Multi-lineage Human iPSC-Derived Platforms for Disease Modeling and Drug Discovery

Sharma, Arun; Sances, Samuel; Workman, Michael J.; Svendsen, Clive N.

doi:10.1016/j.stem.2020.02.011

Cited by 207 publications

(171 citation statements)

References 259 publications

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…Using the dSMADi strategy ( Figure 6A), we rapidly generated NSCs sufficient for 184 plates (384-well format) enabling the knockdown of 21,584 genes (three unique siRNAs for each target gene). These high-throughput screens confirmed previously reported targets (Li et al, 2019) (Cahan and Daley, 2013;Choi et al, 2015;Sharma et al, 2020). Another challenge is continuous passage of self-renewing hPSCs, while cell differentiation experiments are initiated in parallel.…”

Section: Zika Virus Infection Of Robotically Generated Cardiomyocytessupporting

confidence: 84%

“…Derivation of large quantities of hiPSC-derived cardiomyocytes and hepatocytes is of particular interest for drug development, toxicology studies, and regenerative medicine (Kimbrel and Lanza, 2020;Sharma et al, 2020). To generate cardiomyocytes, we adopted a kit-based protocol for automated differentiation of hPSCs ( Figure 7A).…”

Section: Standardized Production Of Functional Cardiomyocytes and Hepmentioning

confidence: 99%

See 1 more Smart Citation

Robotic High-Throughput Biomanufacturing and Functional Differentiation of Human Pluripotent Stem Cells

Tristan

Ormanoglu

Slamecka

et al. 2020

Preprint

View full text Add to dashboard Cite

Efficient translation of human induced pluripotent stem cells (hiPSCs) depends on implementing scalable cell manufacturing strategies that ensure optimal self-renewal and functional differentiation. Currently, manual culture of hiPSCs is highly variable and labor-intensive posing significant challenges for high-throughput applications. Here, we established a robotic platform and automated all essential steps of hiPSC culture and differentiation under chemically defined conditions. This streamlined approach allowed rapid and standardized manufacturing of billions of hiPSCs that can be produced in parallel from up to 90 different patient-and disease-specific cell lines. Moreover, we established automated multi-lineage differentiation to generate primary embryonic germ layers and more mature phenotypes such as neurons, cardiomyocytes, and hepatocytes. To validate our approach, we carefully compared robotic and manual cell culture and performed molecular and functional cell characterizations (e.g. bulk culture and single-cell transcriptomics, mass cytometry, metabolism, electrophysiology, Zika virus experiments) in order to benchmark industrial-scale cell culture operations towards building an integrated platform for efficient cell manufacturing for disease modeling, drug screening, and cell therapy. Combining stem cell-based models and non-stop robotic cell culture may become a powerful strategy to increase scientific rigor and productivity, which are particularly important during public health emergencies (e.g. opioid crisis, COVID-19 pandemic).

show abstract

Section: Zika Virus Infection Of Robotically Generated Cardiomyocytessupporting

confidence: 84%

Section: Standardized Production Of Functional Cardiomyocytes and Hepmentioning

confidence: 99%

Robotic High-Throughput Biomanufacturing and Functional Differentiation of Human Pluripotent Stem Cells

Tristan

Ormanoglu

Slamecka

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Improved methods to convert human induced pluripotent stem cells (hiPSCs) to multiple somatic lineages have enabled in vitro mass production of patient-specific cells, including hiPSC-derived cardiomyocytes (hiPSC-CMs) (Sharma et al, 2020). The hiPSC-CMs express relevant proteins found in adult human CMs, can spontaneously contract, can be made in weeks using defined differentiation protocols, and can be genetically customized using genome editing (Sharma et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Sharma

García

Arumugaswami

et al. 2020

Preprint

Self Cite

115

152

View full text Add to dashboard Cite

words):Coronavirus disease 2019 is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well-understood. We used human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) as a model system to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and immunofluorescence demonstrated that SARS-CoV-2 can enter and replicate within hiPSC-CMs, localizing at perinuclear locations within the cytoplasm. Viral cytopathic effect induced hiPSC-CM apoptosis and cessation of beating after 72 hours of infection. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating the mechanisms of infection and potentially a cardiac-specific antiviral drug screening platform.was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

show abstract

“…Developmental biology research has focused on optimizing devices, culture conditions, materials, and timing to better recapitulate the myocardium environment in vivo [ 4 , 70 ]. While the use of iPSCs-CMs in clinical therapeutics is still far off, near-term potential may lie in applications that serve as a platform for heart disease modeling and personalized medicine [ 71 ].…”

Section: Challenges For Use Of Ipscs In Heart Disease Therapymentioning

confidence: 99%

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

Jiang

Liang

Huang

et al. 2020

IJMS

View full text Add to dashboard Cite

Limited adult cardiac cell proliferation after cardiovascular disease, such as heart failure, hampers regeneration, resulting in a major loss of cardiomyocytes (CMs) at the site of injury. Recent studies in cellular reprogramming approaches have provided the opportunity to improve upon previous techniques used to regenerate damaged heart. Using these approaches, new CMs can be regenerated from differentiation of iPSCs (similar to embryonic stem cells), the direct reprogramming of fibroblasts [induced cardiomyocytes (iCMs)], or induced cardiac progenitors. Although these CMs have been shown to functionally repair infarcted heart, advancements in technology are still in the early stages of development in research laboratories. In this review, reprogramming-based approaches for generating CMs are briefly introduced and reviewed, and the challenges (including low efficiency, functional maturity, and safety issues) that hinder further translation of these approaches into a clinical setting are discussed. The creative and combined optimal methods to address these challenges are also summarized, with optimism that further investigation into tissue engineering, cardiac development signaling, and epigenetic mechanisms will help to establish methods that improve cell-reprogramming approaches for heart regeneration.

show abstract

Multi-lineage Human iPSC-Derived Platforms for Disease Modeling and Drug Discovery

Cited by 207 publications

References 259 publications

Robotic High-Throughput Biomanufacturing and Functional Differentiation of Human Pluripotent Stem Cells

Robotic High-Throughput Biomanufacturing and Functional Differentiation of Human Pluripotent Stem Cells

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

Contact Info

Product

Resources

About