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Cells
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Pluripotent Stem Cells for Disease Modelling
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Pluripotent Stem Cells for Disease Modelling

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 41453

Special Issue Editors

Dr. Lezanne Ooi

E-Mail Website
Guest Editor
Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, Australia
Interests: induced pluripotent stem cells; neurodegeneration; neurodevelopment; neuroprotection; Alzheimer’s disease; motor neuron disease; dementia
Special Issues, Collections and Topics in MDPI journals
Dr. Mirella Dottori

E-Mail Website
Guest Editor
Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong, Australia
Interests: human pluripotent stem cells; neurodevelopment; peripheral sensory neurons; neurodegeneration; Friedreich’s ataxia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleauges,

There is a growing appreciation that the use of human cells in vitro is important for preclinical drug testing and identifying disease mechanisms that can lead to the development of novel therapeutic strategies. The use of pluripotent stem cells for disease modelling and drug discovery has thus exploded over the last decade and almost every disease can be modelled in vitro. Central to the utility of pluripotent stem cells is the development of protocols that yield functional disease-relevant cell types that recapitulate disease phenotypes. The aim of this Special Issue is to provide protocols and assays that are used in pluripotent stem cells disease modelling and to highlight the strengths and weaknesses of the approaches currently available. The articles will be a valuable resource for the disease modelling scientific community.

Dr. Lezanne Ooi
Dr. Mirella Dottori
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

  • pluripotent stem cells
  • disease modelling
  • drug discovery
  • differentiation
  • functional characterisation
  • cell phenotype

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Related Special Issue

Published Papers (6 papers)

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Research

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17 pages, 4431 KiB  
Article
Differentiation of Human Induced Pluripotent Stem Cells from Patients with Severe COPD into Functional Airway Epithelium
by Engi Ahmed, Mathieu Fieldes, Chloé Bourguignon, Joffrey Mianné, Aurélie Petit, Myriam Jory, Chantal Cazevieille, Hassan Boukhaddaoui, James P. Garnett, Christophe Hirtz, Gladys Massiera, Isabelle Vachier, Said Assou, Arnaud Bourdin and John De Vos
Cells 2022, 11(15), 2422; https://doi.org/10.3390/cells11152422 - 5 Aug 2022
Cited by 7 | Viewed by 3524
Abstract
Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. [...] Read more.
Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air–liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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21 pages, 3487 KiB  
Article
Generation of Isogenic hiPSCs with Targeted Edits at Multiple Intronic SNPs to Study the Effects of the Type 2 Diabetes Associated KCNQ1 Locus in American Indians
by Anup K. Nair, Michael Traurig, Jeff R. Sutherland, Yunhua L. Muller, Emma D. Grellinger, Lucas Saporito, Robert G. Nelson, Clifton Bogardus and Leslie J. Baier
Cells 2022, 11(9), 1446; https://doi.org/10.3390/cells11091446 - 25 Apr 2022
Cited by 4 | Viewed by 2537
Abstract
The top genetic association signal for type 2 diabetes (T2D) in Southwestern American Indians maps to intron 15 of KCNQ1, an imprinted gene. We aim to understand the biology whereby variation at this locus affects T2D specifically in this genomic background. To [...] Read more.
The top genetic association signal for type 2 diabetes (T2D) in Southwestern American Indians maps to intron 15 of KCNQ1, an imprinted gene. We aim to understand the biology whereby variation at this locus affects T2D specifically in this genomic background. To do so, we obtained human induced pluripotent stem cells (hiPSC) derived from American Indians. Using these iPSCs, we show that imprinting of KCNQ1 and CDKN1C during pancreatic islet-like cell generation from iPSCs is consistent with known imprinting patterns in fetal pancreas and adult islets and therefore is an ideal model system to study this locus. In this report, we detail the use of allele-specific guide RNAs and CRISPR to generate isogenic hiPSCs that differ only at multiple T2D associated intronic SNPs at this locus which can be used to elucidate their functional effects. Characterization of these isogenic hiPSCs identified a few aberrant cell lines; namely cell lines with large hemizygous deletions in the putative functional region of KCNQ1 and cell lines hypomethylated at the KCNQ1OT1 promoter. Comparison of an isogenic cell line with a hemizygous deletion to the parental cell line identified CDKN1C and H19 as differentially expressed during the endocrine progenitor stage of pancreatic-islet development. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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23 pages, 5316 KiB  
Article
Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids
by Ilkka Fagerlund, Antonios Dougalis, Anastasia Shakirzyanova, Mireia Gómez-Budia, Anssi Pelkonen, Henna Konttinen, Sohvi Ohtonen, Mohammad Feroze Fazaludeen, Marja Koskuvi, Johanna Kuusisto, Damián Hernández, Alice Pebay, Jari Koistinaho, Tuomas Rauramaa, Šárka Lehtonen, Paula Korhonen and Tarja Malm
Cells 2022, 11(1), 124; https://doi.org/10.3390/cells11010124 - 30 Dec 2021
Cited by 51 | Viewed by 9422
Abstract
Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show [...] Read more.
Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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17 pages, 3312 KiB  
Article
Development of Functional Thyroid C Cell-like Cells from Human Pluripotent Cells in 2D and in 3D Scaffolds
by Kwaku Dad Abu-Bonsrah, Donald F. Newgreen and Mirella Dottori
Cells 2021, 10(11), 2897; https://doi.org/10.3390/cells10112897 - 26 Oct 2021
Cited by 4 | Viewed by 3673
Abstract
Medullary thyroid carcinoma contributes to about 3–4% of thyroid cancers and affects C cells rather than follicular cells. Thyroid C cell differentiation from human pluripotent stem cells has not been reported. We report the stepwise differentiation of human embryonic stem cells into thyroid [...] Read more.
Medullary thyroid carcinoma contributes to about 3–4% of thyroid cancers and affects C cells rather than follicular cells. Thyroid C cell differentiation from human pluripotent stem cells has not been reported. We report the stepwise differentiation of human embryonic stem cells into thyroid C cell-like cells through definitive endoderm and anterior foregut endoderm and ultimobranchial body-like intermediates in monolayer and 3D Matrigel culture conditions. The protocol involved sequential treatment with interferon/transferrin/selenium/pyruvate, foetal bovine serum, and activin A, then IGF-1 (Insulin-like growth factor 1), on the basis of embryonic thyroid developmental sequence. As well as expressing C cell lineage relative to follicular-lineage markers by qPCR (quantitative polymerase chain reaction) and immunolabelling, these cells by ELISA (enzyme-linked immunoassay) exhibited functional properties in vitro of calcitonin storage and release of calcitonin on calcium challenge. This method will contribute to developmental studies of the human thyroid gland and facilitate in vitro modelling of medullary thyroid carcinoma and provide a valuable platform for drug screening. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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Review

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25 pages, 2542 KiB  
Review
Assaying Microglia Functions In Vitro
by Emily Maguire, Natalie Connor-Robson, Bethany Shaw, Rachel O’Donoghue, Nina Stöberl and Hazel Hall-Roberts
Cells 2022, 11(21), 3414; https://doi.org/10.3390/cells11213414 - 28 Oct 2022
Cited by 9 | Viewed by 8940
Abstract
Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy neuronal networks, carrying out immune surveillance, mediating inflammatory responses, and disposing of unwanted material. A wide variety of [...] Read more.
Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy neuronal networks, carrying out immune surveillance, mediating inflammatory responses, and disposing of unwanted material. A wide variety of pathological conditions present with microglia dysregulation, highlighting the importance of these cells in both normal brain function and disease. Studies into microglial function in the context of both health and disease thus have the potential to provide tremendous insight across a broad range of research areas. In vitro culture of microglia, using primary cells, cell lines, or induced pluripotent stem cell derived microglia, allows researchers to generate reproducible, robust, and quantifiable data regarding microglia function. A broad range of assays have been successfully developed and optimised for characterizing microglial morphology, mediation of inflammation, endocytosis, phagocytosis, chemotaxis and random motility, and mediation of immunometabolism. This review describes the main functions of microglia, compares existing protocols for measuring these functions in vitro, and highlights common pitfalls and future areas for development. We aim to provide a comprehensive methodological guide for researchers planning to characterise microglial functions within a range of contexts and in vitro models. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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32 pages, 1814 KiB  
Review
Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays
by Anssi Pelkonen, Cristiana Pistono, Pamela Klecki, Mireia Gómez-Budia, Antonios Dougalis, Henna Konttinen, Iveta Stanová, Ilkka Fagerlund, Ville Leinonen, Paula Korhonen and Tarja Malm
Cells 2022, 11(1), 106; https://doi.org/10.3390/cells11010106 - 29 Dec 2021
Cited by 22 | Viewed by 11271
Abstract
Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have [...] Read more.
Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells for Disease Modelling)
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