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Biomedicines
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The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs)
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The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs)

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 9562

Special Issue Editor

Dr. Xiufang Guo

E-Mail Website
Guest Editor
1. NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL 32826, USA
2. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
Interests: stem cell culture; reprogramming; stem cell biology; patch-clamp electrophysiology; synapses differentiation; skeletal muscle; mitochondria; regenerative medicine

Special Issue Information

Dear Colleagues,

Since the first generation of induced pluripotent stem cells (iPSCs) in 2006, the development of iPSC technology has ushered in a revolutionary new era for studying diseases and developing therapies. Human iPSCs have unmatchable advantages, including pluripotency, potentially limitless expandability, easy accessibility, avoidance of ethical concerns associated with embryonic stem cells or human tissues, and the potential to develop patient-specific models for personalized medicine. These traits make iPSCs an ideal cell source for disease modeling, drug discovery, and regenerative medicine. One quickly evolving field of iPSC technology is the development of human-based in vitro disease models by utilizing patient-iPSCs or those generated by CRISPR/Cas9 gene editing. These models, through the integration of multidisciplinary technologies, are finding increasing applications in pathogenesis study and drug efficacy and toxicity testing. Another is for regenerative medicine, such as autologous or allogenic cell therapy, although they are still challenged by the high standard requirements for quality control. In summary, iPSC technology, with the assistance of other technologies, holds great promise for tackling human diseases.

In this Special issue, studies in all the fields of iPSC technology are invited, from stem cell generation and differentiation to disease modeling and stem cell therapy; progress or challenges encountered; and in vitro or in vivo. Studies reporting breakthrough discoveries in the scientific understanding of iPSC or technological developments will be particularly encouraged. Both research articles and reviews are welcome.

Dr. Xiufang Guo
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • iPSC
  • cell differentiation
  • disease model
  • disease-in-a-dish
  • body-on-a-chip
  • CRISPR/Cas9
  • gene edition
  • stem cell therapy
  • cell transplantation
  • translational

Published Papers (7 papers)

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Research

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16 pages, 3089 KiB  
Article
Inhibition of Metalloproteinases Extends Longevity and Function of In Vitro Human iPSC-Derived Skeletal Muscle
by Natali Barakat, Himanshi Jangir, Leandro Gallo, Marcella Grillo, Xiufang Guo and James Hickman
Biomedicines 2024, 12(4), 856; https://doi.org/10.3390/biomedicines12040856 - 12 Apr 2024
Viewed by 309
Abstract
In vitro culture longevity has long been a concern for disease modeling and drug testing when using contractable cells. The dynamic nature of certain cells, such as skeletal muscle, contributes to cell surface release, which limits the system’s ability to conduct long-term studies. [...] Read more.
In vitro culture longevity has long been a concern for disease modeling and drug testing when using contractable cells. The dynamic nature of certain cells, such as skeletal muscle, contributes to cell surface release, which limits the system’s ability to conduct long-term studies. This study hypothesized that regulating the extracellular matrix (ECM) dynamics should be able to prolong cell attachment on a culture surface. Human induced pluripotent stem cell (iPSC)-derived skeletal muscle (SKM) culture was utilized to test this hypothesis due to its forceful contractions in mature muscle culture, which can cause cell detachment. By specifically inhibiting matrix metalloproteinases (MMPs) that work to digest components of the ECM, it was shown that the SKM culture remained adhered for longer periods of time, up to 80 days. Functional testing of myofibers indicated that cells treated with the MMP inhibitors, tempol, and doxycycline, displayed a significantly reduced fatigue index, although the fidelity was not affected, while those treated with the MMP inducer, PMA, indicated a premature detachment and increased fatigue index. The MMP-modulating activity by the inhibitors and inducer was further validated by gel zymography analysis, where the MMP inhibitor showed minimally active MMPs, while the inducer-treated cells indicated high MMP activity. These data support the hypotheses that regulating the ECM dynamics can help maximize in vitro myotube longevity. This proof-of-principle strategy would benefit the modeling of diseases that require a long time to develop and the evaluation of chronic effects of potential therapeutics. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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23 pages, 14564 KiB  
Article
Efficient Treatment of Pulpitis via Transplantation of Human Pluripotent Stem Cell-Derived Pericytes Partially through LTBP1-Mediated T Cell Suppression
by Anqi Li, Zhuoran Li, Weicheng Chiu, Chuanfeng Xiong, Qian Chen, Junhua Chen, Xingqiang Lai, Weiqiang Li, Qiong Ke, Jia Liu and Xinchun Zhang
Biomedicines 2023, 11(12), 3199; https://doi.org/10.3390/biomedicines11123199 - 01 Dec 2023
Viewed by 879
Abstract
Dental pulp pericytes are reported to have the capacity to generate odontoblasts and express multiple cytokines and chemokines that regulate the local immune microenvironment, thus participating in the repair of dental pulp injury in vivo. However, it has not yet been reported whether [...] Read more.
Dental pulp pericytes are reported to have the capacity to generate odontoblasts and express multiple cytokines and chemokines that regulate the local immune microenvironment, thus participating in the repair of dental pulp injury in vivo. However, it has not yet been reported whether the transplantation of exogenous pericytes can effectively treat pulpitis, and the underlying molecular mechanism remains unknown. In this study, using a lineage-tracing mouse model, we showed that most dental pulp pericytes are derived from cranial neural crest. Then, we demonstrated that the ablation of pericytes could induce a pulpitis-like phenotype in uninfected dental pulp in mice, and we showed that the significant loss of pericytes occurs during pupal inflammation, implying that the transplantation of pericytes may help to restore dental pulp homeostasis during pulpitis. Subsequently, we successfully generated pericytes with immunomodulatory activity from human pluripotent stem cells through the intermediate stage of the cranial neural crest with a high level of efficiency. Most strikingly, for the first time we showed that, compared with the untreated pulpitis group, the transplantation of hPSC-derived pericytes could substantially inhibit vascular permeability (the extravascular deposition of fibrinogen, ** p < 0.01), alleviate pulpal inflammation (TCR+ cell infiltration, * p < 0.05), and promote the regeneration of dentin (** p < 0.01) in the mouse model of pulpitis. In addition, we discovered that the knockdown of latent transforming growth factor beta binding protein 1 (LTBP1) remarkably suppressed the immunoregulation ability of pericytes in vitro and compromised their in vivo regenerative potential in pulpitis. These results indicate that the transplantation of pericytes could efficiently rescue the aberrant phenotype of pulpal inflammation, which may be partially due to LTBP1-mediated T cell suppression. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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15 pages, 1880 KiB  
Article
An Induced Pluripotent Stem Cell-Derived Human Blood–Brain Barrier (BBB) Model to Test the Crossing by Adeno-Associated Virus (AAV) Vectors and Antisense Oligonucleotides
by Jamuna Selvakumaran, Simona Ursu, Melissa Bowerman, Ngoc Lu-Nguyen, Matthew J. Wood, Alberto Malerba and Rafael J. Yáñez-Muñoz
Biomedicines 2023, 11(10), 2700; https://doi.org/10.3390/biomedicines11102700 - 04 Oct 2023
Viewed by 1455
Abstract
The blood–brain barrier (BBB) is the specialised microvasculature system that shields the central nervous system (CNS) from potentially toxic agents. Attempts to develop therapeutic agents targeting the CNS have been hindered by the lack of predictive models of BBB crossing. In vitro models [...] Read more.
The blood–brain barrier (BBB) is the specialised microvasculature system that shields the central nervous system (CNS) from potentially toxic agents. Attempts to develop therapeutic agents targeting the CNS have been hindered by the lack of predictive models of BBB crossing. In vitro models mimicking the human BBB are of great interest, and advances in induced pluripotent stem cell (iPSC) technologies and the availability of reproducible differentiation protocols have facilitated progress. In this study, we present the efficient differentiation of three different wild-type iPSC lines into brain microvascular endothelial cells (BMECs). Once differentiated, cells displayed several features of BMECs and exhibited significant barrier tightness as measured by trans-endothelial electrical resistance (TEER), ranging from 1500 to >6000 Ωcm2. To assess the functionality of our BBB models, we analysed the crossing efficiency of adeno-associated virus (AAV) vectors and peptide-conjugated antisense oligonucleotides, both currently used in genetic approaches for the treatment of rare diseases. We demonstrated superior barrier crossing by AAV serotype 9 compared to serotype 8, and no crossing by a cell-penetrating peptide-conjugated antisense oligonucleotide. In conclusion, our study shows that iPSC-based models of the human BBB display robust phenotypes and could be used to screen drugs for CNS penetration in culture. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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15 pages, 2303 KiB  
Article
c-Myc/microRNA-17-92 Axis Phase-Dependently Regulates PTEN and p21 Expression via ceRNA during Reprogramming to Mouse Pluripotent Stem Cells
by Tomoaki Ishida, Tomoe Ueyama, Dai Ihara, Yukihiro Harada, Sae Nakagawa, Kaho Saito, Shu Nakao and Teruhisa Kawamura
Biomedicines 2023, 11(6), 1737; https://doi.org/10.3390/biomedicines11061737 - 16 Jun 2023
Cited by 2 | Viewed by 1377
Abstract
Induced pluripotent stem cells (iPSCs) are promising cell sources for regenerative medicine and disease modeling. iPSCs are commonly established by introducing the defined reprogramming factors Oct4, Sox2, Klf4, and c-Myc. However, iPSC reprogramming efficiency remains low. Although recent studies have identified microRNAs that [...] Read more.
Induced pluripotent stem cells (iPSCs) are promising cell sources for regenerative medicine and disease modeling. iPSCs are commonly established by introducing the defined reprogramming factors Oct4, Sox2, Klf4, and c-Myc. However, iPSC reprogramming efficiency remains low. Although recent studies have identified microRNAs that contribute to efficient reprogramming, the underlying molecular mechanisms are not completely understood. miR-17-92 is highly expressed in embryonic stem cells and may play an important role in regulating stem cell properties. Therefore, we examined the role of miR-17-92 in the induction of mouse iPSC production. c-Myc-mediated miR-17-92 upregulation increased reprogramming efficiency, whereas CRISPR/Cas9-based deletion of the miR-17-92 cluster decreased reprogramming efficiency. A combination of in silico and microarray analyses revealed that Pten and cyclin-dependent kinase inhibitor 1 (known as p21) are common target genes of miR-17 and miR-20a, which are transcribed from the miR-17-92 cluster. Moreover, miR-17-92 downregulated p21 in the early phase and PTEN in the mid-to-late phase of reprogramming. These downregulations were perturbed by introducing the 3′ UTR of PTEN and p21, respectively, suggesting that PTEN and p21 mRNAs are competing endogenous RNAs (ceRNA) against miR-17-92. Collectively, we propose that the c-Myc-mediated expression of miR-17-92 is involved in iPSC reprogramming through the phase-dependent inhibition of PTEN and p21 in a ceRNA manner, thus elucidating an underlying mechanism of iPSC reprogramming. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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15 pages, 4486 KiB  
Article
In Vivo CaV3 Channel Inhibition Promotes Maturation of Glucose-Dependent Ca2+ Signaling in Human iPSC-Islets
by Kaixuan Zhao, Yue Shi, Jia Yu, Lina Yu, Martin Köhler, Amber Mael, Anthony Kolton, Thomas Joyce, Jon Odorico, Per-Olof Berggren and Shao-Nian Yang
Biomedicines 2023, 11(3), 807; https://doi.org/10.3390/biomedicines11030807 - 07 Mar 2023
Cited by 1 | Viewed by 1447
Abstract
CaV3 channels are ontogenetically downregulated with the maturation of certain electrically excitable cells, including pancreatic β cells. Abnormally exaggerated CaV3 channels drive the dedifferentiation of mature β cells. This led us to question whether excessive CaV3 channels, [...] Read more.
CaV3 channels are ontogenetically downregulated with the maturation of certain electrically excitable cells, including pancreatic β cells. Abnormally exaggerated CaV3 channels drive the dedifferentiation of mature β cells. This led us to question whether excessive CaV3 channels, retained mistakenly in engineered human-induced pluripotent stem cell-derived islet (hiPSC-islet) cells, act as an obstacle to hiPSC-islet maturation. We addressed this question by using the anterior chamber of the eye (ACE) of immunodeficient mice as a site for recapitulation of in vivo hiPSC-islet maturation in combination with intravitreal drug infusion, intravital microimaging, measurements of cytoplasmic-free Ca2+ concentration ([Ca2+]i) and patch clamp analysis. We observed that the ACE is well suited for recapitulation, observation and intervention of hiPSC-islet maturation. Intriguingly, intraocular hiPSC-islet grafts, retrieved intact following intravitreal infusion of the CaV3 channel blocker NNC55-0396, exhibited decreased basal [Ca2+]i levels and increased glucose-stimulated [Ca2+]i responses. Insulin-expressing cells of these islet grafts indeed expressed the NNC55-0396 target CaV3 channels. Intraocular hiPSC-islets underwent satisfactory engraftment, vascularization and light scattering without being influenced by the intravitreally infused NNC55-0396. These data demonstrate that inhibiting CaV3 channels facilitates the maturation of glucose-activated Ca2+ signaling in hiPSC-islets, supporting the notion that excessive CaV3 channels as a developmental error impede the maturation of engineered hiPSC-islet insulin-expressing cells. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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Review

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20 pages, 1221 KiB  
Review
Ca2+-Mediated Signaling Pathways: A Promising Target for the Successful Generation of Mature and Functional Stem Cell-Derived Pancreatic Beta Cells In Vitro
by Razik Bin Abdul Mu-u-min, Abdoulaye Diane, Asma Allouch and Heba H. Al-Siddiqi
Biomedicines 2023, 11(6), 1577; https://doi.org/10.3390/biomedicines11061577 - 29 May 2023
Viewed by 2182
Abstract
Diabetes mellitus is a chronic disease affecting over 500 million adults globally and is mainly categorized as type 1 diabetes mellitus (T1DM), where pancreatic beta cells are destroyed, and type 2 diabetes mellitus (T2DM), characterized by beta cell dysfunction. This review highlights the [...] Read more.
Diabetes mellitus is a chronic disease affecting over 500 million adults globally and is mainly categorized as type 1 diabetes mellitus (T1DM), where pancreatic beta cells are destroyed, and type 2 diabetes mellitus (T2DM), characterized by beta cell dysfunction. This review highlights the importance of the divalent cation calcium (Ca2+) and its associated signaling pathways in the proper functioning of beta cells and underlines the effects of Ca2+ dysfunction on beta cell function and its implications for the onset of diabetes. Great interest and promise are held by human pluripotent stem cell (hPSC) technology to generate functional pancreatic beta cells from diabetic patient-derived stem cells to replace the dysfunctional cells, thereby compensating for insulin deficiency and reducing the comorbidities of the disease and its associated financial and social burden on the patient and society. Beta-like cells generated by most current differentiation protocols have blunted functionality compared to their adult human counterparts. The Ca2+ dynamics in stem cell-derived beta-like cells and adult beta cells are summarized in this review, revealing the importance of proper Ca2+ homeostasis in beta-cell function. Consequently, the importance of targeting Ca2+ function in differentiation protocols is suggested to improve current strategies to use hPSCs to generate mature and functional beta-like cells with a comparable glucose-stimulated insulin secretion (GSIS) profile to adult beta cells. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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Other

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10 pages, 7479 KiB  
Case Report
Generation and Characterization of a Human-Derived and Induced Pluripotent Stem Cell (iPSC) Line from an Alzheimer’s Disease Patient with Neuropsychiatric Symptoms
by Ram Sagar, Cristina Zivko, Ariadni Xydia, David C. Weisman, Constantine G. Lyketsos and Vasiliki Mahairaki
Biomedicines 2023, 11(12), 3313; https://doi.org/10.3390/biomedicines11123313 - 15 Dec 2023
Cited by 1 | Viewed by 1067
Abstract
Agitation is one of the most eminent characteristics of neuropsychiatric symptoms (NPS) affecting people living with Alzheimer’s and Dementia and has serious consequences for patients and caregivers. The current consensus is that agitation results, in part, from the disruption of ascending monoamine regulators [...] Read more.
Agitation is one of the most eminent characteristics of neuropsychiatric symptoms (NPS) affecting people living with Alzheimer’s and Dementia and has serious consequences for patients and caregivers. The current consensus is that agitation results, in part, from the disruption of ascending monoamine regulators of cortical circuits, especially the loss of serotonergic activity. It is believed that the first line of treatment for these conditions is selective serotonin reuptake inhibitors (SSRIs), but these are effective in only about 40% of patients. Person-specific biomarkers, for example, ones based on in vitro iPSC-derived models of serotonin activity, which predict who with Agitation responds to an SSRI, are a major clinical priority. Here, we report the generation of human-induced pluripotent stem cells (iPSCs) from a 74-year-old AD patient, the homozygous APOE ε4/ε4 carrier, who developed Agitation. His iPSCs were reprogrammed from peripheral blood mononuclear cells (PBMCs) using the transient expression of pluripotency genes. These display typical iPSC characteristics that are karyotypically normal and attain the capacity to differentiate into three germ layers. The newly patient-derived iPSC line offers a unique resource to investigate the underlying mechanisms associated with neuropsychiatric symptom progression in AD. Full article
(This article belongs to the Special Issue The Promise and Challenge of Induced Pluripotent Stem Cells (iPSCs))
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