem cells’ (MSCs) multipotency are unclear. Although the expression of the pluripotency factor OCT4 has been detected in MSCs, whether it has a functional role in adult stem cells is still controversial. We hypothesized that a physiological expression level of OCT4 is important to regulate MSCs’ multipotency and trigger differentiation in response to environmental signals. Here, we specifically suppressed OCT4 in MSCs by using siRNA technology before directed differentiation. OCT4 expression levels were reduced by 82% in siOCT4-MSCs, compared with controls. Interestingly, siOCT4-MSCs also presented a hypermethylated OCT4 promoter. OCT4 silencing significantly impaired the ability of MSCs to differentiate into osteoblasts. Histologic and macroscopic analysis showed a lower degree of mineralization in siOCT4-MSCs than in controls. Moreover, OCT4 silencing prevented the up-regulation of osteoblast lineage-associated genes during differentiation. Similarly, OCT4 silencing resulted in decreased MSC differentiation potential towards the adipogenic lineage. The accumulation of lipids was reduced 3.0-fold in siOCT4-MSCs, compared with controls. The up-regulation of genes engaged in the early stages of adipogenesis was also suppressed in siOCT4-MSCs. Our findings provide evidence of a functional role for OCT4 in MSCs and indicate that a basal expression of this transcription factor is essential for their multipotent capacity. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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15 pages, 3406 KiB

Open AccessArticle

Increased Expression of Cell Surface SSEA-1 is Closely Associated with Naïve-Like Conversion from Human Deciduous Teeth Dental Pulp Cells-Derived iPS Cells

by Emi Inada, Issei Saitoh, Naoko Kubota, Yoko Iwase, Tomoya Murakami, Tadashi Sawami, Youichi Yamasaki and Masahiro Sato

Int. J. Mol. Sci. 2019, 20(7), 1651; https://doi.org/10.3390/ijms20071651 - 3 Apr 2019

Cited by 12 | Viewed by 3842

Abstract

Stage-specific embryonic antigen 1 (SSEA-1) is an antigenic epitope (also called CD15 antigen) defined as a Lewis X carbohydrate structure and known to be expressed in murine embryonal carcinoma cells, mouse embryonic stem cells (ESCs), and murine and human germ cells, but not human ESCs/induced pluripotent stem cells (iPSCs). It is produced by α1,3-fucosyltransferase IX gene (FUT9), and F9 ECCs having a disrupted FUT9 locus by gene targeting are reported to exhibit loss of SSEA-1 expression on their cell surface. Mouse ESCs are pluripotent cells and therefore known as “naïve stem cells (NSCs).” In contrast, human ESCs/iPSCs are thought to be epiblast stem cells (EpiSCs) that are slightly more differentiated than NSCs. Recently, it has been demonstrated that treatment of EpiSCs with several reprograming-related drugs can convert EpiSCs to cells similar to NSCs, which led us to speculate that SSEA-1 may have been expressed in these NSC-like EpiSCs. Immunocytochemical staining of these cells with anti-SSEA-1 revealed increased expression of this epitope. RT-PCR analysis also confirmed increased expression of FUT9 transcripts as well as other stemness-related transcripts such as REX-1 (ZFP42). These results suggest that SSEA-1 can be an excellent marker for human NSCs. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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17 pages, 3678 KiB

Open AccessArticle

Generation of iPSCs from Jaw Periosteal Cells Using Self-Replicating RNA

by Felix Umrath, Heidrun Steinle, Marbod Weber, Hans-Peter Wendel, Siegmar Reinert, Dorothea Alexander and Meltem Avci-Adali

Int. J. Mol. Sci. 2019, 20(7), 1648; https://doi.org/10.3390/ijms20071648 - 3 Apr 2019

Cited by 14 | Viewed by 4497

Abstract

Jaw periosteal cells (JPCs) represent a suitable stem cell source for bone tissue engineering (BTE) applications. However, challenges associated with limited cell numbers, stressful cell sorting, or the occurrence of cell senescence during in vitro passaging and the associated insufficient osteogenic potential in vitro of JPCs and other mesenchymal stem/stromal cells (MSCs) are main hurdles and still need to be solved. In this study, for the first time, induced pluripotent stem cells (iPSCs) were generated from human JPCs to open up a new source of stem cells for BTE. For this purpose, a non-integrating self-replicating RNA (srRNA) encoding reprogramming factors and green fluorescent protein (GFP) as a reporter was used to obtain JPC-iPSCs with a feeder- and xeno-free reprogramming protocol to meet the highest safety standards for future clinical applications. Furthermore, to analyze the potential of these iPSCs as a source of osteogenic progenitor cells, JPC-iPSCs were differentiated into iPSC-derived mesenchymal stem/stromal like cells (iMSCs) and further differentiated to the osteogenic lineage under xeno-free conditions. The produced iMSCs displayed MSC marker expression and morphology as well as strong mineralization during osteogenic differentiation. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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17 pages, 3345 KiB

Open AccessArticle

Functional Assessment of Patient-Derived Retinal Pigment Epithelial Cells Edited by CRISPR/Cas9

by Leah P. Foltz, Sara E. Howden, James A. Thomson and Dennis O. Clegg

Int. J. Mol. Sci. 2018, 19(12), 4127; https://doi.org/10.3390/ijms19124127 - 19 Dec 2018

Cited by 19 | Viewed by 5790

Abstract

Retinitis pigmentosa is the most common form of inherited blindness and can be caused by a multitude of different genetic mutations that lead to similar phenotypes. Specifically, mutations in ubiquitously expressed splicing factor proteins are known to cause an autosomal dominant form of the disease, but the retina-specific pathology of these mutations is not well understood. Fibroblasts from a patient with splicing factor retinitis pigmentosa caused by a missense mutation in the PRPF8 splicing factor were used to produce three diseased and three CRISPR/Cas9-corrected induced pluripotent stem cell (iPSC) clones. We differentiated each of these clones into retinal pigment epithelial (RPE) cells via directed differentiation and analyzed the RPE cells in terms of gene and protein expression, apicobasal polarity, and phagocytic ability. We demonstrate that RPE cells can be produced from patient-derived and corrected cells and they exhibit morphology and functionality similar but not identical to wild-type RPE cells in vitro. Functionally, the RPE cells were able to establish apicobasal polarity and phagocytose photoreceptor outer segments at the same capacity as wild-type cells. These data suggest that patient-derived iPSCs, both diseased and corrected, are able to differentiate into RPE cells with a near normal phenotype and without differences in phagocytosis, a result that differs from previous mouse models. These RPE cells can now be studied to establish a disease-in-a-dish system relevant to retinitis pigmentosa. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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14 pages, 1573 KiB

Open AccessArticle

Induction of Expandable Adipose-Derived Mesenchymal Stem Cells from Aged Mesenchymal Stem Cells by a Synthetic Self-Replicating RNA

by Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Shinji Kitamura, Issei Saitoh, Masami Watanabe and Hirofumi Noguchi

Int. J. Mol. Sci. 2018, 19(11), 3489; https://doi.org/10.3390/ijms19113489 - 6 Nov 2018

Cited by 6 | Viewed by 4951

Abstract

Adipose-derived mesenchymal stem cells (ADSCs) have attracted attention due to their potential for use in the treatment of various diseases. However, the self-renewal capacity of ADSCs is restricted and their function diminishes during passage. We previously generated induced tissue-specific stem cells from mouse pancreatic cells using a single synthetic self-replicating Venezuelan Equine Encephalitis (VEE)-reprogramming factor (RF) RNA replicon (SR-RNA) expressing the reprogramming factors POU class 5 homeobox 1 (OCT4), Krueppel-like factor 4 (KLF4), Sex determining region Y-box 2 (SOX2), and Glis Family Zinc Finger 1 (GLIS1). This vector was used to generate induced pluripotent stem (iPS) cells. Here, we applied this SR-RNA vector to generate human iTS cells from aged mesenchymal stem cells (hiTS-M cells) deficient in self-renewal that were derived from adipose tissue. These hiTS-M cells transfected with the SR-RNA vector survived for 15 passages. The hiTS-M cells expressed cell surface markers similar to those of human adipose-derived mesenchymal stem cells (hADSCs) and differentiated into fat cells and osteoblasts. Global gene expression profiling showed that hiTS-M cells were transcriptionally similar to hADSCs. These data suggest that the generation of iTS cells has important implications for the clinical application of autologous stem cell transplantation. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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Review

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16 pages, 1352 KiB

Open AccessReview

Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming

by Ken Nishimura, Aya Fukuda and Koji Hisatake

Int. J. Mol. Sci. 2019, 20(9), 2254; https://doi.org/10.3390/ijms20092254 - 7 May 2019

Cited by 48 | Viewed by 6975

Abstract

Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), hold a huge promise for regenerative medicine, drug development, and disease modeling. PSCs have unique metabolic features that are akin to those of cancer cells, in which glycolysis predominates to produce energy as well as building blocks for cellular components. Recent studies indicate that the unique metabolism in PSCs is not a mere consequence of their preference for a low oxygen environment, but is an active process for maintaining self-renewal and pluripotency, possibly in preparation for rapid response to the metabolic demands of differentiation. Understanding the regulatory mechanisms of this unique metabolism in PSCs is essential for proper derivation, generation, and maintenance of PSCs. In this review, we discuss the metabolic features of PSCs and describe the current understanding of the mechanisms of the metabolic shift during reprogramming from somatic cells to iPSCs, in which the metabolism switches from oxidative phosphorylation (OxPhos) to glycolysis. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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42 pages, 4771 KiB

Open AccessReview

Production of Mesenchymal Stem Cells through Stem Cell Reprogramming

by Ahmed Abdal Dayem, Soo Bin Lee, Kyeongseok Kim, Kyung Min Lim, Tak-il Jeon, Jaekwon Seok and Ssang-Goo Cho

Int. J. Mol. Sci. 2019, 20(8), 1922; https://doi.org/10.3390/ijms20081922 - 18 Apr 2019

Cited by 56 | Viewed by 8114

Abstract

Mesenchymal stem cells (MSCs) possess a broad spectrum of therapeutic applications and have been used in clinical trials. MSCs are mainly retrieved from adult or fetal tissues. However, there are many obstacles with the use of tissue-derived MSCs, such as shortages of tissue sources, difficult and invasive retrieval methods, cell population heterogeneity, low purity, cell senescence, and loss of pluripotency and proliferative capacities over continuous passages. Therefore, other methods to obtain high-quality MSCs need to be developed to overcome the limitations of tissue-derived MSCs. Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are considered potent sources for the derivation of MSCs. PSC-derived MSCs (PSC-MSCs) may surpass tissue-derived MSCs in proliferation capacity, immunomodulatory activity, and in vivo therapeutic applications. In this review, we will discuss basic as well as recent protocols for the production of PSC-MSCs and their in vitro and in vivo therapeutic efficacies. A better understanding of the current advances in the production of PSC-MSCs will inspire scientists to devise more efficient differentiation methods that will be a breakthrough in the clinical application of PSC-MSCs. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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13 pages, 549 KiB

Open AccessReview

Cell Reprogramming in Tumorigenesis and Its Therapeutic Implications for Breast Cancer

by Pei-Yi Chu, Ming-Feng Hou, Ji-Ching Lai, Long-Fong Chen and Chang-Shen Lin

Int. J. Mol. Sci. 2019, 20(8), 1827; https://doi.org/10.3390/ijms20081827 - 12 Apr 2019

Cited by 14 | Viewed by 4886

Abstract

Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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13 pages, 922 KiB

Open AccessReview

Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration

by Hidenori Tani, Taketaro Sadahiro and Masaki Ieda

Int. J. Mol. Sci. 2018, 19(9), 2629; https://doi.org/10.3390/ijms19092629 - 5 Sep 2018

Cited by 33 | Viewed by 7046

Abstract

Cardiac diseases are among the most common causes of death globally. Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Although pluripotent reprogramming has been developed, it has obstacles, such as a potential risk of tumor formation, poor survival of the transplanted cells, and high cost. We previously reported that fibroblasts can be directly reprogrammed to cardiomyocytes by overexpressing a combination of three cardiac-specific transcription factors (Gata4, Mef2c, Tbx5 (together, GMT)). We and other groups have promoted cardiac reprogramming by the addition of certain miRNAs, cytokines, and epigenetic factors, and unraveled new molecular mechanisms of cardiac reprogramming. More recently, we discovered that Sendai virus (SeV) vector expressing GMT could efficiently and rapidly reprogram fibroblasts into integration-free cardiomyocytes in vitro via robust transgene expression. Gene delivery of SeV-GMT also improves cardiac function and reduces fibrosis after myocardial infarction in mice. Through direct cardiac reprogramming, new cardiomyocytes can be generated and scar tissue reduced to restore cardiac function, and, thus, direct cardiac reprogramming may serve as a powerful strategy for cardiac regeneration. Here, we provide an overview of the previous reports and current challenges in this field. Full article

(This article belongs to the Special Issue Cell Reprogramming, II)

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