Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

Li, Chun; Oikonomopoulos, Angelos; Sayed, Nazish; Wu, Joseph C.

doi:10.1242/dev.156166

Cited by 218 publications

(166 citation statements)

References 65 publications

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“…One limitation of our study is that our single-cell iPSC-CM model cannot capture tissue or systemic level contributions of increased wall thickness and extracellular matrix changes, 37 which may also contribute to DD in HCM. Other factors, such as changes in myocardium stiffness, conduction blockade, aging, and increased fibrosis cannot be recapitulated in our current model.…”

Section: Discussionmentioning

confidence: 99%

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

Yang

Rhee

et al. 2019

European Heart Journal

113

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Aims Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery. Methods and results In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload. Conclusion In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.

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Section: Discussionmentioning

confidence: 99%

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

Yang

Rhee

et al. 2019

European Heart Journal

113

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“…Over the past decade, iPSC-based technologies have demonstrated many advantages to model a wide range of human diseases (Liu, Oikonomopoulos, Sayed, & Wu, 2018). Their unique versatility and ability to retain the genetic background of the patient donor offer to yield new perspectives in disease de Rus Jacquet biology and spark the promise of more translational drug discovery efforts.…”

Section: Background Informationmentioning

confidence: 99%

Preparation and Co‐Culture of iPSC‐Derived Dopaminergic Neurons and Astrocytes

Jacquet

2019

CP Cell Biology

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Induced pluripotent stem cell (iPSC)‐based models are powerful tools to study neurodegenerative diseases such as Parkinson's disease. The differentiation of patient‐derived neurons and astrocytes allows investigation of the molecular mechanisms responsible for disease onset and development. In particular, these two cell types can be mono‐ or co‐cultured to study the influence of cell‐autonomous and non‐cell‐autonomous contributors to neurodegenerative diseases. We developed a streamlined procedure to produce high‐quality/high‐purity cultures of dopaminergic neurons and astrocytes that originate from the same population of midbrain floor‐plate progenitors. This unit describes differentiation, quality control, culture parameters, and troubleshooting tips to ensure the highest quality and reproducibility of research results. © 2019 The Authors. Basic Protocol 1: Differentiation of iPSCs into midbrain‐patterned neural progenitor cells Support Protocol: Quality control of neural progenitor cells Basic Protocol 2: Differentiation of neural progenitor cells into astrocytes Basic Protocol 3: Differentiation of neural progenitor cells into dopaminergic neurons Basic Protocol 4: Co‐culture of iPSC‐derived neurons and astrocytes

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“…However, current two‐dimensional (2D) differentiation protocols typically produce singular cell types, but not multiple cell types, from pluripotent stem cells (PSCs) . Previous studies on in vitro disease modeling were based on 2D differentiation systems and could not fully recapitulate in vivo disease pathology, as organs consist of a highly orchestrated three‐dimensional (3D) structure comprising multiple cell types, each of which has a unique function. Indeed, previous iPSC‐based in vitro modeling studies of Parkinson's disease (PD) using 2D differentiation technology described either no PD‐associated pathophysiology (no phenotype and non‐PD phenotype) or only early‐stage symptoms of PD such as a neuronal differentiation defect, abnormal autophagy, and accumulation of α‐synuclein, without recapitulating the end‐stage pathophysiology of PD such as massive midbrain dopaminergic (mDA) neuron–selective cell death …”

Section: Introductionmentioning

confidence: 99%

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

et al. 2020

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Recent studies have demonstrated the generation of midbrain-like organoids (MOs) from human pluripotent stem cells. However, the low efficiency of MO generation and the relatively immature and heterogeneous structures of the MOs hinder the translation of these organoids from the bench to the clinic. Here we describe the robust generation of MOs with homogeneous distribution of midbrain dopaminergic (mDA) neurons. Our MOs contain not only mDA neurons but also other neuronal subtypes as well as functional glial cells, including astrocytes and oligodendrocytes. Furthermore, our MOs exhibit mDA neuron-specific cell death upon treatment with 1-methyl-4-phenyl-1,-2,3,6-tetrahydropyridine, indicating that MOs could be a proper human model system for studying the in vivo pathology of Parkinson's disease (PD). Our optimized conditions for producing homogeneous and mature MOs might provide an advanced patientspecific platform for in vitro disease modeling as well as for drug screening for PD.

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Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

Cited by 218 publications

References 65 publications

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

Preparation and Co‐Culture of iPSC‐Derived Dopaminergic Neurons and Astrocytes

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

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