-
Nature Communications Jun 2023While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via...
While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.
Topics: Animals; Mice; Pluripotent Stem Cells; Cell Differentiation; Induced Pluripotent Stem Cells; Thorax; Mesoderm
PubMed: 37311756
DOI: 10.1038/s41467-023-39099-9 -
International Journal of Molecular... Sep 2020The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to... (Review)
Review
The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to retrace pathologic phenotypes, elucidate molecular mechanisms, and discover therapies using simple and reproducible techniques. In the past years, several human cell types have been utilized for these goals, including heterologous systems, cardiovascular and non-cardiovascular primary cells, and embryonic stem cells. The introduction of induced pluripotent stem cells and their differentiation potential brought new prospects for large-scale cardiovascular experiments, bypassing ethical concerns of embryonic stem cells and providing an advanced tool for disease modeling, diagnosis, and therapy. Each model has its advantages and disadvantages in terms of accessibility, maintenance, throughput, physiological relevance, recapitulation of the disease. A higher level of complexity in diseases modeling has been achieved with multicellular co-cultures. Furthermore, the important progresses reached by bioengineering during the last years, together with the opportunities given by pluripotent stem cells, have allowed the generation of increasingly advanced in vitro three-dimensional tissue-like constructs mimicking in vivo physiology. This review provides an overview of the main cell models used in cardiovascular research, highlighting the pros and cons of each, and describing examples of practical applications in disease modeling.
Topics: Animals; Bioengineering; Cardiovascular Diseases; Cell Differentiation; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Models, Biological
PubMed: 32887493
DOI: 10.3390/ijms21176388 -
Stem Cell Research May 2021The Korea National Stem Cell Bank has been banking pluripotent stem cell (PSC) lines since 2012. Quality-controlled and ethically sourced cell lines were developed for...
The Korea National Stem Cell Bank has been banking pluripotent stem cell (PSC) lines since 2012. Quality-controlled and ethically sourced cell lines were developed for distribution. Currently (as of 2020), among the 69 deposited lines, 4 research-grade human embryonic stem cell (hESC) lines and 19 induced pluripotent stem cell (iPSC) lines have been distributed. Good manufacturing practices (GMP)-compliant homozygous iPSC lines for regenerative medicine with homozygous HLA haplotypes that cover 51% of the Korean population have been deposited as well. To ensure the quality of the cell lines, we performed eighteen different quality tests on the identity, sterility, consistency, stability and safety of the cell lines. Regarding genetic stability, we are collecting SNPchip, WES, Methyl-seq, and RNA-seq data, which are open to the public.
Topics: Cell Line; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Republic of Korea
PubMed: 33714852
DOI: 10.1016/j.scr.2021.102270 -
Journal of Cardiology Nov 2020Pluripotent stem cells (PSCs), which include embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively), have great potential in regenerative medicine... (Review)
Review
Pluripotent stem cells (PSCs), which include embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively), have great potential in regenerative medicine for heart diseases due to their virtually unlimited cardiogenic capacity. Many preclinical studies have described the functional benefits after transplantation of PSC-derived cardiomyocytes (PSC-CMs). However, transient ventricular arrhythmias were detected after injection into non-human primates and swine ischemic hearts; as engrafted PSC-CMs form an electrical coupling between host and graft, the immature characteristics of PSC-CMs may serve as an ectopic pacemaker. We are entering a critical time in the development of novel therapies using PSC-CMs, with the recent first clinical trial using human iPSC-CMs (hiPSC-CMs) being launched in Japan. In this review, we summarize the updated knowledge, perspectives, and limitations of PSC-CMs for heart regeneration.
Topics: Animals; Cell Differentiation; Heart; Humans; Myocytes, Cardiac; Pluripotent Stem Cells; Regeneration
PubMed: 32690435
DOI: 10.1016/j.jjcc.2020.03.013 -
International Journal of Molecular... Jan 2021For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of... (Review)
Review
For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cells, Cultured; Drug Discovery; Embryo, Mammalian; Embryonic Development; Human Embryonic Stem Cells; Humans; Models, Animal; Organoids; Pluripotent Stem Cells
PubMed: 33440617
DOI: 10.3390/ijms22020637 -
Current Opinion in Genetics &... Aug 2023The totipotent embryo initiates transcription during zygotic or embryonic genome activation (EGA, ZGA). ZGA occurs at the 8-cell stage in humans and its failure leads to... (Review)
Review
The totipotent embryo initiates transcription during zygotic or embryonic genome activation (EGA, ZGA). ZGA occurs at the 8-cell stage in humans and its failure leads to developmental arrest. Understanding the molecular pathways underlying ZGA and totipotency is essential to comprehend human development. Recently, human 8-cell-like cells (8CLCs) have been discovered in vitro that resemble the 8-cell embryo. 8CLCs exist among naive pluripotent stem cells and can be induced genetically or chemically. Their ZGA-like transcriptome, transposable element activation, 8-cell embryo-specific protein expression, and developmental properties make them an exceptional model system to study early embryonic cell-state transitions and human totipotency programs in vitro.
Topics: Humans; Pluripotent Stem Cells; Human Embryonic Stem Cells; Zygote; Genome, Human
PubMed: 37356343
DOI: 10.1016/j.gde.2023.102066 -
Cell Stem Cell Mar 2022Human naive pluripotent stem cells have the remarkable ability to generate blastoids comprising trophectoderm, epiblast, and hypoblast-like cells. In this issue,...
Human naive pluripotent stem cells have the remarkable ability to generate blastoids comprising trophectoderm, epiblast, and hypoblast-like cells. In this issue, Taubenschmid-Stowers et al. (2022) show that human naive pluripotent stem cell cultures contain cells that resemble the 8-cell human embryo, providing a model to study zygotic genome activation.
Topics: Embryo, Mammalian; Germ Layers; Humans; Pluripotent Stem Cells
PubMed: 35245463
DOI: 10.1016/j.stem.2022.01.015 -
Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells.Nature Communications Dec 2023Cardiac fibroblasts play an essential role in the development of the heart and are implicated in disease progression in the context of fibrosis and regeneration. Here,...
Cardiac fibroblasts play an essential role in the development of the heart and are implicated in disease progression in the context of fibrosis and regeneration. Here, we establish a simple organoid culture platform using human pluripotent stem cell-derived epicardial cells and ventricular cardiomyocytes to study the development, maturation, and heterogeneity of cardiac fibroblasts under normal conditions and following treatment with pathological stimuli. We demonstrate that this system models the early interactions between epicardial cells and cardiomyocytes to generate a population of fibroblasts that recapitulates many aspects of fibroblast behavior in vivo, including changes associated with maturation and in response to pathological stimuli associated with cardiac injury. Using single cell transcriptomics, we show that the hPSC-derived organoid fibroblast population displays a high degree of heterogeneity that approximates the heterogeneity of populations in both the normal and diseased human heart. Additionally, we identify a unique subpopulation of fibroblasts possessing reparative features previously characterized in the hearts of model organisms. Taken together, our system recapitulates many aspects of human cardiac fibroblast specification, development, and maturation, providing a platform to investigate the role of these cells in human cardiovascular development and disease.
Topics: Humans; Cell Differentiation; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Fibroblasts; Myocytes, Cardiac
PubMed: 38081833
DOI: 10.1038/s41467-023-43312-0 -
International Journal of Molecular... Jul 2023The development of regenerative medicine provides new options for the treatment of end-stage liver diseases. Stem cells, such as bone marrow mesenchymal stem cells,... (Review)
Review
The development of regenerative medicine provides new options for the treatment of end-stage liver diseases. Stem cells, such as bone marrow mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs), are effective tools for tissue repair in regenerative medicine. iPSCs are an appropriate source of hepatocytes for the treatment of liver disease due to their unlimited multiplication capacity, their coverage of the entire range of genetics required to simulate human disease, and their evasion of ethical implications. iPSCs have the ability to gradually produce hepatocyte-like cells (HLCs) with homologous phenotypes and physiological functions. However, how to induce iPSCs to differentiate into HLCs efficiently and accurately is still a hot topic. This review describes the existing approaches for inducing the differentiation of iPSCs into HLCs, as well as some challenges faced, and summarizes various parameters for determining the quality and functionality of HLCs. Furthermore, the application of iPSCs for in vitro hepatoprotective drug screening and modeling of liver disease is discussed. In conclusion, iPSCs will be a dependable source of cells for stem-cell therapy to treat end-stage liver disease and are anticipated to facilitate individualized treatment for liver disease in the future.
Topics: Humans; Hepatocytes; Pluripotent Stem Cells; Cell Differentiation; Induced Pluripotent Stem Cells; Liver Diseases
PubMed: 37511351
DOI: 10.3390/ijms241411592 -
Trends in Molecular Medicine Sep 2019Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of... (Review)
Review
Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs.
Topics: Animals; Biomarkers; Cell Differentiation; Cell- and Tissue-Based Therapy; Disease Models, Animal; Gene Editing; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Muscular Dystrophies; Myoblasts, Cardiac; Pluripotent Stem Cells; Regeneration; Stem Cell Transplantation; Transgenes
PubMed: 31473142
DOI: 10.1016/j.molmed.2019.07.004