A noncoding RNA modulator potentiates phenylalanine metabolism in mice

Science ◽  
2021 ◽  
Vol 373 (6555) ◽  
pp. 662-673 ◽  
Author(s):  
Yajuan Li ◽  
Zhi Tan ◽  
Yaohua Zhang ◽  
Zhao Zhang ◽  
Qingsong Hu ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Therapeutic Strategy ◽  
Phenylalanine Hydroxylase ◽  
Induced Pluripotent Stem Cell ◽  
Enzymatic Activities ◽  
Inherited Metabolic Disorders ◽  
Musty Odor ◽  
Phenylalanine Metabolism ◽  
Induced Pluripotent

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell–differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair−/− and PahR408W/R408W mice and improved the Phe tolerance of these mice.

scholarly journals The Role of Autophagy During Differentiation and in Enhancing the Longevity of Induced Pluripotent Stem Cell-Derived Endothelial Cells

2020 ◽  
Vol 1 ◽  
pp. 254
Author(s):  
Katherine E. Hekman ◽  
Kyle Koss ◽  
David Z. Ivancic ◽  
Congcong He ◽  
Jason A. Wertheim
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro

2018 ◽  
Vol 360 ◽  
pp. 88-98 ◽  
Author(s):  
Liang Guo ◽  
Sandy Eldridge ◽  
Michael Furniss ◽  
Jodie Mussio ◽  
Myrtle Davis
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Personalized medicine in cardio-oncology: the role of induced pluripotent stem cell

2019 ◽  
Vol 115 (5) ◽  
pp. 949-959 ◽  
Author(s):  
Nazish Sayed ◽  
Mohamed Ameen ◽  
Joseph C Wu
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Association Studies ◽  
Induced Pluripotent Stem Cell ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Genomic Variants ◽  
Induced Pluripotent

Abstract Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.

scholarly journals Human Induced Pluripotent Stem Cell-Derived Vascular Cells: Recent Progress and Future Directions

2021 ◽  
Vol 8 (11) ◽  
pp. 148
Author(s):  
Jee Eun Oh ◽  
Cholomi Jung ◽  
Young-sup Yoon
Keyword(s):  
Animal Models ◽  
Induced Pluripotent Stem Cell ◽  
Great Promise ◽  
Vascular Cells ◽  
Future Directions ◽  
Tissue Repair And Regeneration ◽  
Therapeutic Benefits ◽  
Cardiovascular Regeneration ◽  
Induced Pluripotent

Human induced pluripotent stem cells (hiPSCs) hold great promise for cardiovascular regeneration following ischemic injury. Considerable effort has been made toward the development and optimization of methods to differentiate hiPSCs into vascular cells, such as endothelial and smooth muscle cells (ECs and SMCs). In particular, hiPSC-derived ECs have shown robust potential for promoting neovascularization in animal models of cardiovascular diseases, potentially achieving significant and sustained therapeutic benefits. However, the use of hiPSC-derived SMCs that possess high therapeutic relevance is a relatively new area of investigation, still in the earlier investigational stages. In this review, we first discuss different methodologies to derive vascular cells from hiPSCs with a particular emphasis on the role of key developmental signals. Furthermore, we propose a standardized framework for assessing and defining the EC and SMC identity that might be suitable for inducing tissue repair and regeneration. We then highlight the regenerative effects of hiPSC-derived vascular cells on animal models of myocardial infarction and hindlimb ischemia. Finally, we address several obstacles that need to be overcome to fully implement the use of hiPSC-derived vascular cells for clinical application.

scholarly journals 3213 Unraveling the role of Phospholamban (PLN) in humans via the characterization of Induced Pluripotent Stem Cell (iPSC) Cardiomyocytes (CM) derived from carriers of a lethal PLN mutation

2019 ◽  
Vol 3 (s1) ◽  
pp. 26-26
Author(s):  
Maria Giovanna Trivieri ◽  
Francesca Stillitano ◽  
Delaine Ceholski ◽  
Irene Turnbull ◽  
Kevin Costa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
State Of The Art ◽  
Induced Pluripotent Stem Cell ◽  
Relevant Model ◽  
Study Population ◽  
Induced Pluripotent ◽  
Ca Homeostasis

OBJECTIVES/SPECIFIC AIMS: To study the biology of Phosholamban (PLN) in a human relevant model. METHODS/STUDY POPULATION: State of the art stem-cell technologies using iPSC-CMs derived from carriers of a lethal PLN mutation. RESULTS/ANTICIPATED RESULTS: Our preliminary data demonstrate that this particular PLN mutation (L39) results in reduced expression and mis-localization of PLN as well as increased incidence of early after depolarization in isolated iPSC-CMs. DISCUSSION/SIGNIFICANCE OF IMPACT: Phospholamban (PLN) is a critical regulator of Ca++ homeostasis yet many uncertainties still remain regarding its role in humans. Our study will provide unique insights into the pathophysiology of this protein in HF.

scholarly journals Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1746-1765 ◽  
Author(s):  
Ana Cascalho ◽  
Joyce Foroozandeh ◽  
Lise Hennebel ◽  
Jef Swerts ◽  
Christine Klein ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Phosphatidic Acid ◽  
Mouse Models ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Motor Dysfunction ◽  
Neurological Dysfunction ◽  
Knock Out ◽  
Induced Pluripotent

Abstract TOR1A/TorsinA mutations cause two incurable diseases: a recessive congenital syndrome that can be lethal, and a dominantly-inherited childhood-onset dystonia (DYT-TOR1A). TorsinA has been linked to phosphatidic acid lipid metabolism in Drosophila melanogaster. Here we evaluate the role of phosphatidic acid phosphatase (PAP) enzymes in TOR1A diseases using induced pluripotent stem cell-derived neurons from patients, and mouse models of recessive Tor1a disease. We find that Lipin PAP enzyme activity is abnormally elevated in human DYT-TOR1A dystonia patient cells and in the brains of four different Tor1a mouse models. Its severity also correlated with the dosage of Tor1a/TOR1A mutation. We assessed the role of excess Lipin activity in the neurological dysfunction of Tor1a disease mouse models by interbreeding these with Lpin1 knock-out mice. Genetic reduction of Lpin1 improved the survival of recessive Tor1a disease-model mice, alongside suppressing neurodegeneration, motor dysfunction, and nuclear membrane pathology. These data establish that TOR1A disease mutations cause abnormal phosphatidic acid metabolism, and suggest that approaches that suppress Lipin PAP enzyme activity could be therapeutically useful for TOR1A diseases.

scholarly journals Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amin Ahmadi ◽  
Reza Moghadasali ◽  
Vahid Ezzatizadeh ◽  
Zeinab Taghizadeh ◽  
Seyed Mahdi Nassiri ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Membranous Nephropathy ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Glomerular Diseases ◽  
Heavy Proteinuria ◽  
Immune Mediated ◽  
Induced Pluripotent ◽  
Shed Light

Abstract Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

A PRC2-Dependent Repressive Role of PRDM14 in Human Embryonic Stem Cells and Induced Pluripotent Stem Cell Reprogramming

Stem Cells ◽  
2013 ◽  
Vol 31 (4) ◽  
pp. 682-692 ◽  
Author(s):  
Yun-Shen Chan ◽  
Jonathan Göke ◽  
Xinyi Lu ◽  
Nandini Venkatesan ◽  
Bo Feng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Cell Reprogramming ◽  
Induced Pluripotent
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