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1
Sarker, Drishty B., Yu Xue, Faiza Mahmud, Jonathan A. Jocelyn, and Qing-Xiang Amy Sang. "Interconversion of Cancer Cells and Induced Pluripotent Stem Cells." Cells 13, no. 2 (January 10, 2024): 125. http://dx.doi.org/10.3390/cells13020125.
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Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.
2
Slukvin, Igor. "Induced Pluripotent Stem Cells and Erythrocyte Production." Blood 120, no. 21 (November 16, 2012): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v120.21.sci-38.sci-38.
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Abstract Abstract SCI-38 Induced pluripotent stem cells (iPSCs) are somatic cells that have been turned into embryonic-like stem cells by forced expression of factors critical for establishing pluripotency. Because iPSCs can be differentiated into any type of cell in the human body, including hematopoietic cells, they are seen as a logical alternative source of red blood cells (RBCs) for transfusion. In addition, the unlimited expansion potential of iPSCs makes it easy to adopt iPSC technology for RBC biomanufacturing. iPSCs can be generated from any type of donor, including O/Rh-negative universal donors and donors with very rare blood phenotypes, which makes it possible to generate blood products to accommodate virtually all patient groups. We have developed an approach for generating large quantities of RBCs from iPSCs by inducing them to differentiate into CD34+CD43+ hematopoietic progenitors in coculture with OP9 stromal cells, followed by selective expansion of erythroid cells in serum-free media with erythropoiesis-supporting cytokines. Erythroid cultures produced by this approach consist of leukocyte-free populations of CD235a+ RBCs with robust expansion potential and long (up to 90 days) life spans. In these cultures, up to 1.8×105 RBCs can be generated from a single iPSC. Similar to embryonic stem cells, iPSC-derived RBCs express predominantly embryonic and fetal hemoglobin, with very little adult hemoglobin. It is already feasible to adopt iPSC technologies for producing cGMP-grade RBCs using defined animal-product-free differentiation conditions. However, the induction of the complete switch from embryonic to fetal and adult hemoglobin, as well as the terminal maturation and enucleation of iPSC-derived erythroid cells, remains a significant challenge. We recently identified at least three distinct waves of hematopoietic progenitors with erythroid potential in iPSC differentiation cultures. The characterization of erythroid cells produced from these waves of hematopoiesis may help to define populations with definitive erythroid potential and facilitate the production of erythrocytes from iPSCs. Additional critical steps toward translating iPSC-based RBC technologies to the clinic include the development of bioreactor-based-technology for further scaling-up of cell production, and evaluation of the therapeutic potential and safety of human pluripotent stem cell-derived blood cells in animal models. Overall, the manufacturing of RBCs provides several advantages. It can improve the continuity of the blood supply, minimize/eliminate the risk of infection transmission, reduce the incidence of hemolytic and nonhemolytic transfusion reactions, and provide an opportunity to generate RBCs that fit specific clinical needs by using genetically engineered iPSCs or iPSCs with rare blood groups. Disclosures: Slukvin: CDI: Consultancy, Equity Ownership; Cynata: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
3
Zhou, Yang, Miao Li, Kuangyi Zhou, James Brown, Tasha Tsao, Xinjian Cen, Tiffany Husman, Aarushi Bajpai, Zachary Spencer Dunn, and Lili Yang. "Engineering-Induced Pluripotent Stem Cells for Cancer Immunotherapy." Cancers 14, no. 9 (May 1, 2022): 2266. http://dx.doi.org/10.3390/cancers14092266.
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Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an “unlimited supply” for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy.
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Chang, Chia-Yu, Hsiao-Chien Ting, Ching-Ann Liu, Hong-Lin Su, Tzyy-Wen Chiou, Horng-Jyh Harn, and Shinn-Zong Lin. "Induced Pluripotent Stem Cells." Cell Transplantation 27, no. 11 (June 12, 2018): 1588–602. http://dx.doi.org/10.1177/0963689718775406.
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Many neurodegenerative diseases are progressive, complex diseases without clear mechanisms or effective treatments. To study the mechanisms underlying these diseases and to develop treatment strategies, a reliable in vitro modeling system is critical. Induced pluripotent stem cells (iPSCs) have the ability to self-renew and possess the differentiation potential to become any kind of adult cell; thus, they may serve as a powerful material for disease modeling. Indeed, patient cell-derived iPSCs can differentiate into specific cell lineages that display the appropriate disease phenotypes and vulnerabilities. In this review, we highlight neuronal differentiation methods and the current development of iPSC-based neurodegenerative disease modeling tools for mechanism study and drug screening, with a discussion of the challenges and future inspiration for application.
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Ohnuki, Mari, and Kazutoshi Takahashi. "Present and future challenges of induced pluripotent stem cells." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1680 (October 19, 2015): 20140367. http://dx.doi.org/10.1098/rstb.2014.0367.
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Growing old is our destiny. However, the mature differentiated cells making up our body can be rejuvenated to an embryo-like fate called pluripotency which is an ability to differentiate into all cell types by enforced expression of defined transcription factors. The discovery of this induced pluripotent stem cell (iPSC) technology has opened up unprecedented opportunities in regenerative medicine, disease modelling and drug discovery. In this review, we introduce the applications and future perspectives of human iPSCs and we also show how iPSC technology has evolved along the way.
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Yulin, X., L. Lizhen, Z. Lifei, F. Shan, L. Ru, H. Kaimin, and He Huang. "Efficient Generation of Induced Pluripotent Stem Cells from Human Bone Marrow Mesenchymal Stem Cells." Folia Biologica 58, no. 6 (2012): 221–30. http://dx.doi.org/10.14712/fb2012058060221.
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Ectopic expression of defined sets of genetic factors can reprogramme somatic cells to induced pluripotent stem cells (iPSCs) that closely resemble embryonic stem cells. However, the low reprogramming efficiency is a significant handicap for mechanistic studies and potential clinical application. In this study, we used human bone marrow-derived mesenchymal stem cells (hBMMSCs) as target cells for reprogramming and investigated efficient iPSC generation from hBMMSCs using the compounds of p53 siRNA, valproic acid (VPA) and vitamin C (Vc) with four transcription factors OCT4, SOX2, KLF4, and c-MYC (compound induction system). The synergetic mechanism of the compounds was studied. Our results showed that the compound induction system could efficiently reprogramme hBMMSCs to iPSCs. hBMMSC-derived iPSC populations expressed pluripotent markers and had multi-potential to differentiate into three germ layer-derived cells. p53 siRNA, VPA and Vc had a synergetic effect on cell reprogramming and the combinatorial use of these substances greatly improved the efficiency of iPSC generation by suppressing the expression of p53, decreasing cell apoptosis, up-regulating the expression of the pluripotent gene OCT4 and modifying the cell cycle. Therefore, our study highlights a straightforward method for improving the speed and efficiency of iPSC generation and provides versatile tools for investigating early developmental processes such as haemopoiesis and relevant diseases. In addition, this study provides a paradigm for the combinatorial use of genetic factors and molecules to improve the efficiency of iPSC generation.
7
Choi, Kyung-Dal, Junying Yu, Kimberly Smuga-Otto, Jessica Dias, Giorgia Salvagiotto, Maxim Vodyanik, James Thomson, and Igor Slukvin. "Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells." Blood 112, no. 11 (November 16, 2008): 731. http://dx.doi.org/10.1182/blood.v112.11.731.731.
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Abstract Induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity for modeling of human diseases in vitro as well as for developing novel approaches for regenerative therapy based on immunologically compatible cells. In the present study, we employed an OP9 differentiation system to characterize the hematopoietic differentiation potential of seven human iPSC lines obtained from human fetal, neonatal, and adult fibroblasts through reprogramming with POU5F1, SOX2, NANOG, and LIN28 and compared it with the differentiation potential of five human embryonic stem cell lines (hESC; H1, H7, H9, H13, and H14). Similar to hESCs, all iPSCs in coculture with OP9 generated all types of colony forming cells (CFCs) as well as CD34+ cells that can be separated into distinct subsets based on differential expression of CD43 and CD31. CD34+CD31+CD43− cells obtained from all iPSCs expressed molecules present on endothelial cells and readily formed a monolayer when placed in endothelial conditions, while hematopoietic CFC potential was restricted to CD43+ cells. iPSC-derived CD43+ cells could be separated into three major subsets based on differential expression of CD235a/CD41a and CD45: CD235a+CD41a+/− (erythro-megakaryocytic progenitors), and lin-CD34+CD43+CD45− (multipotent), and lin-CD34+CD43+CD45+ (myeloid-skewed) primitive hematopoietic cells. Both subsets of primitive hematopoietic cells expressed genes associated with myeloid and lymphoid development, although myeloid genes were upregulated in CD45+ cells, which are skewed toward myeloid differentiation. Cytogenetic analysis demonstrated that iPSCs and derived from them CD43+ cells maintained normal karyotype. In addition short tandem repeat analysis of CFCs generated from IMR90-1 cells has been performed to confirm that blood cells are in fact derived from reprogrammed IMR90 cells, and not from contaminating hESCs. While we observed some variations in the efficiency of hematopoietic differentiation between different iPSCs, the pattern of differentiation was very similar in all seven tested iPSC and five hESC lines. Using different cytokine combinations and culture conditions we were able to expand iPSC-derived myeloid progenitors and induce their differentiation toward red blood cells, neutrophils, eosinophils, macrophages, ostoeclasts, dendritic and Langerhans cells. Although several issues remain to be resolved before iPSC-derived blood cells can be administered to humans for therapeutic purposes, patient-specific iPSCs can already be used for characterization of mechanisms of blood diseases and to identify molecules that can correct affected genetic networks.
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Yang, Guang, Hyenjong Hong, April Torres, Kristen Malloy, Gourav Choudhury, Jeffrey Kim, and Marcel Daadi. "Standards for Deriving Nonhuman Primate-Induced Pluripotent Stem Cells, Neural Stem Cells and Dopaminergic Lineage." International Journal of Molecular Sciences 19, no. 9 (September 17, 2018): 2788. http://dx.doi.org/10.3390/ijms19092788.
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Humans and nonhuman primates (NHP) are similar in behavior and in physiology, specifically the structure, function, and complexity of the immune system. Thus, NHP models are desirable for pathophysiology and pharmacology/toxicology studies. Furthermore, NHP-derived induced pluripotent stem cells (iPSCs) may enable transformative developmental, translational, or evolutionary studies in a field of inquiry currently hampered by the limited availability of research specimens. NHP-iPSCs may address specific questions that can be studied back and forth between in vitro cellular assays and in vivo experimentations, an investigational process that in most cases cannot be performed on humans because of safety and ethical issues. The use of NHP model systems and cell specific in vitro models is evolving with iPSC-based three-dimensional (3D) cell culture systems and organoids, which may offer reliable in vitro models and reduce the number of animals used in experimental research. IPSCs have the potential to give rise to defined cell types of any organ of the body. However, standards for deriving defined and validated NHP iPSCs are missing. Standards for deriving high-quality iPSC cell lines promote rigorous and replicable scientific research and likewise, validated cell lines reduce variability and discrepancies in results between laboratories. We have derived and validated NHP iPSC lines by confirming their pluripotency and propensity to differentiate into all three germ layers (ectoderm, mesoderm, and endoderm) according to standards and measurable limits for a set of marker genes. The iPSC lines were characterized for their potential to generate neural stem cells and to differentiate into dopaminergic neurons. These iPSC lines are available to the scientific community. NHP-iPSCs fulfill a unique niche in comparative genomics to understand gene regulatory principles underlying emergence of human traits, in infectious disease pathogenesis, in vaccine development, and in immunological barriers in regenerative medicine.
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Dai, Rui, Ricardo Rossello, Chun-chun Chen, Joeran Kessler, Ian Davison, Ute Hochgeschwender, and Erich D. Jarvis. "Maintenance and Neuronal Differentiation of Chicken Induced Pluripotent Stem-Like Cells." Stem Cells International 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/182737.
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Pluripotent stem cells have the potential to become any cell in the adult body, including neurons and glia. Avian stem cells could be used to study questions, like vocal learning, that would be difficult to examine with traditional mouse models. Induced pluripotent stem cells (iPSCs) are differentiated cells that have been reprogrammed to a pluripotent stem cell state, usually using inducing genes or other molecules. We recently succeeded in generating avian iPSC-like cells using mammalian genes, overcoming a limitation in the generation and use of iPSCs in nonmammalian species (Rosselló et al., 2013). However, there were no established optimal cell culture conditions for avian iPSCs to establish long-term cell lines and thus to study neuronal differentiationin vitro. Here we present an efficient method of maintaining chicken iPSC-like cells and for differentiating them into action potential generating neurons.
10
Wattanapanitch, Methichit. "Recent Updates on Induced Pluripotent Stem Cells in Hematological Disorders." Stem Cells International 2019 (May 2, 2019): 1–15. http://dx.doi.org/10.1155/2019/5171032.
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Over the past decade, enormous progress has been made in the field of induced pluripotent stem cells (iPSCs). Patients’ somatic cells such as skin fibroblasts or blood cells can be used to generate disease-specific pluripotent stem cells, which have unlimited proliferation and can differentiate into all cell types of the body. Human iPSCs offer great promises and opportunities for treatments of degenerative diseases and studying disease pathology and drug screening. So far, many iPSC-derived disease models have led to the discovery of novel pathological mechanisms as well as new drugs in the pipeline that have been tested in the iPSC-derived cells for efficacy and potential toxicities. Furthermore, recent advances in genome editing technology in combination with the iPSC technology have provided a versatile platform for studying stem cell biology and regenerative medicine. In this review, an overview of iPSCs, patient-specific iPSCs for disease modeling and drug screening, applications of iPSCs and genome editing technology in hematological disorders, remaining challenges, and future perspectives of iPSCs in hematological diseases will be discussed.
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Gao, Penglin, Chuanhe Sun, Weilong Liao, Wenfei Jiang, Te Liu, and Weidong Pan. "Integrative Research of Induction of Pluripotent Stem Cells." Integrative Medicine International 4, no. 3-4 (November 29, 2017): 115–24. http://dx.doi.org/10.1159/000479182.
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Since the Japanese scientist Shinya Yamanaka used a viral vector to transfer the combination of 4 factors into differentiated somatic cells and reprogramed them to obtain similar embryonic stem cells and induced pluripotent stem cells (iPSCs), it provided one integrative method for studying many medical fields. Patient-derived iPSCs have provided an opportunity to study human diseases for which no suitable model systems are available. iPSC technology has since become a major breakthrough in the field of stem cell research. With the continuous development of iPSC technology and the continuous improvement of technical levels, excellent advances have become more and more common in the basic research and medical fields of life sciences. This article reviews the development history, clinical application, and problems and prospects of iPSC, and focuses on the application of iPSC in neurological diseases.
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Vaskova, E. A., A. E. Stekleneva, S. P. Medvedev, and S. M. Zakian. "“Epigenetic Memory” Phenomenon in Induced Pluripotent Stem Cells." Acta Naturae 5, no. 4 (December 15, 2013): 15–21. http://dx.doi.org/10.32607/20758251-2013-5-4-15-21.
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To date biomedicine and pharmacology have required generating new and more consummate models. One of the most perspective trends in this field is using induced pluripotent stem cells (iPSCs). iPSC application requires careful high-throughput analysis at the molecular, epigenetic, and functional levels. The methods used have revealed that the expression pattern of genes and microRNA, DNA methylation, as well as the set and pattern of covalent histone modifications in iPSCs, are very similar to those in embryonic stem cells. Nevertheless, iPSCs have been shown to possess some specific features that can be acquired during the reprogramming process or are remnants of epigenomes and transcriptomes of the donor tissue. These residual signatures of epigenomes and transcriptomes of the somatic tissue of origin were termed epigenetic memory. In this review, we discuss the epigenetic memory phenomenon in the context of the reprogramming process, its influence on iPSC properties, and the possibilities of its application in cell technologies.
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Wang, Hansen, and Laurie C. Doering. "Induced Pluripotent Stem Cells to Model and Treat Neurogenetic Disorders." Neural Plasticity 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/346053.
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Remarkable advances in cellular reprogramming have made it possible to generate pluripotent stem cells from somatic cells, such as fibroblasts obtained from human skin biopsies. As a result, human diseases can now be investigated in relevant cell populations derived from induced pluripotent stem cells (iPSCs) of patients. The rapid growth of iPSC technology has turned these cells into multipurpose basic and clinical research tools. In this paper, we highlight the roles of iPSC technology that are helping us to understand and potentially treat neurological diseases. Recent studies using iPSCs to model various neurogenetic disorders are summarized, and we discuss the therapeutic implications of iPSCs, including drug screening and cell therapy for neurogenetic disorders. Although iPSCs have been used in animal models with promising results to treat neurogenetic disorders, there are still many issues associated with reprogramming that must be addressed before iPSC technology can be fully exploited with translation to the clinic.
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Jin, Kai, Jing Zhou, Gaoyuan Wu, Zeyu Li, Xilin Zhu, Youchen Liang, Tingting Li, et al. "CHIR99021 and Brdu Are Critical in Chicken iPSC Reprogramming via Small-Molecule Screening." Genes 15, no. 9 (September 13, 2024): 1206. http://dx.doi.org/10.3390/genes15091206.
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Background/Objectives: Induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells into cells with most of the ESC (embryonic stem cell) characteristics show promise toward solving ethical problems currently facing stem cell research and eventually yield clinical grade pluripotent stem cells for therapies and regenerative medicine. In recent years, an increasing body of research suggests that the chemical induction of pluripotency (CIP) method can yield iPSCs in vitro, yet its application in avian species remains unreported. Methods: Herein, we successfully obtained stably growing chicken embryonic fibroblasts (CEFs) using the tissue block adherence method and employed 12 small-molecule compounds to induce chicken iPSC formation. Results: The final optimized iPSC induction system was bFGF (10 ng/mL), CHIR99021 (3 μM), RepSox (5 μM), DZNep (0.05 μM), BrdU (10 μM), BMP4 (10 ng/mL), vitamin C (50 μg/mL), EPZ-5676 (5 μM), and VPA (0.1 mM). Optimization of the induction system revealed that the highest number of clones was induced with 8 × 104 cells per well and at 1.5 times the original concentration. Upon characterization, these clones exhibited iPSC characteristics, leading to the development of a stable compound combination for iPSC generation in chickens. Concurrently, employing a deletion strategy to investigate the functionality of small-molecule compounds during induction, we identified CHIR99021 and BrdU as critical factors for inducing chicken iPSC formation. Conclusions: In conclusion, this study provides a reference method for utilizing small-molecule combinations in avian species to reprogram cells and establish a network of cell fate determination mechanisms.
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Shrestha, Rupendra. "Induced pluripotent stem cells are Japanese brand sources for therapeutic cells to pretrial clinical research." Progress in Stem Cell 7, no. 1 (June 8, 2020): 296–303. http://dx.doi.org/10.15419/psc.v7i1.409.
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iPSCs are promising and have potential benefits for medical use, understanding human organogenesis, and cell therapy for advanced diseases. iPSCs are derived pluripotent cells which can further differentiate into functional human cell-lineages, such as neuronal, epithelial cells, cardiac cell, immune cell, and blood cells, etc. Thirteen years on, the discovery of iPSC has revolutionized the field of regenerative medicine, and also the number of clinical studies using iPSC has been growing rapidly worldwide. However, Japan is leading the race of iPSC-based studies and clinical trials due to government support. The Japanese government implemented the world’s fastest approval system and set to host first pretrial clinical studies using iPSC derived therapeutic products. Also, multinational companies of Japan are investing enormously in iPSC-based research for mobilization of iPSC-derived regenerative products to the research institution globally. This review presents an overview of iPSCs, potential benefits, commercialization of iPSC, iPSC-based pretrial clinical studies, and iPSC biobanking in Japan.
16
Lin, Tongxiang, and Shouhai Wu. "Reprogramming with Small Molecules instead of Exogenous Transcription Factors." Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/794632.
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Induced pluripotent stem cells (iPSCs) could be employed in the creation of patient-specific stem cells, which could subsequently be used in various basic and clinical applications. However, current iPSC methodologies present significant hidden risks with respect to genetic mutations and abnormal expression which are a barrier in realizing the full potential of iPSCs. A chemical approach is thought to be a promising strategy for safety and efficiency of iPSC generation. Many small molecules have been identified that can be used in place of exogenous transcription factors and significantly improve iPSC reprogramming efficiency and quality. Recent studies have shown that the use of small molecules results in the generation of chemically induced pluripotent stem cells from mouse embryonic fibroblast cells. These studies might lead to new areas of stem cell research and medical applications, not only human iPSC by chemicals alone, but also safe generation of somatic stem cells for cell based clinical trials and other researches. In this paper, we have reviewed the recent advances in small molecule approaches for the generation of iPSCs.
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Tang, Hailing, Mengjie Rui, Chuang Yu, Tao Chu, Chao Li, Zhenzhen Zhan, Hao Cao, Hangwen Li, Zhongmin Liu, and Haifa Shen. "Nanotechnology in Generation and Biomedical Application of Induced Pluripotent Stem Cells." Nano LIFE 08, no. 04 (November 30, 2018): 1841002. http://dx.doi.org/10.1142/s1793984418410027.
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Induced pluripotent stem cells (iPSCs) have a tremendous potential in biomedical applications. Nanotechnology has played an essential role on reprogramming iPSCs. In the current review, we will summarize recent progress on application of nanoparticles and other nanotechnology-based platforms in iPSC generation and in study of iPSC biology. We will also highlight the importance of nanotechnology on biomedical application of iPSCs.
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Leventoux, Nicolas, Satoru Morimoto, Kent Imaizumi, Yuta Sato, Shinichi Takahashi, Kyoko Mashima, Mitsuru Ishikawa, et al. "Human Astrocytes Model Derived from Induced Pluripotent Stem Cells." Cells 9, no. 12 (December 13, 2020): 2680. http://dx.doi.org/10.3390/cells9122680.
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Induced pluripotent stem cell (iPSC)-based disease modeling has a great potential for uncovering the mechanisms of pathogenesis, especially in the case of neurodegenerative diseases where disease-susceptible cells can usually not be obtained from patients. So far, the iPSC-based modeling of neurodegenerative diseases has mainly focused on neurons because the protocols for generating astrocytes from iPSCs have not been fully established. The growing evidence of astrocytes’ contribution to neurodegenerative diseases has underscored the lack of iPSC-derived astrocyte models. In the present study, we established a protocol to efficiently generate iPSC-derived astrocytes (iPasts), which were further characterized by RNA and protein expression profiles as well as functional assays. iPasts exhibited calcium dynamics and glutamate uptake activity comparable to human primary astrocytes. Moreover, when co-cultured with neurons, iPasts enhanced neuronal synaptic maturation. Our protocol can be used for modeling astrocyte-related disease phenotypes in vitro and further exploring the contribution of astrocytes to neurodegenerative diseases.
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Papapetrou, Eirini P. "Induced Pluripotent Stem Cells to Model Blood Diseases." Blood 132, Supplement 1 (November 29, 2018): SCI—15—SCI—15. http://dx.doi.org/10.1182/blood-2018-99-109425.
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Abstract Our group is developing induced pluripotent stem cell (iPSC) models of myeloid malignancies, including MDS, MPN and AML. We are generating iPSCs from the bone marrow or blood of patients, which can be maintained indefinitely as pluripotent cell lines and, upon in vitro differentiation along hematopoietic lineages, exhibit hallmark features of these diseases. By integrating mutational analyses with cell reprogramming we can derive iPSCs capturing dominant clones, subclones and normal cells from the same patient and thus have established a collection of iPSC lines representing distinct disease stages along the spectrum of myeloid transformation: predisposition syndromes/preleukemic cells/clonal hematopoiesis; low risk MDS; high risk MDS; and MDS/AML. In parallel, we are using the CRISPR/Cas9 system to introduce or correct mutations in normal or malignant iPSCs, respectively, in isogenic settings and sequential CRISPR gene editing to model mutational cooperation. We recently reported that iPSC lines derived from patients with AML re-establish upon differentiation a leukemic phenotype characterized by extensive proliferation of immature myeloid cells that serially transplant a lethal leukemia into NSG mice (Kotini et al. Cell Stem Cell 2017). Strikingly, we observed that the AML-iPSC-derived hematopoietic stem/progenitor cells (HSPCs) contain two morphologically and immunophenotypically distinct cell subpopulations: a cell fraction (adherent, A) exhibiting adherent growth and containing immature cells with an HSC immunophenotype (CD34+/CD38-/CD90+/CD45RA-/CD49f+); and a non-adherent fraction (suspension, S) of more differentiated cells. Fate-tracking experiments revealed a hierarchical organization, with the A cells renewing themselves and continuously giving rise to the S cells through symmetric and asymmetric divisions. The NSG engraftment potential was largely contained within the adherent cell fraction. Thus, AML-iPSCs exhibit the hallmarks of a leukemia stem cell (LSC) model, namely phenotypic and functional heterogeneity and hierarchical organization, with the A fraction containing LSCs that serially transplant leukemia and give rise to more differentiated cells (S fraction) without engraftment potential. LSCs are believed to be a prominent source of AML relapse, but their rarity and the unavailability of universal and specific immunophenotypic markers prohibits their prospective isolation and makes the study of their properties challenging. This new iPSC-based AML-LSC model enables us for the first time to prospectively obtain large numbers of genetically clonal human LSCs and perform genome-wide integrative molecular analyses and large-scale screening to identify key molecular mechanisms sustaining the properties of LSCs as potential new therapeutic targets. Using this model we characterized the effects of previously proposed compounds with LSC selectivity in self-renewal vs differentiation of LSCs. We also screened a small molecule library of 1280 compounds in the A and S cells in parallel to identify compounds with selectivity for the former as candidates for LSC-specific targeting. Disclosures No relevant conflicts of interest to declare.
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Yang, Yi-Ping, Yu-Jer Hsiao, Kao-Jung Chang, Shania Foustine, Yu-Ling Ko, Yi-Ching Tsai, Hsiao-Yun Tai, et al. "Pluripotent Stem Cells in Clinical Cell Transplantation: Focusing on Induced Pluripotent Stem Cell-Derived RPE Cell Therapy in Age-Related Macular Degeneration." International Journal of Molecular Sciences 23, no. 22 (November 9, 2022): 13794. http://dx.doi.org/10.3390/ijms232213794.
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Human pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represent valuable cell sources to replace diseased or injured tissues in regenerative medicine. iPSCs exhibit the potential for indefinite self-renewal and differentiation into various cell types and can be reprogrammed from somatic tissue that can be easily obtained, paving the way for cell therapy, regenerative medicine, and personalized medicine. Cell therapies using various iPSC-derived cell types are now evolving rapidly for the treatment of clinical diseases, including Parkinson’s disease, hematological diseases, cardiomyopathy, osteoarthritis, and retinal diseases. Since the first interventional clinical trial with autologous iPSC-derived retinal pigment epithelial cells (RPEs) for the treatment of age-related macular degeneration (AMD) was accomplished in Japan, several preclinical trials using iPSC suspensions or monolayers have been launched, or are ongoing or completed. The evolution and generation of human leukocyte antigen (HLA)-universal iPSCs may facilitate the clinical application of iPSC-based therapies. Thus, iPSCs hold great promise in the treatment of multiple retinal diseases. The efficacy and adverse effects of iPSC-based retinal therapies should be carefully assessed in ongoing and further clinical trials.
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Durnaoglu, Serpen, Sermin Genc, and Kursad Genc. "Patient-Specific Pluripotent Stem Cells in Neurological Diseases." Stem Cells International 2011 (2011): 1–17. http://dx.doi.org/10.4061/2011/212487.
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Many human neurological diseases are not currently curable and result in devastating neurologic sequelae. The increasing availability of induced pluripotent stem cells (iPSCs) derived from adult human somatic cells provides new prospects for cellreplacement strategies and disease-related basic research in a broad spectrum of human neurologic diseases. Patient-specific iPSC-based modeling of neurogenetic and neurodegenerative diseases is an emerging efficient tool forin vitromodeling to understand disease and to screen for genes and drugs that modify the disease process. With the exponential increase in iPSC research in recent years, human iPSCs have been successfully derived with different technologies and from various cell types. Although there remain a great deal to learn about patient-specific iPSC safety, the reprogramming mechanisms, better ways to direct a specific reprogramming, ideal cell source for cellular grafts, and the mechanisms by which transplanted stem cells lead to an enhanced functional recovery and structural reorganization, the discovery of the therapeutic potential of iPSCs offers new opportunities for the treatment of incurable neurologic diseases. However, iPSC-based therapeutic strategies need to be thoroughly evaluated in preclinical animal models of neurological diseases before they can be applied in a clinical setting.
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Petkov, Stoyan. "THE QUEST FOR PORCINE PLURIPOTENT STEM CELLS." Reproduction, Fertility and Development 25, no. 1 (2013): 319. http://dx.doi.org/10.1071/rdv25n1ab342.
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The isolation of embryonic stem cells (ESC) and embryonic germ cells (EGC) from early embryos is a major milestone in modern science and holds a great potential for human medicine. In 2007, Shinia Yamanaka and co-workers reprogrammed somatic cells to pluripotency by induced expression of pluripotency transcription factors. These so-called induced pluripotent stem cells (iPSC) are equivalent to ESC in terms of pluripotency and have the same potential for use in regenerative therapies. However, before the use of pluripotent cells or their derivatives in humans, potential therapies need to be tested in suitable animal models to ensure their safety. In this respect, the domestic pig is particularly suited for the testing of stem cell-based therapies intended for humans, since in general physiology and metabolism are similar in human and pigs. Since the isolation of the different types of pluripotent cells in human and mouse, there have been reports of derivation of ESC-like and EGC-like cell lines from porcine embryos. Despite the significant progress that has been reported in these studies, none of the described porcine cell lines have fulfilled all of the criteria for pluripotency, such as long-term maintenance and the ability to differentiate into all of the cells in the organism, including the germ line. This has prevented the use of these cells in the genetic engineering of livestock as well as their therapeutic application in animal models for human diseases. The derivation of the first porcine cell lines with iPSC characteristics (Ezashi et al. 2009 PNAS 27, 10 993–10 998) has provided a viable alternative to the ESC/EGC, and some major successes have been already achieved. The majority of the putative iPSC described in the literature have demonstrated pluripotent characteristics such as expression of various pluripotency markers and an ability to differentiate into the three primary germ layers in vivo by forming teratomas in immunodeficient mice. One group has reported the derivation of iPSC lines that have been capable to generate chimeras with germline contribution (West et al. 2011 Stem Cells 29, 1640–1643), which is the first fully confirmed report of successfully produced porcine germ line chimera to date. Additionally, the differentiation of putative iPSC into rod photoreceptors and their integration into the retinas of recipient pigs has been reported (Zhou et al. 2011 Stem Cells 29, 972–980). Despite these major achievements, some challenges remain to be overcome in order to make porcine iPSC more widely applicable in disease models and in the transgenic technology. Due to some variations in the morphological and molecular characteristics of the reported putative iPSC lines, it needs to be determined which markers are the hallmarks of truly pluripotent porcine iPSC. Second, it is still not clear which are the optimal culture conditions for derivation and long-term culture of these cells. Since the culture conditions used today have been proven ineffective to maintain pluripotency in porcine ESC and EGC, the question remains whether the continuous expression of the transgenes is an important factor in the long-term culture of iPSC. Finally, it needs to be determined whether putative porcine iPSC derived from cell types other than multipotent stem cells (such as mesenchymal stem cells used by West et al., 2011) possess full pluripotency, which should be demonstrated by germ line chimera production via blastocyst injection or tetraploid complementation.
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Mah, Nancy, Andreas Kurtz, Antonie Fuhr, Stefanie Seltmann, Ying Chen, Nils Bultjer, Johannes Dewender, Ayuen Lual, Rachel Steeg, and Sabine C. Mueller. "The Management of Data for the Banking, Qualification, and Distribution of Induced Pluripotent Stem Cells: Lessons Learned from the European Bank for Induced Pluripotent Stem Cells." Cells 12, no. 23 (December 1, 2023): 2756. http://dx.doi.org/10.3390/cells12232756.
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The European Bank for induced pluripotent Stem Cells (EBiSC) was established in 2014 as a non-profit project for the banking, quality control, and distribution of human iPSC lines for research around the world. EBiSC iPSCs are deposited from diverse laboratories internationally and, hence, a key activity for EBiSC is standardising not only the iPSC lines themselves but also the data associated with them. This includes enabling unique nomenclature for the cells, as well as applying uniformity to the data provided by the cell line generator versus quality control data generated by EBiSC, and providing mechanisms to share personal data in a secure and GDPR-compliant manner. A joint approach implemented by EBiSC and the human pluripotent stem cell registry (hPSCreg®) has provided a solution that enabled hPSCreg® to improve its registration platform for iPSCs and EBiSC to have a pipeline for the import, standardisation, storage, and management of data associated with EBiSC iPSCs. In this work, we describe the experience of cell line data management for iPSC banking throughout the course of EBiSC’s development as a central European banking infrastructure and present a model for how this could be implemented by other iPSC repositories to increase the FAIRness of iPSC research globally.
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Ng, Xiao Yu, Gary S. L. Peh, Gary Hin-Fai Yam, Hwee Goon Tay, and Jodhbir S. Mehta. "Corneal Endothelial-Like Cells Derived from Induced Pluripotent Stem Cells for Cell Therapy." International Journal of Molecular Sciences 24, no. 15 (August 4, 2023): 12433. http://dx.doi.org/10.3390/ijms241512433.
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Corneal endothelial dysfunction is one of the leading causes of corneal blindness, and the current conventional treatment option is corneal transplantation using a cadaveric donor cornea. However, there is a global shortage of suitable donor graft material, necessitating the exploration of novel therapeutic approaches. A stem cell-based regenerative medicine approach using induced pluripotent stem cells (iPSCs) offers a promising solution, as they possess self-renewal capabilities, can be derived from adult somatic cells, and can be differentiated into all cell types including corneal endothelial cells (CECs). This review discusses the progress and challenges in developing protocols to induce iPSCs into CECs, focusing on the different media formulations used to differentiate iPSCs to neural crest cells (NCCs) and subsequently to CECs, as well as the characterization methods and markers that define iPSC-derived CECs. The hurdles and solutions for the clinical application of iPSC-derived cell therapy are also addressed, including the establishment of protocols that adhere to good manufacturing practice (GMP) guidelines. The potential risks of genetic mutations in iPSC-derived CECs associated with long-term in vitro culture and the danger of potential tumorigenicity following transplantation are evaluated. In all, this review provides insights into the advancement and obstacles of using iPSC in the treatment of corneal endothelial dysfunction.
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Jiang, Peng, Stephanie N. Rushing, Chi-wing Kong, Jidong Fu, Deborah Kuo-Ti Lieu, Camie W. Chan, Wenbin Deng, and Ronald A. Li. "Electrophysiological properties of human induced pluripotent stem cells." American Journal of Physiology-Cell Physiology 298, no. 3 (March 2010): C486—C495. http://dx.doi.org/10.1152/ajpcell.00251.2009.
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Human embryonic stem cells (hESCs) can self-renew while maintaining their pluripotency. Direct reprogramming of adult somatic cells to induced pluripotent stem cells (iPSCs) has been reported. Although hESCs and human iPSCs have been shown to share a number of similarities, such basic properties as the electrophysiology of iPSCs have not been explored. Previously, we reported that several specialized ion channels are functionally expressed in hESCs. Using transcriptomic analyses as a guide, we observed tetraethylammonium (TEA)-sensitive (IC50 = 3.3 ± 2.7 mM) delayed rectifier K+ currents ( IKDR) in 105 of 110 single iPSCs (15.4 ± 0.9 pF). IKDR in iPSCs displayed a current density of 7.6 ± 3.8 pA/pF at +40 mV. The voltage for 50% activation ( V1/2) was −7.9 ± 2.0 mV, slope factor k = 9.1 ± 1.5. However, Ca2+-activated K+ current ( IKCa), hyperpolarization-activated pacemaker current ( If), and voltage-gated sodium channel (NaV) and voltage-gated calcium channel (CaV) currents could not be measured. TEA inhibited iPSC proliferation (EC50 = 7.8 ± 1.2 mM) and viability (EC50 = 5.5 ± 1.0 mM). By contrast, 4-aminopyridine (4-AP) inhibited viability (EC50 = 4.5 ± 0.5 mM) but had less effect on proliferation (EC50 = 0.9 ± 0.5 mM). Cell cycle analysis further revealed that K+ channel blockers inhibited proliferation primarily by arresting the mitotic phase. TEA and 4-AP had no effect on iPSC differentiation as gauged by ability to form embryoid bodies and expression of germ layer markers after induction of differentiation. Neither iberiotoxin nor apamin had any function effects, consistent with the lack of IKCa in iPSCs. Our results reveal further differences and similarities between human iPSCs and hESCs. A better understanding of the basic biology of iPSCs may facilitate their ultimate clinical application.
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Zhu, Liang-Fang, Qiu-Ru Chen, Shao-Zhen Chen, Ling-Yan Wang, Xiao-Feng Luo, Jin-Hua Ren, Xiao-Hong Yuan, et al. "The Construction and Identification of Induced Pluripotent Stem Cells Derived from Acute Myelogenous Leukemia Cells." Cellular Physiology and Biochemistry 41, no. 4 (2017): 1661–74. http://dx.doi.org/10.1159/000471246.
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Objective: The present study aimed to establish an induced pluripotent stem cell (iPSC) line from acute myelogenous leukemia (AML) cells in vitro and identify their biological characteristics. Methods: Cells from the AML-infiltrated skin from an M6 patient were infected with a lentivirus carrying OCT4, SOX2, KLF4 and C-MYC to induce iPSCs. The characteristics of the iPSCs were confirmed by alkaline phosphatase (ALP) staining. The proliferation ability of iPSCs was detected with a CCK-8 assay. The expression of pluripotency markers was measured by immunostaining, and the expression of stem cell-related genes was detected by qRT-PCR; distortion during the induction process was detected by karyotype analysis; the differentiation potential of iPSCs was determined by embryoid body-formation and teratoma-formation assays. ALP staining confirmed that these cells exhibited positive staining and had the characteristics of iPSCs. Results: The CCK-8 assay showed that the iPSCs had the ability to proliferate. Immunostaining demonstrated that iPSC clones showed positive expression of NANOG, SSEA-3, SSEA-4, TRA-1-60 and TRA-1-81. qRT-PCR results revealed that the mRNA expression of Nanog, Lin28, Cripto, FOX3, DNMT3b, DPPA2, and DPPA4 significantly increased in iPSCs. Karyotype analysis found no chromosome aberration in the iPSCs. The results of the embryoid body-formation and teratoma-formation assays indicated that the iPSCs had the potential to differentiate into all three germ layers. Conclusion: Our study provided evidence that an iPSC line derived from AML cells was successfully established.
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Spyrou, James, David K. Gardner, and Alexandra J. Harvey. "Metabolism Is a Key Regulator of Induced Pluripotent Stem Cell Reprogramming." Stem Cells International 2019 (May 5, 2019): 1–10. http://dx.doi.org/10.1155/2019/7360121.
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Reprogramming to pluripotency involves drastic restructuring of both metabolism and the epigenome. However, induced pluripotent stem cells (iPSC) retain transcriptional memory, epigenetic memory, and metabolic memory from their somatic cells of origin and acquire aberrant characteristics distinct from either other pluripotent cells or parental cells, reflecting incomplete reprogramming. As a critical link between the microenvironment and regulation of the epigenome, nutrient availability likely plays a significant role in the retention of somatic cell memory by iPSC. Significantly, relative nutrient availability impacts iPSC reprogramming efficiency, epigenetic regulation and cell fate, and differentially alters their ability to respond to physiological stimuli. The significance of metabolites during the reprogramming process is central to further elucidating how iPSC retain somatic cell characteristics and optimising culture conditions to generate iPSC with physiological phenotypes to ensure their reliable use in basic research and clinical applications. This review serves to integrate studies on iPSC reprogramming, memory retention and metabolism, and identifies areas in which current knowledge is limited.
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Adiwinata Pawitan, Jeanne. "Prospect of Induced Pluripotent Stem Cell Genetic Repair to Cure Genetic Diseases." Stem Cells International 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/498197.
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In genetic diseases, where the cells are already damaged, the damaged cells can be replaced by new normal cells, which can be differentiated from iPSC. To avoid immune rejection, iPSC from the patient’s own cell can be developed. However, iPSC from the patients’s cell harbors the same genetic aberration. Therefore, before differentiating the iPSCs into required cells, genetic repair should be done. This review discusses the various technologies to repair the genetic aberration in patient-derived iPSC, or to prevent the genetic aberration to cause further damage in the iPSC-derived cells, such as Zn finger and TALE nuclease genetic editing, RNA interference technology, exon skipping, and gene transfer method. In addition, the challenges in using the iPSC and the strategies to manage the hurdles are addressed.
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Lau, Edward, David T. Paik, and Joseph C. Wu. "Systems-Wide Approaches in Induced Pluripotent Stem Cell Models." Annual Review of Pathology: Mechanisms of Disease 14, no. 1 (January 24, 2019): 395–419. http://dx.doi.org/10.1146/annurev-pathmechdis-012418-013046.
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Human induced pluripotent stem cells (iPSCs) provide a renewable supply of patient-specific and tissue-specific cells for cellular and molecular studies of disease mechanisms. Combined with advances in various omics technologies, iPSC models can be used to profile the expression of genes, transcripts, proteins, and metabolites in relevant tissues. In the past 2 years, large panels of iPSC lines have been derived from hundreds of genetically heterogeneous individuals, further enabling genome-wide mapping to identify coexpression networks and elucidate gene regulatory networks. Here, we review recent developments in omics profiling of various molecular phenotypes and the emergence of human iPSCs as a systems biology model of human diseases.
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Kwon, Sujin, Jung Sun Park, Byungkuk Min, and Yong-Kook Kang. "Differences in the Gene Expression Profiles of Slow- and Fast-Forming Preinduced Pluripotent Stem Cell Colonies." Stem Cells International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/195928.
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Induced pluripotent stem cells (iPSCs) are generated through a gradual process in which somatic cells undergo a number of stochastic events. In this study, we examined whether two different doxycycline-inducible iPSCs, slow-forming 4F2A-iPSCs and fast-forming NGFP-iPSCs, have equivalent levels of pluripotency. Multiplex reverse-transcriptase PCR generated gene expression profiles (GEPs) of 13 pluripotency genes in single initially formed-iPSC (if-iPSC) colonies of NGFP and 4F2A group. Assessment of GEP difference using a weighted root mean square deviation (wRMSD) indicates that 4F2A if-iPSCs are more closely related to mESCs than NGFP if-iPSCs. Consistently,NanogandSox2genes were more frequently derepressed in 4F2A if-iPSC group. We further examined 20 genes that are implicated in reprogramming. They were, overall, more highly expressed in NGFP if-iPSCs, differing from the pluripotency genes being more expressed in 4F2A if-iPSCs. wRMSD analysis for these reprogramming-related genes confirmed that the 4F2A if-iPSC colonies were less deviated from mESCs than the NGFP if-iPSC colonies. Our findings suggest that more important in attaining a better reprogramming is the mode of action by the given reprogramming factors, rather than the total activity of them exerting to the cells, as the thin-but-long-lasting mode of action in 4F2A if-iPSCs is shown to be more effective than its full-but-short-lasting mode in NGFP if-iPSCs.
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Fang, Yi-Hsien, Saprina P. H. Wang, Zi-Han Gao, Sheng-Nan Wu, Hsien-Yuan Chang, Pei-Jung Yang, Ping-Yen Liu, and Yen-Wen Liu. "Efficient Cardiac Differentiation of Human Amniotic Fluid-Derived Stem Cells into Induced Pluripotent Stem Cells and Their Potential Immune Privilege." International Journal of Molecular Sciences 21, no. 7 (March 29, 2020): 2359. http://dx.doi.org/10.3390/ijms21072359.
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Mature mammalian hearts possess very limited regenerative potential. The irreversible cardiomyocyte loss after heart injury can lead to heart failure and death. Pluripotent stem cells (PSCs) can differentiate into cardiomyocytes for cardiac repair, but there are obstacles to their clinical application. Among these obstacles is their potential for post-transplant rejection. Although human amniotic fluid-derived stem cells (hAFSCs) are immune privileged, they cannot induce cardiac differentiation. Thus, we generated hAFSC-derived induced PSCs (hAFSC-iPSCs) and used a Wnt-modulating differentiation protocol for the cardiac differentiation of hAFSC-iPSCs. In vitro studies using flow cytometry, immunofluorescence staining, and patch-clamp electrophysiological study, were performed to identify the characteristics of hAFSC-iPSC-derived cardiomyocytes (hAFSC-iPSC-CMs). We injected hAFSC-iPSC-CMs intramuscularly into rat infarcted hearts to evaluate the therapeutic potential of hAFSC-iPSC-CM transplantation. At day 21 of differentiation, the hAFSC-iPSC-CMs expressed cardiac-specific marker (cardiac troponin T), presented cardiomyocyte-specific electrophysiological properties, and contracted spontaneously. Importantly, these hAFSC-iPSC-CMs demonstrated low major histocompatibility complex (MHC) class I antigen expression and the absence of MHC class II antigens, indicating their low immunogenicity. The intramyocardial transplantation of hAFSC-iPSC-CMs restored cardiac function, partially remuscularized the injured region, and reduced fibrosis in the rat infarcted hearts. Therefore, hAFSC-iPSCs are potential candidates for the repair of infarcted myocardium.
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Vo, Linda Thuy, David H. Nguyen, Theodore Roth, Alexander Marson, George Q. Daley, and Jeffrey A. Bluestone. "Engineering antigen-specific T cells from human pluripotent stem cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 103.12. http://dx.doi.org/10.4049/jimmunol.200.supp.103.12.
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Abstract Immunotherapy has rapidly emerged as a promising treatment for many different types of cancer. Ongoing clinical trials continue to validate the efficacy of T cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) T cells, as a valid therapeutic approach. As such, new sources of both autologous and “off the shelf” T cells available in large qualities would be invaluable to widespread application of these treatments. Human induced pluripotent stem cells (iPSCs) represent a potentially inexhaustible source of clinically useful cell types. Previous studies have demonstrated the feasibility of generating T cells from iPSCs, but yields have been low due to the inefficiency of lymphoid differentiation. Here, we report a cell engineering platform capable of generating large numbers of T cells from iPSCs using a combination of transcription factors and chromatin modifiers. We initially performed a loss-of-function screen to identify regulators that enhance lymphoid potential in iPSC-derived hematopoietic progenitors. We found that repression of the Polycomb group protein EZH1 uniquely enhanced multilineage hematopoietic output from human iPSCs in vitro and in vivo. EZH1 directly modulates the expression of HSC and lymphoid genes in iPSC-derived hematopoietic progenitors and its knockdown enhances chromatin accessibility of these loci. Coupled with CAR and genome editing technologies, iPSC-derived CAR T cells release effector cytokines and mediate antigen-specific anti-tumor responses. Future work is aimed at improving antigen-specificity of iPSC-derived T cells. Together, this work highlights the utility of chromatin modifiers as cell engineering targets to enhance blood differentiation from human iPSCs.
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Mehra, Vedika, Jyoti Bikram Chhetri, Samira Ali, and Claire Roddie. "The Emerging Role of Induced Pluripotent Stem Cells as Adoptive Cellular Immunotherapeutics." Biology 12, no. 11 (November 11, 2023): 1419. http://dx.doi.org/10.3390/biology12111419.
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Adoptive cell therapy (ACT) has transformed the treatment landscape for cancer and infectious disease through the investigational use of chimeric antigen receptor T-cells (CAR-Ts), tumour-infiltrating lymphocytes (TILs) and viral-specific T-cells (VSTs). Whilst these represent breakthrough treatments, there are subsets of patients who fail to respond to autologous ACT products. This is frequently due to impaired patient T-cell function or “fitness” as a consequence of prior treatments and age, and can be exacerbated by complex manufacturing protocols. Further, the manufacture of autologous, patient-specific products is time-consuming, expensive and non-standardised. Induced pluripotent stem cells (iPSCs) as an allogeneic alternative to patient-specific products can potentially overcome the issues outlined above. iPSC technology provides an unlimited source of rejuvenated iPSC-derived T-cells (T-iPSCs) or natural killer (NK) cells (NK-iPSCs), and in the context of the growing field of allogeneic ACT, iPSCs have enormous potential as a platform for generating off-the-shelf, standardised, “fit” therapeutics for patients. In this review, we evaluate current and future applications of iPSC technology in the CAR-T/NK, TIL and VST space. We discuss current and next-generation iPSC manufacturing protocols, and report on current iPSC-based adoptive therapy clinical trials to elucidate the potential of this technology as the future of ACT.
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Shafa, Mehdi, Tylor Walsh, Krishna Morgan Panchalingam, Thomas Richardson, Laura Menendez, Xinghui Tian, Sahana Suresh Babu, et al. "Long-Term Stability and Differentiation Potential of Cryopreserved cGMP-Compliant Human Induced Pluripotent Stem Cells." International Journal of Molecular Sciences 21, no. 1 (December 23, 2019): 108. http://dx.doi.org/10.3390/ijms21010108.
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The clinical effectiveness of human induced pluripotent stem cells (iPSCs) is highly dependent on a few key quality characteristics including the generation of high quality cell bank, long-term genomic stability, post-thaw viability, plating efficiency, retention of pluripotency, directed differentiation, purity, potency, and sterility. We have already reported the establishment of iPSC master cell banks (MCBs) and working cell banks (WCBs) under current good manufacturing procedure (cGMP)-compliant conditions. In this study, we assessed the cellular and genomic stability of the iPSC lines generated and cryopreserved five years ago under cGMP-compliant conditions. iPSC lines were thawed, characterized, and directly differentiated into cells from three germ layers including cardiomyocytes (CMs), neural stem cells (NSCs), and definitive endoderm (DE). The cells were also expanded in 2D and 3D spinner flasks to evaluate their long-term expansion potential in matrix-dependent and feeder-free culture environment. All three lines successfully thawed and attached to the L7TM matrix, and formed typical iPSC colonies that expressed pluripotency markers over 15 passages. iPSCs maintained their differentiation potential as demonstrated with spontaneous and directed differentiation to the three germ layers and corresponding expression of specific markers, respectfully. Furthermore, post-thaw cells showed normal karyotype, negative mycoplasma, and sterility testing. These cells maintained both their 2D and 3D proliferation potential after five years of cryopreservation without acquiring karyotype abnormality, loss of pluripotency, and telomerase activity. These results illustrate the long-term stability of cGMP iPSC lines, which is an important step in establishing a reliable, long-term source of starting materials for clinical and commercial manufacturing of iPSC-derived cell therapy products.
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Sandt, Christophe, Olivier Feraud, Ali G. Turhan, Paul Dumas, and Annelise Bennaceur-Griscelli. "IDENTIFICATION of Infrared SPECTRAL Signature of INDUCED Pluripotent STEM CELLS (iPSC)." Blood 116, no. 21 (November 19, 2010): 4792. http://dx.doi.org/10.1182/blood.v116.21.4792.4792.
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Abstract Abstract 4792 Recent technological advances in cell reprogramming by generation of induced pluripotent stem cells (iPSC) offer major perspectives in disease modelling and future hopes for providing novel stem cells sources in regenerative medicine. However, research on iPSC still requires refining the criteria of the pluripotency stage of these cells and exploration of their equivalent functionality to human embryonic stem cells (hESC). In this work, we report that the use of the Synchrotron-based FTIR microspectroscopy allows following the infrared spectral modification of the differentiated cells during the reprogramming process as well as the comparison between iPSC with hESC. The model that we studied consisted on the use of human ES cell line H9 grown on murine embryonic fibroblasts in the presence of bFGF. We have generated mesenchymal stem cells from the H9 cell line (H9-MSC) and we used them to generate iPSC (iPSC-H9) by the enforced expression of pluripotency genes Oct4, Sox2, Lin28 and Nanog. We have also followed the same approach on murine cells by generating murine iPSC from murine ES cells by retrovirus mediated gene transfer of Oct4, Sox2, c-Myc and Klf4. iPSC were characterized by expression of pluripotency markers, and teratoma assays. Infrared Spectral fingerprints of the original H9, MSC-H9 and iPSC-H9 as well as differentiated murine fibroblasts and murine iPSC were acquired at sub-cellular resolution using a synchrotron-powered infrared microscope. In murine system, the spectral signature of iPSC has been compared to that of D3, a well-characterized murine ES cell line. The spectral signature of iPSC and ESC displays a marked difference with those of the differentiated cells used before reprogrammation regardless the origin of the target cell (mesenchymal stem cells or murine fibroblasts). We unambiguously demonstrate for the first time to our knowledge, that the human and murine iPSC retrieve the same chemical composition with an indistinguishable spectral signature from their embryonic stem cells counterparts. Importantly, the spectral signatures were found to be specific to each of the cell line, as evidenced using pattern recognition methods and illustrated the genetic biodiversity of each iPSC and ESC. Thus, in addition to the classical pluripotency markers, FTIR microspectroscopy signature could be a rapid methodology to evaluate the pluripotency after somatic cell reprogramming. Disclosures: No relevant conflicts of interest to declare.
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Chonabayashi, Kazuhisa, Masahiro Kawahara, Keisuke Okita, Masatoshi Nishizawa, Norimitsu Kadowaki, Akifumi Takaori-Kondo, Shinya Yamanaka, and Yoshinori Yoshida. "Patient-Specific Induced Pluripotent Stem Cells Recapitulate the Maturation Defect of Myelodysplastic Syndromes." Blood 124, no. 21 (December 6, 2014): 3232. http://dx.doi.org/10.1182/blood.v124.21.3232.3232.
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Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell diseases characterized by inefficient hematopoiesis and risk of progression to acute myeloid leukemia with poor prognosis. Although massive parallel sequencing studies have revealed a number of genomic alterations associated with MDS, functional consequences of these alterations remain poorly understood, mainly due to a difficulty in the ex vivo culture of primary MDS cells and a lack of good animal models. Induced pluripotent stem cells (iPSCs) from MDS patients are expected to provide a new platform for elucidation of the pathogenesis of MDS. We attempted to generate iPSCs from peripheral blood mononuclear cells of a MDS patient (RAEB-1 by WHO classification) with chromosome 20q deletion, using episomal methods. We successfully established more than 30 iPSC lines derived from Non-T cells as well as 6 iPSC lines derived from T cells at the same time. Karyotyping and SNP-CGH analysis revealed that most of the Non-T-cell-derived iPSC lines (Del20q-iPSC lines) have the isolated 20q deletion at q11.2-13.1 identical to those of the primary MDS cells, whereas all T-cell-derived iPSC lines (NK-T-iPSC lines) have normal karyotype. In order to evaluate chromosome stability, we validated karyotype of 3 randomly selected Del20q-iPSC lines after 30 passages and found no additional chromosomal aberrations other than deletion 20q. Del20q-iPSC lines displayed characteristic morphology and expressed pluripotent stem cell markers at the levels comparable to those in isogenic NK-T-iPSC lines and ES cell lines. Nine randomly selected Del20q-iPSC lines and all 6 NK-T-iPSC lines formed teratomas. Next, we performed microarray analysis in CD34+38-CD43+lineage- hematopoietic progenitor cells (HPCs) re-induced from 6 Del20q-iPSC lines and 3 NK-T-iPSC lines. 315 genes were up-regulated (fold change >2) and 437 genes were down-regulated (fold change <0.5) in Del20q-iPSC-derived HPCs compared to isogenic NK-T-iPSC-derived HPCs. In particular, expression levels of 48 genes located on 20q11.2-13.1 had reduced expression by at least 2 fold (76 genes by 1.5 fold). Finally, we investigated the potential of hematopoietic differentiation in 9 Del20q-iPSC lines and 6 isogenic NK-T-iPSC lines. The efficiency of HPC production assessed by the OP9 co-culture system and the embryoid body differentiation culture system was comparable between Del20q-iPSC lines and NK-T-iPSC lines. However, colony forming capacity of iPSC-derived HPCs in methylcellulose culture and granulocyte and erythroid differentiation of iPSCs were severely impaired in all tested Del20q-iPSC lines (CFU-C numbers: 23±4 vs 114±16 per 2,500 HPCs, p< .001; CD66b+/CD11b+ cells: 3.9±1.2% vs 49.0±6.7%, p< .001; CD235a+ cells: 3.8±2.9% vs 32.2±5.2%, p< .001, in Del20q-iPSC lines vs NK-T-iPSC lines respectively). These results indicate that Del20q-iPSC lines are capable of exhibiting the identical feature of the MDS patient. This iPSC-based system could be useful for studying the precise molecular mechanisms of MDS and may also allow testing new therapeutic compounds under genetically defined conditions. Disclosures Yamanaka: iPS Academia Japan: Consultancy.
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Amalakanti, *Sridhar, Vijaya Chandra Reddy Avula, and Sachin Singh. "SYSTEMATIC REVIEW OF INDUCED PLURIPOTENT STEM CELL THERAPY IN TRAUMATIC BRAIN INJURY." International Journal of Neuropsychopharmacology 28, Supplement_1 (February 2025): i364—i365. https://doi.org/10.1093/ijnp/pyae059.649.
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Abstract Background Traumatic brain injury (TBI) is a major global health problem with limited treatment options. Induced pluripotent stem cells (iPSCs) have emerged as a promising therapy for neural regeneration and repair after TBI. Aims & Objectives This systematic review aimed to evaluate preclinical studies on the efficacy of iPSC- based therapies for functional recovery after TBI. Method From, PubMed, Ovid Medline, Cochrane Library, SCOPUS, and Web of Science 102 studies were found for studies on iPSCs in TBI animal models. Included studies (n=9) used neural stem cells derived from iPSCs transplanted into rodent models of TBI. Outcome measures were brain injury volume, functional recovery, and tissue repair biomarkers. Study quality was assessed using a 10-point scale. Results The majority of studies showed significant improvement in motor function, cognition, and social behavior with iPSC therapy. Transplanted iPSC-neural stem cells migrated to injury sites, differentiated into neurons and glia, reduced lesion size, and increased neural repair markers. Higher quality scores were noted for studies reporting randomization, blinded assessment, and temperature control. Discussion & Conclusions Preclinical evidence demonstrates the potential of iPSC-derived neural stem cell transplantation to improve functional outcomes after TBI through neuroregenerative effects. Further research is warranted to evaluate safety, optimize protocols, and translate findings to clinical trials for TBI patients. iPSC-based therapies may offer new hope for recovery after this devastating injury.
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Zhang, Teng, Cheng Qian, Mengyao Song, Yu Tang, Yueke Zhou, Guanglu Dong, Qiuhong Shen, et al. "Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy." International Journal of Molecular Sciences 25, no. 5 (February 26, 2024): 2680. http://dx.doi.org/10.3390/ijms25052680.
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Since its inception, induced pluripotent stem cell (iPSC) technology has been hailed as a powerful tool for comprehending disease etiology and advancing drug screening across various domains. While earlier iPSC-based disease modeling and drug assessment primarily operated at the cellular level, recent years have witnessed a significant shift towards organoid-based investigations. Organoids derived from iPSCs offer distinct advantages, particularly in enabling the observation of disease progression and drug metabolism in an in vivo-like environment, surpassing the capabilities of iPSC-derived cells. Furthermore, iPSC-based cell therapy has emerged as a focal point of clinical interest. In this review, we provide an extensive overview of non-integrative reprogramming methods that have evolved since the inception of iPSC technology. We also deliver a comprehensive examination of iPSC-derived organoids, spanning the realms of the nervous system, cardiovascular system, and oncology, as well as systematically elucidate recent advancements in iPSC-related cell therapies.
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Marpaung, David Septian Sumanto, and Ayu Oshin Yap Sinaga. "A mini review on production of pluripotency factors (Oct4, Sox2, Klf4 and c-Myc) through recombinant protein technology." Communications in Science and Technology 5, no. 1 (July 2, 2020): 1–4. http://dx.doi.org/10.21924/cst.5.1.2020.171.
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The four transcription factors OCT4, SOX2, KLF4 and c-MYC are highly expressed in embryonic stem cells (ESC) and their overexpression can induce pluripotency, the ability to differentiate into all cell types of an organism. The ectopic expression such transcription factors could reprogram somatic stem cells become induced pluripotency stem cells (iPSC), an embryonic stem cells-like. Production of recombinant pluripotency factors gain interests due to high demand from generation of induced pluripotent stem cells in regenerative medical therapy recently. This review will focus on demonstrate the recent advances in recombinant pluripotency factor production using various host.
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Moslem, Mohsen, Irina Eberle, Iuliia Weber, Reinhard Henschler, and Tobias Cantz. "Mesenchymal Stem/Stromal Cells Derived from Induced Pluripotent Stem Cells Support CD34posHematopoietic Stem Cell Propagation and Suppress Inflammatory Reaction." Stem Cells International 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/843058.
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Mesenchymal stem/stromal cells (MSCs) represent a promising cell source for research and therapeutic applications, but their restrictedex vivopropagation capabilities limit putative applications. Substantial self-renewing of stem cells can be achieved by reprogramming cells into induced pluripotent stem cells (iPSCs) that can be easily expanded as undifferentiated cells even in mass culture. Here, we investigated a differentiation protocol enabling the generation and selection of human iPSC-derived MSCs exhibiting relevant surface marker expression profiles (CD105 and CD73) and functional characteristics. We generated such iPSC-MSCs from fibroblasts and bone marrow MSCs utilizing two different reprogramming constructs. All such iPSC-MSCs exhibited the characteristics of normal bone marrow-derived (BM) MSCs. In direct comparison to BM-MSCs our iPSC-MSCs exhibited a similar surface marker expression profile but shorter doubling times without reaching senescence within 20 passages. Considering functional capabilities, iPSC-MSCs provided supportive feeder layer for CD34+hematopoietic stem cells’ self-renewal and colony forming capacities. Furthermore, iPSC-MSCs gained immunomodulatory function to suppress CD4+cell proliferation, reduce proinflammatory cytokines in mixed lymphocyte reaction, and increase regulatory CD4+/CD69+/CD25+T-lymphocyte population. In conclusion, we generated fully functional MSCs from various iPSC lines irrespective of their starting cell source or reprogramming factor composition and we suggest that such iPSC-MSCs allow repetitive cell applications for advanced therapeutic approaches.
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Ishii, Koji, Koki Abe, Teiji Sakamoto, Hisashi Hasebe, and Shogo Miyata. "Effects of Clump Size on the Pluripotency and Proliferation in the Passaging Process of Mouse Induced Pluripotent Stem Cells." Processes 12, no. 11 (October 30, 2024): 2387. http://dx.doi.org/10.3390/pr12112387.
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Induced pluripotent stem cells (iPSCs) are a promising cell source because of their pluripotency and self-renewal abilities. However, there is a risk of pluripotency loss during cell expansion. Particularly, cell passaging is associated with a higher risk of decreasing cell quality. There are two iPSC passaging methods: single-cell and clump passaging. Single-cell passaging is a rapid and simple method for cell manipulation, whereas clump passaging is superior for maintaining iPSC pluripotency. Therefore, clump passaging is a robust method for expanding iPSCs while maintaining their pluripotency. However, clump size control during clump passaging is difficult because colony fragmentation is performed manually by pipetting the colonies detached from the cell culture substrates. In this study, the effect of pipetting on iPSC colony fragmentation was evaluated and the relationship between iPSC clump size and pluripotency was clarified. An automated pipetting device was developed to standardize the clump passage process. The effect of clump size on the pluripotency and proliferative capacity of mouse iPSCs was investigated. Clump size was controlled by varying the number of pipetting cycles, and pluripotency and proliferation were assessed via alkaline phosphatase staining and flow cytometry. Our results revealed that a decrease in clump size corresponded to an increase in cell proliferation, while pluripotency maintenance was optimized under specific clump sizes. These results underscore the significance of clump size for stem cell quality, emphasizing the need for a balanced approach to maintain pluripotency while fostering proliferation in the cell expansion culture for iPSCs.
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Ahmad, Ruhel, Vincenza Sportelli, Michael Ziller, Dietmar Spengler, and Anke Hoffmann. "Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells." Cells 7, no. 9 (September 17, 2018): 140. http://dx.doi.org/10.3390/cells7090140.
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Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor’s genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.
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Hu, Xinchao, Chengyuan Mao, Liyuan Fan, Haiyang Luo, Zhengwei Hu, Shuo Zhang, Zhihua Yang, et al. "Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells." Stem Cells International 2020 (March 12, 2020): 1–15. http://dx.doi.org/10.1155/2020/1061470.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease. The molecular mechanisms of PD at the cellular level involve oxidative stress, mitochondrial dysfunction, autophagy, axonal transport, and neuroinflammation. Induced pluripotent stem cells (iPSCs) with patient-specific genetic background are capable of directed differentiation into dopaminergic neurons. Cell models based on iPSCs are powerful tools for studying the molecular mechanisms of PD. The iPSCs used for PD studies were mainly from patients carrying mutations in synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), cytoplasmic protein sorting 35 (VPS35), and variants in glucosidase beta acid (GBA). In this review, we summarized the advances in molecular mechanisms of Parkinson’s disease using iPSC models.
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Wang, Xiaotong, Zhenbo Han, Ying Yu, Zihang Xu, Benzhi Cai, and Ye Yuan. "Potential Applications of Induced Pluripotent Stem Cells for Cardiovascular Diseases." Current Drug Targets 20, no. 7 (May 9, 2019): 763–74. http://dx.doi.org/10.2174/1389450120666181211164147.
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Owning the high incidence and disability rate in the past decades, to be expected, cardiovascular diseases (CVDs) have become one of the leading death causes worldwide. Currently, induced pluripotent stem cells (iPSCs), with the potential to form fresh myocardium and improve the functions of damaged hearts, have been studied widely in experimental CVD therapy. Moreover, iPSC-derived cardiomyocytes (CMs), as novel disease models, play a significant role in drug screening, drug safety assessment, along with the exploration of pathological mechanisms of diseases. Furthermore, a lot of studies have been carried out to clarify the biological basis of iPSCs and its derived cells in the treatment of CVDs. Their molecular mechanisms were associated with release of paracrine factors, regulation of miRNAs, mechanical support of new tissues, activation of specific pathways and specific enzymes, etc. In addition, a few small chemical molecules and suitable biological scaffolds play positive roles in enhancing the efficiency of iPSC transplantation. This article reviews the development and limitations of iPSCs in CVD therapy, and summarizes the latest research achievements regarding the application of iPSCs in CVDs.
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Maali, Amirhosein, Faezeh Maroufi, Farzin Sadeghi, Amir Atashi, Reza Kouchaki, Mona Moghadami, and Mehdi Azad. "Induced pluripotent stem cell technology: trends in molecular biology, from genetics to epigenetics." Epigenomics 13, no. 8 (April 2021): 631–47. http://dx.doi.org/10.2217/epi-2020-0409.
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Induced pluripotent stem cell (iPSC) technology, based on autologous cells’ reprogramming to the embryonic state, is a new approach in regenerative medicine. Current advances in iPSC technology have opened up new avenues for multiple applications, from basic research to clinical therapy. Thus, conducting iPSC trials have attracted increasing attention and requires an extensive understanding of the molecular basis of iPSCs. Since iPSC reprogramming is based on the methods inducing the expression of specific genes involved in pluripotency states, it can be concluded that iPSC reprogramming is strongly influenced by epigenetics. In this study, we reviewed the molecular basis of reprogramming, including the reprogramming factors (OCT4, SOX2, KLF4, c-MYC, NANOG, ESRRB, LIN28 as well as their regulatory networks), applied vectors (retroviral vectors, adenoviral vectors, Sendaiviral vectors, episomal plasmids, piggyBac, simple vectors, etc.) and epigenetic modifications (miRNAs, histones and DNA methylation states) to provide a comprehensive guide for reprogramming studies.
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Edo, Ayaka, Sunao Sugita, Yoko Futatsugi, Junki Sho, Akishi Onishi, Yoshiaki Kiuchi, and Masayo Takahashi. "Capacity of Retinal Ganglion Cells Derived from Human Induced Pluripotent Stem Cells to Suppress T-Cells." International Journal of Molecular Sciences 21, no. 21 (October 22, 2020): 7831. http://dx.doi.org/10.3390/ijms21217831.
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Retinal ganglion cells (RGCs) are impaired in patients such as those with glaucoma and optic neuritis, resulting in permanent vision loss. To restore visual function, development of RGC transplantation therapy is now underway. Induced pluripotent stem cells (iPSCs) are an important source of RGCs for human allogeneic transplantation. We therefore analyzed the immunological characteristics of iPSC-derived RGCs (iPSC-RGCs) to evaluate the possibility of rejection after RGC transplantation. We first assessed the expression of human leukocyte antigen (HLA) molecules on iPSC-RGCs using immunostaining, and then evaluated the effects of iPSC-RGCs to activate lymphocytes using the mixed lymphocyte reaction (MLR) and iPSC-RGC co-cultures. We observed low expression of HLA class I and no expression of HLA class II molecules on iPSC-RGCs. We also found that iPSC-RGCs strongly suppressed various inflammatory immune cells including activated T-cells in the MLR assay and that transforming growth factor-β2 produced by iPSC-RGCs played a critical role in suppression of inflammatory cells in vitro. Our data suggest that iPSC-RGCs have low immunogenicity, and immunosuppressive capacity on lymphocytes. Our study will contribute to predicting immune attacks after RGC transplantation.
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Gallegos-Cardenas, A., K. Wang, E. T. Jordan, R. West, F. D. West, J. Y. Yang, and S. L. Stice. "191 ROBUST GENERATION OF NEURAL STEM CELLS FROM PIG INDUCED PLURIPOTENT STEM CELLS FOR TRANSLATIONAL NEURAL REGENERATIVE MEDICINE." Reproduction, Fertility and Development 26, no. 1 (2014): 210. http://dx.doi.org/10.1071/rdv26n1ab191.
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The generation of pig induced pluripotent stem cells (iPSC) opened the possibility to evaluate autologous neural cell therapy as a viable option for human patients. However, it is necessary to demonstrate whether pig iPSC are capable of in vitro neural differentiation similar to human iPSC in order to perform in vitro and in vivo comparative studies. Multiple laboratories have generated pig iPSC that have been characterised using pluripotent markers such as SSEA4 and POU5F1. However, correlations of pluripotent marker expression profiles among iPSC lines and their neural differentiation potential has not been fully explored. Because neural rosettes (NR) are composed of neural stem cells, our goal was to demonstrate that NR from pig iPSC can be generated, isolated, and expanded in vitro from multiple porcine iPSC lines similar to human iPSC and that the level of pluripotency in the starting porcine iPSC population (POUF51 and SSEA4 expression) could influence NRs development. Three lines of pig iPSC L1, L2, and L3 were cultured on matrigel-coated plates in mTeSR1 medium (Stemcell Technologies Inc., Vancouver, BC, Canada) and passaged every 3 to 4 days. For neural induction (NI), pig iPSC were disaggregated using dispase and plated. After 24 h, cells were maintained in N2 media [77% DMEM/F12, 10 ng mL–1 bovine fibroblast growth factor (bFGF), and 1X N2] for 15 days. To evaluate the differentiation potential to neuron and glial cells, NR were isolated, expanded in vitro and cultured for three weeks in AB2 medium (AB2, 1X ANS, and 2 mM L-Glutamine). Immunostaining assays were performed to determine pluripotent (POU5F1 and SSEA4), tight junction (ZO1), neural epithelial (Pax6 and Sox1), neuron (Tuj1), astrocyte (GFAP), and oligodendrocyte (O4) marker expression. Line L2 (POU5F1high and SSEA4low) showed a high potential to form NR (6.3.5%, P < 0.05) in comparison to the other 2 lines L1 (POU5F1low and SSEA4low) and L3 (POU5F1low and SSEA4high) upon NI. The NR immunocytochemistry results from Line L2 showed the presence of Pax6+ and Sox1– NRs cells at day 9 post-neural induction and that ZO1 started to localise at the apical border of NRs. At day 13, NRs cells were Pax6+ and Sox1+, and ZO1 was localised to the lumen of NR. After isolation and culture in vitro, NR cells expressed transcription factors PLAGL1, DACH1, and OTX2 through 2 passages, but were not detected in later passages. However, rosette cytoarchitecture was present up until passage 7 and were still Pax6+/Sox1+. NRs at passage 2 were cryopreserved and upon thaw showed normal NR morphology and were Pax6+/Sox1+. To characterise the plasticity of NRs, cells were differentiated. Tuj1 expression was predominant after differentiation indicating a bias towards a neuron phenotype. These results demonstrate that L2 pig iPSC (POUF51high and SSEA4low) have a high potential to form NR and neural differentiation parallels human iPSC neurulation events. Porcine iPSC should be considered as a large animal model for determining the safety and efficacy of human iPSC neural cell therapies.
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Kulcenty, Katarzyna, Joanna P. Wroblewska, Marcin Rucinski, Emilia Kozlowska, Karol Jopek, and Wiktoria M. Suchorska. "MicroRNA Profiling During Neural Differentiation of Induced Pluripotent Stem Cells." International Journal of Molecular Sciences 20, no. 15 (July 26, 2019): 3651. http://dx.doi.org/10.3390/ijms20153651.
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MicroRNAs (miRNA) play an essential role in the regulation of gene expression and influence signaling networks responsible for several cellular processes like differentiation of pluripotent stem cells. Despite several studies on the neurogenesis process, no global analysis of microRNA expression during differentiation of induced pluripotent stem cells (iPSC) to neuronal stem cells (NSC) has been done. Therefore, we compared the profile of microRNA expression in iPSC lines and in NSC lines derived from them, using microarray-based analysis. Two different protocols for NSC formation were used: Direct and two-step via neural rosette formation. We confirmed the new associations of previously described miRNAs in regulation of NSC differentiation from iPSC. We discovered upregulation of miR-10 family, miR-30 family and miR-9 family and downregulation of miR-302 and miR-515 family expression. Moreover, we showed that miR-10 family play a crucial role in the negative regulation of genes expression belonging to signaling pathways involved in neural differentiation: WNT signaling pathway, focal adhesion, and signaling pathways regulating pluripotency of stem cells.
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Lindoso, Rafael Soares, Tais H. Kasai-Brunswick, Gustavo Monnerat Cahli, Federica Collino, Adriana Bastos Carvalho, Antonio Carlos Campos de Carvalho, and Adalberto Vieyra. "Proteomics in the World of Induced Pluripotent Stem Cells." Cells 8, no. 7 (July 11, 2019): 703. http://dx.doi.org/10.3390/cells8070703.
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Omics approaches have significantly impacted knowledge about molecular signaling pathways driving cell function. Induced pluripotent stem cells (iPSC) have revolutionized the field of biological sciences and proteomics and, in particular, has been instrumental in identifying key elements operating during the maintenance of the pluripotent state and the differentiation process to the diverse cell types that form organisms. This review covers the evolution of conceptual and methodological strategies in proteomics; briefly describes the generation of iPSC from a historical perspective, the state-of-the-art of iPSC-based proteomics; and compares data on the proteome and transcriptome of iPSC to that of embryonic stem cells (ESC). Finally, proteomics of healthy and diseased cells and organoids differentiated from iPSC are analyzed.
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Brodehl, Andreas, Hans Ebbinghaus, Marcus-André Deutsch, Jan Gummert, Anna Gärtner, Sandra Ratnavadivel, and Hendrik Milting. "Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies." International Journal of Molecular Sciences 20, no. 18 (September 6, 2019): 4381. http://dx.doi.org/10.3390/ijms20184381.
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In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.