20 Years of Human Pluripotent Stem Cell Research: It All Started with Five Lines

Ludwig, Tenneille E.; Kujak, Angela; Rauti, Antonio; Andrzejewski, Steven; Langbehn, Susan; Mayfield, James; Fuller, Jacqueline; Hara, Yasushi; Bhattacharyya, Anita

doi:10.1016/j.stem.2018.10.009

Cited by 12 publications

(7 citation statements)

References 8 publications

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“…1 The clinical translation of hPSC progenies has made particular progress in recent years. 2 However, routine cell therapies for solid organs such as the heart, pancreas, liver or brain will require large cell quantities estimated at 10 8 to 10 9 cells per patient. 3 For hPSC-derived blood cells such as macrophages 4 and erythrocytes 5 even higher numbers ranging beyond 10 11 cells per patient are discussed.…”

Section: Introductionmentioning

confidence: 99%

High Density Bioprocessing of Human Pluripotent Stem Cells by Metabolic Control and in Silico Modeling

Manstein

Ullmann

Kropp

et al. 2021

Stem Cells Translational Medicine

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To harness the full potential of human pluripotent stem cells (hPSCs) we combined instrumented stirred tank bioreactor (STBR) technology with the power of in silico process modeling to overcome substantial, hPSC-specific hurdles toward their mass production. Perfused suspension culture (3D) of matrix-free hPSC aggregates in STBRs was applied to identify and control process-limiting parameters including pH, dissolved oxygen, glucose and lactate levels, and the obviation of osmolality peaks provoked by high density culture. Media supplements promoted single cell-based process inoculation and hydrodynamic aggregate size control. Wet lab-derived process characteristics enabled predictive in silico modeling as a new rational for hPSC cultivation. Consequently, hPSC line-independent maintenance of exponential cell proliferation was achieved. The strategy yielded 70-fold cell expansion in 7 days achieving an unmatched density of 35 × 10 6 cells/mL equivalent to 5.25 billion hPSC in 150 mL scale while pluripotency, differentiation potential, and karyotype stability was maintained. In parallel, media requirements were reduced by 75% demonstrating the outstanding increase in efficiency. Minimal input to our in silico model accurately predicts all main process parameters; combined with calculation-controlled hPSC aggregation kinetics, linear process upscaling is also enabled and demonstrated for up to 500 mL scale in an independent bioreactor system. Thus, by merging applied stem cell research with recent knowhow from industrial cell fermentation, a new level of hPSC bioprocessing is revealed fueling their automated production for industrial and therapeutic applications.

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Section: Introductionmentioning

confidence: 99%

High Density Bioprocessing of Human Pluripotent Stem Cells by Metabolic Control and in Silico Modeling

Manstein

Ullmann

Kropp

et al. 2021

Stem Cells Translational Medicine

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“…240,241 Combined with their self-regenerative properties, hiPSCs possess many highly desirable features for personalized-regenerative medicine and make them an ideal candidate for regeneration-based therapies in CNS disorders. [242][243][244][245] The transplantation of hiPSCs opens therapeutic strategies to address not only the recovery of lost tissue but also the need for a DMT by using genetically corrected cells. Derived from patients, hiPSCs can undergo a gene-modifying treatment in vitro, for example using CRISPR-Cas9 technology, for targeted correction of the mutated gene.…”

Section: Regenerative Approaches To Neurodegenerationmentioning

confidence: 99%

The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models

et al. 2021

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“…Human pluripotent stem cells (hPSCs), with their potential to generate all the cell types of the human body, hold great promises in regenerative medicine [ 1 ]. In order to realize their production and clinical applications, effective cell culture technologies in maintaining pluripotency and inducing specific cell fates are indispensable, and optimized, chemically defined culture platforms must be established [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone enhances stem cell maintenance and promotes lineage-specific differentiation in human embryonic stem cells

Deng

Zhang²,

Xu³

et al. 2022

Stem Cell Res Ther

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Background Thyroid hormone triiodothyronine (T3) is essential for embryogenesis and is commonly used during in vitro fertilization to ensure successful implantation. However, the regulatory mechanisms of T3 during early embryogenesis are largely unknown. Method To study the impact of T3 on hPSCs, cell survival and growth were evaluated by measurement of cell growth curve, cloning efficiency, survival after passaging, cell apoptosis, and cell cycle status. Pluripotency was evaluated by RT-qPCR, immunostaining and FACS analysis of pluripotency markers. Metabolic status was analyzed using LC–MS/MS and Seahorse XF Cell Mito Stress Test. Global gene expression was analyzed using RNA-seq. To study the impact of T3 on lineage-specific differentiation, cells were subjected to T3 treatment during differentiation, and the outcome was evaluated using RT-qPCR, immunostaining and FACS analysis of lineage-specific markers. Results In this report, we use human pluripotent stem cells (hPSCs) to show that T3 is beneficial for stem cell maintenance and promotes trophoblast differentiation. T3 enhances culture consistency by improving cell survival and passaging efficiency. It also modulates cellular metabolism and promotes energy production through oxidative phosphorylation. T3 helps maintain pluripotency by promoting ERK and SMAD2 signaling and reduces FGF2 dependence in chemically defined culture. Under BMP4 induction, T3 significantly enhances trophoblast differentiation. Conclusion In summary, our study reveals the impact of T3 on stem cell culture through signal transduction and metabolism and highlights its potential role in improving stem cell applications.

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20 Years of Human Pluripotent Stem Cell Research: It All Started with Five Lines

Cited by 12 publications

References 8 publications

High Density Bioprocessing of Human Pluripotent Stem Cells by Metabolic Control and in Silico Modeling

High Density Bioprocessing of Human Pluripotent Stem Cells by Metabolic Control and in Silico Modeling

The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models

Thyroid hormone enhances stem cell maintenance and promotes lineage-specific differentiation in human embryonic stem cells

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