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Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 April 2023) | Viewed by 17306

Special Issue Editor

Dr. Yun-Wen Zheng

E-Mail Website
Guest Editor
1. Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
2. University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki 305-8575, Japan
3. Department of Regenerative Medicine, School of Medicine, Yokohama City University, Yokohama, Kanagawa 234-0006, Japan
Interests: patient iPSCs; hepatic organoids; humanized liver model; multicellular organoid generation; organoid gene editing; stem cell and organoid based disease modeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Pluripotent stem cells (PSCs) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to maintain long-term self-renewing and mimic embryonic developing. In the phase of cells or organoids developed from PSCs, research models for inherited and acquired diseases and drug screening, even preclinical applications can be developed. With the discovery and application of the CRISPR/Cas9, in-depth investigation of physiological and pathological mechanism can be implemented, including but not limited to cell fate tracing and visualization, functional maturation, mutations exploration, gene correction and etiology rescue.

Much work remains to be done involving PSCs/iPSC-derived organoids, the reproducibility, scalability and long-term safety of differentiation and cellular functions, gene editing strategies and its applications in transplantation strategy, immune rejection, disease modeling, drug screening, etc.  We especially welcome the studies on induction of multi-cellular tissue-like structure or organoids from PSCs with novel technologies, and call for elucidation on their specific developmental roadmap in molecular level.

Thus, this special issue mainly calls for paper about advances and progresses of pluripotent stem cell/organoid-based researches in basic which aim to solve or improve the above problems. We invite the authors to submit their original and review articles on these topics.

Dr. Yun-Wen Zheng
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • pluripotent stem cells
  • iPSCs
  • organoid
  • stem cell niche
  • disease modeling
  • drug screening
  • regenerative medicine
  • gene editing
  • CRISPR-Cas9

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Published Papers (7 papers)

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Research

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17 pages, 60159 KiB  
Article
Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity
by Kanako Takahashi, Yuto Ishibashi, Kaori Chujo, Ikuro Suzuki and Kaoru Sato
Int. J. Mol. Sci. 2023, 24(16), 12605; https://doi.org/10.3390/ijms241612605 - 9 Aug 2023
Viewed by 1439
Abstract
Human induced pluripotent stem cell (hiPSC)-derived neural cells have started to be used in safety/toxicity tests at the preclinical stage of drug development. As previously reported, hiPSC-derived neurons exhibit greater tolerance to excitotoxicity than those of primary cultures of rodent neurons; however, the [...] Read more.
Human induced pluripotent stem cell (hiPSC)-derived neural cells have started to be used in safety/toxicity tests at the preclinical stage of drug development. As previously reported, hiPSC-derived neurons exhibit greater tolerance to excitotoxicity than those of primary cultures of rodent neurons; however, the underlying mechanisms remain unknown. We here investigated the functions of L-glutamate (L-Glu) transporters, the most important machinery to maintain low extracellular L-Glu concentrations, in hiPSC-derived neural cells. We also clarified the contribution of respective L-Glu transporter subtypes. At 63 days in vitro (DIV), we detected neuronal circuit functions in hiPSC-derived neural cells by a microelectrode array system (MEA). At 63 DIV, exposure to 100 μM L-Glu for 24 h did not affect the viability of neural cells. 100 µM L-Glu in the medium decreased to almost 0 μM in 60 min. Pharmacological inhibition of excitatory amino acid transporter 1 (EAAT1) and EAAT2 suppressed almost 100% of L-Glu decrease. In the presence of this inhibitor, 100 μM L-Glu dramatically decreased cell viability. These results suggest that in hiPSC-derived neural cells, EAAT1 and EAAT2 are the predominant L-Glu transporters, and their uptake potentials are the reasons for the tolerance of hiPSC-derived neurons to excitotoxicity. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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16 pages, 3945 KiB  
Article
Generation and Functional Characterization of Anti-CD19 Chimeric Antigen Receptor-Natural Killer Cells from Human Induced Pluripotent Stem Cells
by Phatchanat Klaihmon, Xing Kang, Surapol Issaragrisil and Sudjit Luanpitpong
Int. J. Mol. Sci. 2023, 24(13), 10508; https://doi.org/10.3390/ijms241310508 - 22 Jun 2023
Cited by 6 | Viewed by 2730
Abstract
Natural killer (NK) cells are a part of innate immunity that can be activated rapidly in response to malignant transformed cells without prior sensitization. Engineering NK cells to express chimeric antigen receptors (CARs) allows them to be directed against corresponding target tumor antigens. [...] Read more.
Natural killer (NK) cells are a part of innate immunity that can be activated rapidly in response to malignant transformed cells without prior sensitization. Engineering NK cells to express chimeric antigen receptors (CARs) allows them to be directed against corresponding target tumor antigens. CAR-NK cells are regarded as a promising candidate for cellular immunotherapy alternatives to conventional CAR-T cells, due to the relatively low risk of graft-versus-host disease and safer clinical profile. Human induced pluripotent stem cells (iPSCs) are a promising renewable cell source of clinical NK cells. In the present study, we successfully introduced a third-generation CAR targeting CD19, which was validated to have effective signaling domains suitable for NK cells, into umbilical cord blood NK-derived iPSCs, followed by a single-cell clone selection and thorough iPSC characterization. The established single-cell clone of CAR19-NK/iPSCs, which is highly desirable for clinical application, can be differentiated using serum- and feeder-free protocols into functional CAR19-iNK-like cells with improved anti-tumor activity against CD19-positive hematologic cancer cells when compared with wild-type (WT)-iNK-like cells. With the feasibility of being an alternative source for off-the-shelf CAR-NK cells, a library of single-cell clones of CAR-engineered NK/iPSCs targeting different tumor antigens may be created for future clinical application. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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13 pages, 3429 KiB  
Article
Functional Activity of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes on a Mouse Renal Subcapsular Xenograft Model
by Elena V. Chepeleva, Sophia V. Pavlova, Nataliya P. Bgatova, Alexander M. Volkov, Galina M. Kazanskaya and David S. Sergeevichev
Int. J. Mol. Sci. 2023, 24(12), 9792; https://doi.org/10.3390/ijms24129792 - 6 Jun 2023
Viewed by 1562
Abstract
In the treatment of coronary heart disease, the most promising approach for replacing lost contractile elements involves obtaining cardiomyocytes through cardiac differentiation of pluripotent cells. The objective of this study is to develop a technology for creating a functional layer of cardiomyocytes derived [...] Read more.
In the treatment of coronary heart disease, the most promising approach for replacing lost contractile elements involves obtaining cardiomyocytes through cardiac differentiation of pluripotent cells. The objective of this study is to develop a technology for creating a functional layer of cardiomyocytes derived from iPSCs, capable of generating rhythmic activity and synchronous contractions. To expedite the maturation of cardiomyocytes, a renal subcapsular transplantation model was employed in SCID mice. Following explantation, the formation of the cardiomyocyte contractile apparatus was assessed using fluorescence and electron microscopy, while the cytoplasmic oscillation of calcium ions was evaluated through visualization using the fluorescent calcium binding dye Fluo-8. The results demonstrate that transplanted human iPSC-derived cardiomyocyte cell layers, placed under the fibrous capsules of SCID mouse kidneys (for up to 6 weeks), initiate the development of an organized contractile apparatus and retain functional activity along with the ability to generate calcium ion oscillations even after removal from the body. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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20 pages, 34042 KiB  
Article
PDGF Receptors and Signaling Are Required for 3D-Structure Formation and Differentiation of Human iPSC-Derived Hepatic Spheroids
by Syusaku Tsuzuki, Tomoyuki Yamaguchi, Takashi Okumura, Toshiharu Kasai, Yasuharu Ueno and Hideki Taniguchi
Int. J. Mol. Sci. 2023, 24(8), 7075; https://doi.org/10.3390/ijms24087075 - 11 Apr 2023
Cited by 2 | Viewed by 2007
Abstract
Human iPSC-derived liver organoids (LO) or hepatic spheroids (HS) have attracted widespread interest, and the numerous studies on them have recently provided various production protocols. However, the mechanism by which the 3D structures of LO and HS are formed from the 2D-cultured cells [...] Read more.
Human iPSC-derived liver organoids (LO) or hepatic spheroids (HS) have attracted widespread interest, and the numerous studies on them have recently provided various production protocols. However, the mechanism by which the 3D structures of LO and HS are formed from the 2D-cultured cells and the mechanism of the LO and HS maturation remain largely unknown. In this study, we demonstrate that PDGFRA is specifically induced in the cells that are suitable for HS formation and that PDGF receptors and signaling are required for HS formation and maturation. Additionally, in vivo, we show that the localization of PDGFRα is in complete agreement with mouse E9.5 hepatoblasts, which begin to form the 3D-structural liver bud from the single layer. Our results present that PDGFRA play important roles for 3D structure formation and maturation of hepatocytes in vitro and in vivo and provide a clue to elucidate the hepatocyte differentiation mechanism. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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17 pages, 20996 KiB  
Article
Robust Generation of Ready-to-Use Cryopreserved Motor Neurons from Human Pluripotent Stem Cells for Disease Modeling
by Hsiao-Chien Ting, Hong-Lin Su, Mei-Fang Chen, Horng-Jyh Harn, Shinn-Zong Lin, Tzyy-Wen Chiou and Chia-Yu Chang
Int. J. Mol. Sci. 2022, 23(21), 13462; https://doi.org/10.3390/ijms232113462 - 3 Nov 2022
Cited by 6 | Viewed by 2998
Abstract
Human pluripotent stem cell (hPSC)-derived motor neurons (MNs) act as models for motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. However, the MN differentiation efficiency and viability following cryopreservation require further development for application in large-scale studies [...] Read more.
Human pluripotent stem cell (hPSC)-derived motor neurons (MNs) act as models for motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. However, the MN differentiation efficiency and viability following cryopreservation require further development for application in large-scale studies and drug screening. Here, we developed a robust protocol to convert hPSCs into MN cryopreservation stocks (hPSCs were converted into >92% motor neural progenitors and >91% MNs). Near-mature MNs were cryopreserved at a high thawing survival rate and 89% MN marker expression on day 32. Moreover, these MNs exhibited classical electrophysiological properties and neuromuscular junction (NMJ) formation ability within only 4–6 days after thawing. To apply this platform as an MND model, MN stocks were generated from SOD1G85R, SOD1G85G isogenic control, and sporadic ALS hPSC lines. The thawed ALS MNs expressed ALS-specific cytopathies, including SOD1 protein aggregation and TDP-43 redistribution. Thus, a stable and robust protocol was developed to generate ready-to-use cryopreserved MNs without further neuronal maturation processes for application in MND mechanistic studies, NMJ model establishment, and large-scale drug screening. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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13 pages, 6528 KiB  
Article
Nanosheets Based Approach to Elevate the Proliferative and Differentiation Efficacy of Human Wharton’s Jelly Mesenchymal Stem Cells
by Suraj Kumar Singh, Anshuman Singh, Vinod Kumar, Jalaj Gupta, Sima Umrao, Manoj Kumar, Devojit Kumar Sarma, Marcis Leja, Manohar Prasad Bhandari and Vinod Verma
Int. J. Mol. Sci. 2022, 23(10), 5816; https://doi.org/10.3390/ijms23105816 - 22 May 2022
Cited by 3 | Viewed by 2607
Abstract
Mesenchymal stem cell (MSC)-based therapy and tissue repair necessitate the use of an ideal clinical biomaterial capable of increasing cell proliferation and differentiation. Recently, MXenes 2D nanomaterials have shown remarkable potential for improving the functional properties of MSCs. In the present study, we [...] Read more.
Mesenchymal stem cell (MSC)-based therapy and tissue repair necessitate the use of an ideal clinical biomaterial capable of increasing cell proliferation and differentiation. Recently, MXenes 2D nanomaterials have shown remarkable potential for improving the functional properties of MSCs. In the present study, we elucidated the potential of Ti2CTx MXene as a biomaterial through its primary biological response to human Wharton’s Jelly MSCs (hWJ-MSCs). A Ti2CTx nanosheet was synthesized and thoroughly characterized using various microscopic and spectroscopic tools. Our findings suggest that Ti2CTx MXene nanosheet exposure does not alter the morphology of the hWJ-MSCs; however, it causes a dose-dependent (10–200 µg/mL) increase in cell proliferation, and upon using it with conditional media, it also enhanced its tri-lineage differentiation potential, which is a novel finding of our study. A two-fold increase in cell viability was also noticed at the highest tested dose of the nanosheet. The treated hWJ-MSCs showed no sign of cellular stress or toxicity. Taken together, these findings suggest that the Ti2CTx MXene nanosheet is capable of augmenting the proliferation and differentiation potential of the cells. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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Review

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22 pages, 1194 KiB  
Review
The Values and Perspectives of Organoids in the Field of Metabolic Syndrome
by Chen Tan, Min Ding and Yun-Wen Zheng
Int. J. Mol. Sci. 2023, 24(9), 8125; https://doi.org/10.3390/ijms24098125 - 1 May 2023
Cited by 2 | Viewed by 2958
Abstract
Metabolic syndrome (MetS) has become a global health problem, and the prevalence of obesity at all stages of life makes MetS research increasingly important and urgent. However, as a comprehensive and complex disease, MetS has lacked more appropriate research models. The advent of [...] Read more.
Metabolic syndrome (MetS) has become a global health problem, and the prevalence of obesity at all stages of life makes MetS research increasingly important and urgent. However, as a comprehensive and complex disease, MetS has lacked more appropriate research models. The advent of organoids provides an opportunity to address this issue. However, it should be noted that organoids are still in their infancy. The main drawbacks are a lack of maturity, complexity, and the inability to standardize large-scale production. Could organoids therefore be a better choice for studying MetS than other models? How can these limitations be overcome? Here, we summarize the available data to present current progress on pancreatic and hepatobiliary organoids and to answer these open questions. Organoids are of human origin and contain a variety of human cell types necessary to mimic the disease characteristics of MetS in their development. Taken together with the discovery of hepatobiliary progenitors in situ, the dedifferentiation of beta cells in diabetes, and studies on hepatic macrophages, we suggest that promoting endogenous regeneration has the potential to prevent the development of end-stage liver and pancreatic lesions caused by MetS and outline the direction of future research in this field. Full article
(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)
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