scholarly journals Human pluripotent stem cell modeling of tuberous sclerosis complex reveals lineage-specific therapeutic vulnerabilities

2019 ◽  
Author(s):  
Sean P. Delaney ◽  
Lisa M. Julian ◽  
Adam Pietrobon ◽  
Julien Yockell-Lelièvre ◽  
Carole Doré ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Human Pluripotent Stem Cell ◽  
Cell Of Origin ◽  
Mesenchymal Tumors ◽  
Cell Modeling ◽  
System Tumor

SUMMARYmTORC1 hyperactivation resulting from inactivating TSC2 mutations underlie the multi-system tumor disorder tuberous sclerosis complex (TSC) and the rare pulmonary neoplasm lymphangioleiomyomatosis (LAM). Mutation-bearing neural precursor cells (NPCs) lead to the formation of TSC brain tumors during development, while the cell of origin of TSC mesenchymal tumors such as LAM is unknown. We report the first model of multi-system TSC cell types, characterized by NPCs and neural crest cells (NCCs) differentiated in parallel from multiple engineered TSC2−/− human pluripotent stem cell (hPSC) lines. These cells successfully model defining phenotypes of neural and mesenchymal TSC, with transcriptomic signatures reflecting those observed in patient tumors, thus establishing TSC2−/− NCCs as a powerful model of LAM. Employing this rich cellular and transcriptomic resource, we identified lineage-specific catabolic signaling mechanisms that drive divergent cell behavior and therapeutic sensitivities that, in turn, demonstrate the power of employing lineage-specific stem cell models to dissect multi-system diseases.

Human Pluripotent Stem Cell Modeling of Tuberous Sclerosis Complex Reveals Lineage-Specific Therapeutic Vulnerabilities

2020 ◽  
Author(s):  
Sean P. Delaney ◽  
Lisa M. Julian ◽  
Adam Pietrobon ◽  
Julien Yockell-Lelièvre ◽  
Carole Doré ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Pluripotent Stem Cell ◽  
Human Pluripotent Stem Cell ◽  
Cell Modeling

scholarly journals A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types

Stem Cells ◽  
2017 ◽  
Vol 36 (3) ◽  
pp. 313-324 ◽  
Author(s):  
M. Joseph Phillips ◽  
Peng Jiang ◽  
Sara Howden ◽  
Patrick Barney ◽  
Jee Min ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sequence Analysis ◽  
Single Cell ◽  
In Silico ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Retinal Cell ◽  
Human Pluripotent Stem Cell ◽  
Rna Sequence ◽  
Novel Approach

scholarly journals Developmental chromatin programs determine oncogenic competence in melanoma

2020 ◽  
Author(s):  
Arianna Baggiolini ◽  
Scott J. Callahan ◽  
Tuan Trieu ◽  
Mohita M. Tagore ◽  
Emily Montal ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neural Crest ◽  
Pluripotent Stem Cell ◽  
Developmental Regulation ◽  
Molecular Profiling ◽  
Human Pluripotent Stem Cell ◽  
Cell Of Origin ◽  
Cancer Model ◽  
Transcriptional Program ◽  
Proper Response

AbstractOncogenes are only transforming in certain cellular contexts, a phenomenon called oncogenic competence. The mechanisms regulating this competence remain poorly understood. Here, using a combination of a novel human pluripotent stem cell (hPSC)-based cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E depends upon the intrinsic transcriptional program present in the cell of origin. Remarkably, in both systems, melanocytes (MC) are largely resistant to BRAF. In contrast, both neural crest (NC) and melanoblast (MB) populations are readily transformed. Molecular profiling reveals that NC/MB cells have markedly higher expression of chromatin modifying enzymes, and we discovered that the chromatin remodeler ATAD2 is required for response to BRAF and tumor initiation. ATAD2 forms a complex with SOX10, allowing for expression of downstream oncogenic programs. These data suggest that oncogenic competence is mediated by developmental regulation of chromatin factors, which then allow for proper response to those oncogenes.

scholarly journals Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids

2020 ◽  
Author(s):  
Xiaohua Duan ◽  
Yuling Han ◽  
Liuliu Yang ◽  
Benjamin E. Nilsson-Payant ◽  
Pengfei Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Entry ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Human Pluripotent Stem Cell ◽  
Humanized Mouse Model ◽  
Multiple Cell ◽  
Approved Drugs

Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

scholarly journals Cardiac Tissues From Stem Cells

2021 ◽  
Vol 128 (6) ◽  
pp. 775-801
Author(s):  
Giulia Campostrini ◽  
Laura M. Windt ◽  
Berend J. van Meer ◽  
Milena Bellin ◽  
Christine L. Mummery
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Cell Types ◽  
The Body ◽  
Current Status ◽  
Human Pluripotent Stem Cell ◽  
3 Dimensional

The ability of human pluripotent stem cells to form all cells of the body has provided many opportunities to study disease and produce cells that can be used for therapy in regenerative medicine. Even though beating cardiomyocytes were among the first cell types to be differentiated from human pluripotent stem cell, cardiac applications have advanced more slowly than those, for example, for the brain, eye, and pancreas. This is, in part, because simple 2-dimensional human pluripotent stem cell cardiomyocyte cultures appear to need crucial functional cues normally present in the 3-dimensional heart structure. Recent tissue engineering approaches combined with new insights into the dialogue between noncardiomyocytes and cardiomyocytes have addressed and provided solutions to issues such as cardiomyocyte immaturity and inability to recapitulate adult heart values for features like contraction force, electrophysiology, or metabolism. Three-dimensional bioengineered heart tissues are thus poised to contribute significantly to disease modeling, drug discovery, and safety pharmacology, as well as provide new modalities for heart repair. Here, we review the current status of 3-dimensional engineered heart tissues.

scholarly journals Remdesivir but not famotidine inhibits SARS-CoV-2 replication in human pluripotent stem cell-derived intestinal organoids

2020 ◽  
Author(s):  
Jana Krüger ◽  
Rüdiger Groß ◽  
Carina Conzelmann ◽  
Janis A. Müller ◽  
Lennart Koepke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Gastrointestinal Symptoms ◽  
Cell Types ◽  
Human Pluripotent Stem Cell ◽  
Intestinal Organoids

Gastrointestinal symptoms in COVID-19 are associated with prolonged symptoms and increased severity. We employed human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) to analyze SARS-CoV-2 pathogenesis and to validate efficacy of specific drugs in the gut. Certain, but not all cell types in PSC-HIOs express SARS-CoV-2 entry factors ACE2 and TMPRSS2, rendering them susceptible to SARS-CoV-2 infection. Remdesivir, a promising drug to treat COVID-19, effectively suppressed SARS-CoV-2 infection of PSC-HIOs. In contrast, the histamine-2-blocker famotidine showed no effect. Thus, PSC-HIOs provide an interesting platform to study SARS-CoV-2 infection and to identify or validate drugs.

scholarly journals Recent advances in animal and human pluripotent stem cell modeling of cardiac laminopathy

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Yee-Ki Lee ◽  
Yu Jiang ◽  
Xin-Ru Ran ◽  
Yee-Man Lau ◽  
Kwong-Man Ng ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Human Pluripotent Stem Cell ◽  
Recent Advances ◽  
Cell Modeling

scholarly journals Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids

2020 ◽  
Author(s):  
Xiaohua Duan ◽  
Yuling Han ◽  
Liuliu Yang ◽  
Benjamin E. Nilsson-Payant ◽  
Pengfei Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Entry ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Human Pluripotent Stem Cell ◽  
Humanized Mouse Model ◽  
Multiple Cell ◽  
Approved Drugs

Abstract The current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo- entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

scholarly journals Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer’s Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6867 ◽  
Author(s):  
Juan Antonio Garcia-Leon ◽  
Laura Caceres-Palomo ◽  
Elisabeth Sanchez-Mejias ◽  
Marina Mejias-Ortega ◽  
Cristina Nuñez-Diaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Complex Disease ◽  
Disease Modeling ◽  
Target Identification ◽  
Cell Types ◽  
Neural Cells ◽  
Human Pluripotent Stem Cell

Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer’s disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies.

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