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Cells
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iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases
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iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 46680

Special Issue Editors

Prof. Dr. James Adjaye

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Guest Editor
Institute of Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Dusseldorf, Germany
Interests: iPSC-based disease modelling; Alzheimer's disease; Nijmegen breakage syndrome; steatosis patients; acute and chronic kidney injury
Special Issues, Collections and Topics in MDPI journals
Dr. Nina Graffmann

E-Mail Website
Guest Editor
Institute of Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Dusseldorf, Germany
Interests: pluripotent stem cells; in vitro differentiation; hepatocytes; non alcoholic fatty liver disease; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the generation of human-induced pluripotent stem cells (iPSCs) in 2007, numerous protocols have been developed to differentiate iPSCs into cells of all three germ layers. iPSC-derived cellular products have already been applied in regenerative medicine based therapies.

In addition to therapy, in vitro differentiated cells are currently used for drug testing, development, and disease modeling to give valuable insights into underlying mechanisms. iPSC-derived 3D organoids are composed of distinct cell types characteristic within the organ under investigation and adopt specific organ-related structure, thus further increasing their maturity and utility compared to 2D cultured cells. Furthermore, culturing of organoids employing organ-on-a-chip systems has added an additional level of sophistication and enhancement, thus enabling investigations at near-physiological levels.

In this Special Issue, we call for original research, review articles, and meta-analyses related to iPSC-based 2D and 3D disease modeling, encompassing organs derived from all three germ layers. In addition, we are interested in studies demonstrating therapeutic usefulness and safety of iPSC-derived cells.

Prof. James Adjaye
Dr. Nina Graffmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Induced pluripotent stem cells (iPSCs)
  • Genome editing
  • Disease modeling
  • Organoids
  • Organ-on-a-chip
  • Cellular therapeutics
  • Bioinformatics

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Related Special Issue

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 180 KiB  
Editorial
Editorial for Special Issue: iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases
by Nina Graffmann and James Adjaye
Cells 2022, 11(15), 2270; https://doi.org/10.3390/cells11152270 - 22 Jul 2022
Viewed by 1544
Abstract
Human induced pluripotent stem cells (iPSCs) have evolved as a powerful tool to model diseases and study treatment possibilities [...] Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)

Research

Jump to: Editorial, Review

24 pages, 4592 KiB  
Article
Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids
by Soraia Martins, Lars Erichsen, Angeliki Datsi, Wasco Wruck, Wolfgang Goering, Eleftheria Chatzantonaki, Vanessa Cristina Meira de Amorim, Andrea Rossi, Krystyna H. Chrzanowska and James Adjaye
Cells 2022, 11(5), 802; https://doi.org/10.3390/cells11050802 - 25 Feb 2022
Cited by 11 | Viewed by 3294
Abstract
Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (NBN), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed [...] Read more.
Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (NBN), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed induced pluripotent stem cell-derived cerebral organoids from two NBS patients to study the etiology of microcephaly. We show that NBS organoids carrying the homozygous 657del5 NBN mutation are significantly smaller with disrupted cyto-architecture. The organoids exhibit premature differentiation, and Neuronatin (NNAT) over-expression. Furthermore, pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. After exposure to bleomycin, NBS organoids undergo delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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20 pages, 5459 KiB  
Article
The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells
by Lisa Nguyen, Wasco Wruck, Lars Erichsen, Nina Graffmann and James Adjaye
Cells 2022, 11(4), 635; https://doi.org/10.3390/cells11040635 - 11 Feb 2022
Cited by 14 | Viewed by 4523 | Correction
Abstract
Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of [...] Read more.
Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic options are urgently needed. Within the kidney, the glomeruli are involved in blood filtration and waste excretion and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be employed to induce acute glomerular damage and to model glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations revealed the disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell-death-related processes. We conclude that the treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated by an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine-stem-cell-derived kidney organoids can be used to model kidney-associated diseases and drug discovery. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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25 pages, 4231 KiB  
Article
Generation of a NES-mScarlet Red Fluorescent Reporter Human iPSC Line for Live Cell Imaging and Flow Cytometric Analysis and Sorting Using CRISPR-Cas9-Mediated Gene Editing
by Parivash Nouri, Anja Zimmer, Stefanie Brüggemann, Robin Friedrich, Ralf Kühn and Nilima Prakash
Cells 2022, 11(2), 268; https://doi.org/10.3390/cells11020268 - 13 Jan 2022
Cited by 4 | Viewed by 4881
Abstract
Advances in the regenerative stem cell field have propelled the generation of tissue-specific cells in the culture dish for subsequent transplantation, drug screening purposes, or the elucidation of disease mechanisms. One major obstacle is the heterogeneity of these cultures, in which the tissue-specific [...] Read more.
Advances in the regenerative stem cell field have propelled the generation of tissue-specific cells in the culture dish for subsequent transplantation, drug screening purposes, or the elucidation of disease mechanisms. One major obstacle is the heterogeneity of these cultures, in which the tissue-specific cells of interest usually represent only a fraction of all generated cells. Direct identification of the cells of interest and the ability to specifically isolate these cells in vitro is, thus, highly desirable for these applications. The type VI intermediate filament protein NESTIN is widely used as a marker for neural stem/progenitor cells (NSCs/NPCs) in the developing and adult central and peripheral nervous systems. Applying CRISPR-Cas9 technology, we have introduced a red fluorescent reporter (mScarlet) into the NESTIN (NES) locus of a human induced pluripotent stem cell (hiPSC) line. We describe the generation and characterization of NES-mScarlet reporter hiPSCs and demonstrate that this line is an accurate reporter of NSCs/NPCs during their directed differentiation into human midbrain dopaminergic (mDA) neurons. Furthermore, NES-mScarlet hiPSCs can be used for direct identification during live cell imaging and for flow cytometric analysis and sorting of red fluorescent NSCs/NPCs in this paradigm. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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21 pages, 52833 KiB  
Article
Generation of Primordial Germ Cell-like Cells from iPSCs Derived from Turner Syndrome Patients
by Aline Fernanda de Souza, Fabiana Fernandes Bressan, Naira Caroline Godoy Pieri, Ramon Cesar Botigelli, Tamas Revay, Simone Kashima Haddad, Dimas Tadeu Covas, Ester Silveira Ramos, Willian Allan King and Flavio Vieira Meirelles
Cells 2021, 10(11), 3099; https://doi.org/10.3390/cells10113099 - 10 Nov 2021
Cited by 6 | Viewed by 3809
Abstract
Turner syndrome (TS) is a genetic disorder in females with X Chromosome monosomy associated with highly variable clinical features, including premature primary gonadal failure leading to ovarian dysfunction and infertility. The mechanism of development of primordial germ cells (PGCs) and their connection with [...] Read more.
Turner syndrome (TS) is a genetic disorder in females with X Chromosome monosomy associated with highly variable clinical features, including premature primary gonadal failure leading to ovarian dysfunction and infertility. The mechanism of development of primordial germ cells (PGCs) and their connection with ovarian failure in TS is poorly understood. An in vitro model of PGCs from TS would be beneficial for investigating genetic and epigenetic factors that influence germ cell specification. Here we investigated the potential of reprogramming peripheral mononuclear blood cells from TS women (PBMCs-TS) into iPSCs following in vitro differentiation in hPGCLCs. All hiPSCs-TS lines demonstrated pluripotency state and were capable of differentiation into three embryonic layers (ectoderm, endoderm, and mesoderm). The PGCLCs-TS recapitulated the initial germline development period regarding transcripts and protein marks, including the epigenetic profile. Overall, our results highlighted the feasibility of producing in vitro models to help the understanding of the mechanisms associated with germ cell formation in TS. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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17 pages, 3604 KiB  
Article
An Electrophysiological and Pharmacological Study of the Properties of Human iPSC-Derived Neurons for Drug Discovery
by Robert F. Halliwell, Hamed Salmanzadeh, Leanne Coyne and William S. Cao
Cells 2021, 10(8), 1953; https://doi.org/10.3390/cells10081953 - 31 Jul 2021
Cited by 11 | Viewed by 6529
Abstract
Human stem cell-derived neurons are increasingly considered powerful models in drug discovery and disease modeling, despite limited characterization of their molecular properties. Here, we have conducted a detailed study of the properties of a commercial human induced Pluripotent Stem Cell (iPSC)-derived neuron line, [...] Read more.
Human stem cell-derived neurons are increasingly considered powerful models in drug discovery and disease modeling, despite limited characterization of their molecular properties. Here, we have conducted a detailed study of the properties of a commercial human induced Pluripotent Stem Cell (iPSC)-derived neuron line, iCell [GABA] neurons, maintained for up to 3 months in vitro. We confirmed that iCell neurons display neurite outgrowth within 24 h of plating and label for the pan-neuronal marker, βIII tubulin within the first week. Our multi-electrode array (MEA) recordings clearly showed neurons generated spontaneous, spike-like activity within 2 days of plating, which peaked at one week, and rapidly decreased over the second week to remain at low levels up to one month. Extracellularly recorded spikes were reversibly inhibited by tetrodotoxin. Patch-clamp experiments showed that iCell neurons generated spontaneous action potentials and expressed voltage-gated Na and K channels with membrane capacitances, resistances and membrane potentials that are consistent with native neurons. Our single neuron recordings revealed that reduced spiking observed in the MEA after the first week results from development of a dominant inhibitory tone from GABAergic neuron circuit maturation. GABA evoked concentration-dependent currents that were inhibited by the convulsants, bicuculline and picrotoxin, and potentiated by the positive allosteric modulators, diazepam, chlordiazepoxide, phenobarbital, allopregnanolone and mefenamic acid, consistent with native neuronal GABAA receptors. We also show that glycine evoked robust concentration-dependent currents that were inhibited by the neurotoxin, strychnine. Glutamate, AMPA, Kainate and NMDA each evoked concentration-dependent currents in iCell neurons that were blocked by their selective antagonists, consistent with the expression of ionotropic glutamate receptors. The NMDA currents required the presence of the co-agonist glycine and were blocked in a highly voltage-dependent manner by Mg2+ consistent with the properties of native neuronal NMDA receptors. Together, our data suggest that such human iPSC-derived neurons may have significant value in drug discovery and development and may eventually largely replace the need for animal tissues in human biomedical research. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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23 pages, 75708 KiB  
Article
Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease
by Enrique Armijo, George Edwards, Andrea Flores, Jorge Vera, Mohammad Shahnawaz, Fabio Moda, Cesar Gonzalez, Magdalena Sanhueza and Claudio Soto
Cells 2021, 10(7), 1802; https://doi.org/10.3390/cells10071802 - 16 Jul 2021
Cited by 23 | Viewed by 5452
Abstract
Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau [...] Read more.
Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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18 pages, 2990 KiB  
Article
Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia
by Husam Qanash, Yongqin Li, Richard H. Smith, Kaari Linask, Sara Young-Baird, Waleed Hakami, Keyvan Keyvanfar, John S. Choy, Jizhong Zou and Andre Larochelle
Cells 2021, 10(4), 734; https://doi.org/10.3390/cells10040734 - 26 Mar 2021
Cited by 10 | Viewed by 4898
Abstract
Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem [...] Read more.
Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem cell (iPSC) lines were generated from blood mononuclear cells of DBA patients with inactivating mutations in RPS19 and subjected to hematopoietic differentiation to model disease phenotypes. In vitro differentiated hematopoietic cells were used to investigate whether eltrombopag, an FDA-approved mimetic of thrombopoietin with robust intracellular iron chelating properties, could rescue erythropoiesis in DBA by restricting the labile iron pool (LIP) derived from excessive free heme. DBA iPSCs exhibited RPS19 haploinsufficiency, reduction in the 40S/60S ribosomal subunit ratio and early erythroid differentiation arrest in the absence of eltrombopag, compared to control isogenic iPSCs established by CRISPR/Cas9-mediated correction of the RPS19 point mutation. Notably, differentiation of DBA iPSCs in the presence of eltrombopag markedly improved erythroid maturation. Consistent with a molecular mechanism based on intracellular iron chelation, we observed that deferasirox, a clinically licensed iron chelator able to permeate into cells, also enhanced erythropoiesis in our DBA iPSC model. In contrast, erythroid maturation did not improve substantially in DBA iPSC differentiation cultures supplemented with deferoxamine, a clinically available iron chelator that poorly accesses LIP within cellular compartments. These findings identify eltrombopag as a promising new therapeutic to improve anemia in DBA. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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16 pages, 18699 KiB  
Article
Characterization of Early-Onset Finger Osteoarthritis-Like Condition Using Patient-Derived Induced Pluripotent Stem Cells
by Yeri Alice Rim, Yoojun Nam, Narae Park, Kijun Lee, Hyerin Jung, Seung Min Jung, Jennifer Lee and Ji Hyeon Ju
Cells 2021, 10(2), 317; https://doi.org/10.3390/cells10020317 - 4 Feb 2021
Cited by 5 | Viewed by 2489
Abstract
Early osteoarthritis (OA)-like symptoms are difficult to study owing to the lack of disease samples and animal models. In this study, we generated induced pluripotent stem cell (iPSC) lines from a patient with a radiographic early-onset finger osteoarthritis (efOA)-like condition in the distal [...] Read more.
Early osteoarthritis (OA)-like symptoms are difficult to study owing to the lack of disease samples and animal models. In this study, we generated induced pluripotent stem cell (iPSC) lines from a patient with a radiographic early-onset finger osteoarthritis (efOA)-like condition in the distal interphalangeal joint and her healthy sibling. We differentiated those cells with similar genetic backgrounds into chondrogenic pellets (CPs) to confirm efOA. CPs generated from efOA-hiPSCs (efOA-CPs) showed lower levels of COL2A1, which is a key marker of hyaline cartilage after complete differentiation, for 21 days. Increase in pellet size and vacuole-like morphologies within the pellets were observed in the efOA-CPs. To analyze the changes occurred during the development of vacuole-like morphology and the increase in pellet size in efOA-CPs, we analyzed the expression of OA-related markers on day 7 of differentiation and showed an increase in the levels of COL1A1, RUNX2, VEGFA, and AQP1 in efOA-CPs. IL-6, MMP1, and MMP10 levels were also increased in the efOA-CPs. Taken together, we present proof-of-concept regarding disease modeling of a unique patient who showed OA-like symptoms. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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Review

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31 pages, 3023 KiB  
Review
Induced Pluripotent Stem Cells as a Tool for Modeling Hematologic Disorders and as a Potential Source for Cell-Based Therapies
by Ponthip Pratumkaew, Surapol Issaragrisil and Sudjit Luanpitpong
Cells 2021, 10(11), 3250; https://doi.org/10.3390/cells10113250 - 19 Nov 2021
Cited by 14 | Viewed by 7327
Abstract
The breakthrough in human induced pluripotent stem cells (hiPSCs) has revolutionized the field of biomedical and pharmaceutical research and opened up vast opportunities for drug discovery and regenerative medicine, especially when combined with gene-editing technology. Numerous healthy and patient-derived hiPSCs for human disease [...] Read more.
The breakthrough in human induced pluripotent stem cells (hiPSCs) has revolutionized the field of biomedical and pharmaceutical research and opened up vast opportunities for drug discovery and regenerative medicine, especially when combined with gene-editing technology. Numerous healthy and patient-derived hiPSCs for human disease modeling have been established, enabling mechanistic studies of pathogenesis, platforms for preclinical drug screening, and the development of novel therapeutic targets/approaches. Additionally, hiPSCs hold great promise for cell-based therapy, serving as an attractive cell source for generating stem/progenitor cells or functional differentiated cells for degenerative diseases, due to their unlimited proliferative capacity, pluripotency, and ethical acceptability. In this review, we provide an overview of hiPSCs and their utility in the study of hematologic disorders through hematopoietic differentiation. We highlight recent hereditary and acquired genetic hematologic disease modeling with patient-specific iPSCs, and discuss their applications as instrumental drug screening tools. The clinical applications of hiPSCs in cell-based therapy, including the next-generation cancer immunotherapy, are provided. Lastly, we discuss the current challenges that need to be addressed to fulfill the validity of hiPSC-based disease modeling and future perspectives of hiPSCs in the field of hematology. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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