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Cells Oct 2022Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina's spatial and temporal differentiation,... (Review)
Review
Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina's spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized.
Topics: Humans; Organoids; Pluripotent Stem Cells; Retina; Brain; Bioengineering
PubMed: 36359825
DOI: 10.3390/cells11213429 -
Current Cardiology Reports Jun 2020This review summarizes the important role that metabolism plays in driving maturation of human pluripotent stem cell-derived cardiomyocytes. (Review)
Review
PURPOSE OF REVIEW
This review summarizes the important role that metabolism plays in driving maturation of human pluripotent stem cell-derived cardiomyocytes.
RECENT FINDINGS
Human pluripotent stem cell-derived cardiomyocytes provide a model system for human cardiac biology. However, these models have been unable to fully recapitulate the maturity observed in the adult heart. By simulating the glucose to fatty acid transition observed in neonatal mammals, human pluripotent stem cell-derived cardiomyocytes undergo structural and functional maturation also accompanied by transcriptional changes and cell cycle arrest. The role of metabolism in energy production, signaling, and epigenetic modifications illustrates that metabolism and cellular phenotype are intimately linked. Further understanding of key metabolic factors driving cardiac maturation will facilitate the generation of more mature human pluripotent stem cell-derived cardiomyocyte models. This will increase our understanding of cardiac biology and potentially lead to novel therapeutics to enhance heart function.
Topics: Adult; Animals; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Pluripotent Stem Cells; Signal Transduction
PubMed: 32594263
DOI: 10.1007/s11886-020-01303-3 -
Journal of Molecular and Cellular... Feb 2024Cardiac regenerative therapy using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is expected to become an alternative to heart transplantation for severe... (Review)
Review
Cardiac regenerative therapy using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is expected to become an alternative to heart transplantation for severe heart failure. It is now possible to produce large numbers of human pluripotent stem cells (hPSCs) and eliminate non-cardiomyocytes, including residual undifferentiated hPSCs, which can cause teratoma formation after transplantation. There are two main strategies for transplanting hPSC-CMs: injection of hPSC-CMs into the myocardium from the epicardial side, and implantation of hPSC-CM patches or engineered heart tissues onto the epicardium. Transplantation of hPSC-CMs into the myocardium of large animals in a myocardial infarction model improved cardiac function. The engrafted hPSC-CMs matured, and microvessels derived from the host entered the graft abundantly. Furthermore, as less invasive methods using catheters, injection into the coronary artery and injection into the myocardium from the endocardium side have recently been investigated. Since transplantation of hPSC-CMs alone has a low engraftment rate, various methods such as transplantation with the extracellular matrix or non-cardiomyocytes and aggregation of hPSC-CMs have been developed. Post-transplant arrhythmias, imaging of engrafted hPSC-CMs, and immune rejection are the remaining major issues, and research is being conducted to address them. The clinical application of cardiac regenerative therapy using hPSC-CMs has just begun and is expected to spread widely if its safety and efficacy are proven in the near future.
Topics: Animals; Humans; Cell Differentiation; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells; Heart Failure; Induced Pluripotent Stem Cells
PubMed: 38331557
DOI: 10.1016/j.yjmcc.2023.12.001 -
Progress in Molecular Biology and... 2023It is urgent to prepare and store large numbers of clinical trial grade human pluripotent stem (hPS) cells for off-the-shelf use in stem cell therapies. However, stem...
It is urgent to prepare and store large numbers of clinical trial grade human pluripotent stem (hPS) cells for off-the-shelf use in stem cell therapies. However, stem cell banks, which store off-the-shelf stem cells, need financial support and large amounts of technicians for daily cell maintenance. Therefore, it is valuable to create "universal" or "hypoimmunogenic" hPS cells with genome editing engineering by knocking in or out immune-related genes. Only a small number of universal or hypoimmunogenic hPS cell lines should be needed to store for off-the-shelf usage and reduce the large amounts of instruments, consumables and technicians. In this article, we consider how to create hypoimmunogenic or universal hPS cells as well as the demerits of the technology. β2-Microglobulin-knockout hPS cells did not harbor human leukocyte antigen (HLA)-expressing class I cells but led to the activation of natural killer cells. To escape the activities of macrophages and natural killer cells, homozygous hPS cells having a single allele of an HLA class I gene, such as HLA-C, were proposed. Major HLA class Ia molecules were knocked out, and CD47, HLA-G and PD-L1 were knocked in hPS cells utilizing CRISPR/Cas9 genome editing. Finally, some researchers are trying to generate universal hPS cells without genome editing. The cells evaded the activation of not only T cells but also macrophages and natural killer cells. These universal hPS cells have high potential for application in cell therapy.
Topics: Pluripotent Stem Cells; HLA Antigens; Humans; Stem Cell Transplantation; Gene Knockdown Techniques; Gene Knockout Techniques; Gene Editing; Gene Knock-In Techniques; Animals; Transplantation Immunology; Biological Specimen Banks
PubMed: 37678974
DOI: 10.1016/bs.pmbts.2023.02.014 -
Methods in Molecular Biology (Clifton,... 2023The functional unit of human kidney is the nephron. This structure is composed of a glomerulus, connected to a tubule that drains into a collecting duct. The cells which...
The functional unit of human kidney is the nephron. This structure is composed of a glomerulus, connected to a tubule that drains into a collecting duct. The cells which make up the glomerulus are critically important to the appropriate function of this specialised structure. Damage to glomerular cells, particularly the podocytes, is the primary cause of numerous kidney diseases. However, access to and the subsequent culture of human glomerular cells is limited. As such, the ability to generate human glomerular cell types from induced pluripotent stem cells (iPSCs) at scale has garnered great interest. Here, we describe a method to isolate, culture and study 3D human glomeruli from induced pluripotent stem cell (iPSC)-derived kidney organoids in vitro. These 3D glomeruli retain appropriate transcriptional profiles and can be generated from any individual. As isolated glomeruli, they have applicability for disease modelling and drug discovery.
Topics: Humans; Drug Evaluation, Preclinical; Kidney Glomerulus; Pluripotent Stem Cells; Podocytes; Kidney; Induced Pluripotent Stem Cells; Kidney Diseases; Organoids; Cell Differentiation
PubMed: 37423982
DOI: 10.1007/978-1-0716-3179-9_5 -
Neuro-oncology Jul 2023Pluripotent stem cells offer unique avenues to study human-specific aspects of disease and are a highly versatile tool in cancer research. Oncogenic processes and... (Review)
Review
Pluripotent stem cells offer unique avenues to study human-specific aspects of disease and are a highly versatile tool in cancer research. Oncogenic processes and developmental programs often share overlapping transcriptomic and epigenetic signatures, which can be reactivated in induced pluripotent stem cells. With the emergence of brain organoids, the ability to recapitulate brain development and structure has vastly improved, making in vitro models more realistic and hence more suitable for biomedical modeling. This review highlights recent research and current challenges in human pluripotent stem cell modeling of brain and neural crest neoplasms, and concludes with a call for more rigorous quality control and for the development of models for rare tumor subtypes.
Topics: Humans; Neural Crest; Pluripotent Stem Cells; Brain; Induced Pluripotent Stem Cells; Neoplasms
PubMed: 36757217
DOI: 10.1093/neuonc/noad034 -
Heart, Lung & Circulation Jul 2023Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous... (Review)
Review
Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous reports have focussed on xenotransplantation models using immunocompromised animals, studies on immune rejection in allogeneic transplantation models are needed for preclinical and clinical applications. Human leukocyte antigen (HLA) plays an important role in allogeneic transplantation, and cell bank projects are currently underway worldwide to stock induced pluripotent stem cells (iPSCs) generated from healthy individuals with homozygous HLA haplotypes. However, it is difficult to stock iPSCs that match the entire population in these cell banks; thus, several groups have produced hypoimmunogenic PSCs by knocking out HLA. These HLA-knockout PSCs were able to avoid rejection by T cells but still suffered rejection by natural killer (NK) cells caused by 'missing self-recognition'. Recent studies have attempted to generate hypoimmunogenic PSCs with gene editing to inhibit NK cell activation. Regenerative medicine using autologous iPSCs can be an ideal transplantation therapy, but, currently, there are major hurdles to its practical application. Hopefully, further research will resolve these issues. This review provides an overview of the current understanding and progress in this field.
Topics: Animals; Humans; Pluripotent Stem Cells; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Immunity; Regeneration
PubMed: 37029069
DOI: 10.1016/j.hlc.2022.12.014 -
Stem Cell Reports Dec 2023In vivo differentiation of human pluripotent stem cells (hPSCs) has unique advantages, such as multilineage differentiation, angiogenesis, and close cell-cell...
In vivo differentiation of human pluripotent stem cells (hPSCs) has unique advantages, such as multilineage differentiation, angiogenesis, and close cell-cell interactions. To systematically investigate multilineage differentiation mechanisms of hPSCs, we constructed the in vivo hPSC differentiation landscape containing 239,670 cells using teratoma models. We identified 43 cell types, inferred 18 cell differentiation trajectories, and characterized common and specific gene regulation patterns during hPSC differentiation at both transcriptional and epigenetic levels. Additionally, we developed the developmental single-cell Basic Local Alignment Search Tool (dscBLAST), an R-based cell identification tool, to simplify the identification processes of developmental cells. Using dscBLAST, we aligned cells in multiple differentiation models to normally developing cells to further understand their differentiation states. Overall, our study offers new insights into stem cell differentiation and human embryonic development; dscBLAST shows favorable cell identification performance, providing a powerful identification tool for developmental cells.
Topics: Humans; Cell Differentiation; Pluripotent Stem Cells; Gene Expression Regulation; Embryonic Development
PubMed: 37995704
DOI: 10.1016/j.stemcr.2023.10.018 -
Current Cardiology Reports May 2022Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide... (Review)
Review
PURPOSE OF REVIEW
Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, several challenges remain. Here, we review PSC-CM pre-clinical studies, identifying key translational hurdles. We further discuss cell production and characterization strategies, identifying markers that may help generate cells which overcome these barriers.
RECENT FINDINGS
PSC-CMs can robustly repopulate infarcted myocardium with functional, force generating cardiomyocytes. However, current differentiation protocols produce immature and heterogenous cardiomyocytes, creating related issues such as arrhythmogenicity, immunogenicity and poor engraftment. Recent efforts have enhanced our understanding of cardiovascular developmental biology. This knowledge may help implement novel differentiation or gene editing strategies that could overcome these limitations. PSC-CMs are an exciting therapeutic prospect. Despite substantial recent advances, limitations of the technology remain. However, with our continued and increasing biological understanding, these issues are addressable, with several worldwide clinical trials anticipated in the coming years.
Topics: Cell Differentiation; Cell- and Tissue-Based Therapy; Humans; Induced Pluripotent Stem Cells; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells
PubMed: 35275365
DOI: 10.1007/s11886-022-01666-9 -
American Journal of Respiratory Cell... Oct 2021
Topics: Alveolar Epithelial Cells; Induced Pluripotent Stem Cells; Pulmonary Alveoli
PubMed: 34153206
DOI: 10.1165/rcmb.2021-0242ED