Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair

Hartman, Matthew E.; Dai, Dao Fu; Laflamme, Michael A.

doi:10.1016/j.addr.2015.05.004

Cited by 117 publications

(79 citation statements)

References 206 publications

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“…For better recapitulation of human physiology and pathology, in vitro cardiac models now focus on human pluripotent stem cells, including human embryonic stem cells ( hESCs ) and hiPSCs [27, 28] (Table 1). Contracting CMs were first generated from hiPSCs through co-culture with END2 mouse endoderm-like cells, a methodology restricted by its reliance on animal cells [29].…”

Section: Cell Sources For Cardiac Tissue Modelsmentioning

confidence: 99%

In vitro cardiac tissue models: Current status and future prospects

Mathur

Loskill

et al. 2016

Advanced Drug Delivery Reviews

142

127

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Cardiovascular disease is the leading cause of death worldwide. Achieving the next phase of potential treatment strategies and better prognostic tools will require a concerted effort from interdisciplinary fields. Biomaterials-based cardiac tissue models are revolutionizing the area of preclinical research and translational applications. The goal of in vitro cardiac tissue modeling is to create physiological functional models of the human myocardium, which is a difficult task due to the complex structure and function of the human heart. This review describes the advances made in area of in vitro cardiac models using biomaterials and bioinspired platforms. The field has progressed extensively in the past decade, and we envision its applications in the areas of drug screening, disease modeling, and precision medicine.

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Section: Cell Sources For Cardiac Tissue Modelsmentioning

confidence: 99%

In vitro cardiac tissue models: Current status and future prospects

Mathur

Loskill

et al. 2016

Advanced Drug Delivery Reviews

142

127

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“…Human pluripotent stem cells (PSCs) have been widely utilized to generate human cardiomyocytes in vitro for various applications, including disease modeling (disease in a dish model), drug screening, and novel drug discovery, as well as preclinical research for cardiac regeneration in models of myocardial infarction and chronic heart failure [1]. Several methods have been tested and refined to enhance the differentiation efficiency of PSCs into cardiomyocytes, some of which reported the ability to achieve cardiomyocytes population exceeding 90% [2].…”

Section: Introductionmentioning

confidence: 99%

“…Several methods have been tested and refined to enhance the differentiation efficiency of PSCs into cardiomyocytes, some of which reported the ability to achieve cardiomyocytes population exceeding 90% [2]. These protocols typically involve the sequential application to PSCs of factors including activin A, bone morphogenetic protein-4 (BMP-4), inhibitors or activators of Wnt signaling, and matricellular cues (see recent review [1]).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes

Dai

Danoviz

Wiczer

et al. 2017

Stem Cells International

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Human pluripotent stem cells derived cardiomyocytes (PSC-CMs) have been widely used for disease modeling, drug safety screening, and preclinical cell therapy to regenerate myocardium. Most studies have utilized PSC-CM grown in vitro for a relatively short period after differentiation. These PSC-CMs demonstrated structural, electrophysiological, and mechanical features of primitive cardiomyocytes. A few studies have extended in vitro PSC-CM culture time and reported improved maturation of structural and electromechanical properties. The degree of mitochondrial maturation, however, remains unclear. This study characterized the development of mitochondria during prolonged in vitro culture. PSC-CM demonstrated an improved mitochondrial maturation with prolonged culture, in terms of increased mitochondrial relative abundance, enhanced membrane potential, and increased activity of several mitochondrial respiratory complexes. These are in parallel with the maturation of other cellular components. However, the maturation of mitochondria in PSC-CMs grown for extended in vitro culture exhibits suboptimal maturation when compared with the maturation of mitochondria observed in the human fetal heart during similar time interval.

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“…For spinal cord injury treatment, the number of cells required ranges from 2 × 10 6 to 20 × 10 6 per treatment; other general estimates of the cell numbers required for cell-based therapies are 5 × 10 4 to 1 × 10 10 (Chen, Reuveny, & Oh, 2013;Hartman, Dai, & Laflamme, 2016;Kehoe, Jing, Lock, & Tzanakakis, 2010). This range of cell numbers is also relevant to other applications of hiPSCs such as disease modeling (Mekhoubad et al, 2012;Soldner & Jaenisch, 2012), high-throughput drug screening, or fabrication of bioartificial organs.…”

mentioning

confidence: 99%

Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single‐use bioreactors

Kwok

Ueda

Kadari

et al. 2017

J Tissue Eng Regen Med

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The production of human induced pluripotent stem cells (hiPSCs) in quantities that are relevant for cell-based therapies and cell-loaded implants through standard adherent culture is hardly achievable and lacks process scalability. A promising approach to overcoming these hurdles is the culture of hiPSCs in suspension. In this study, stirred suspension culture vessels were investigated for their suitability in the expansion of two hiPSC lines inoculated as a single cell suspension, with a free scalability between volumes of 50 and 2400 ml. The simple and robust two-step process reported here first generates hiPSC aggregates of 324 ± 71 μm diameter in 7 days in 125 ml spinner flasks (100 ml volume). These are subsequently dissociated into a single cell suspension for inoculation in 3000 ml bioreactors (1000 ml volume), finally yielding hiPSC aggregates of 198 ± 58 μm after 7 additional days. In both spinner flasks and bioreactors, hiPSCs can be cultured as aggregates for more than 40 days in suspension, maintain an undifferentiated state as confirmed by the expression of pluripotency markers TRA-1-60, TRA-1-81, SSEA-4, OCT4, and SOX2, can differentiate into cells of all three germ layers, and can be directed to differentiate into specific lineages such as cardiomyocytes. Up to a 16-fold increase in hiPSC quantity at the 100 ml volume was achieved, corresponding to a fold increase per day of 2.28; at the 1000 ml scale, an additional 10-fold increase was achieved. Taken together, 16 × 10 6 hiPSCs were expanded into 2 × 10 9 hiPSCs in 14 days for a fold increase per day of 8.93. This quantity of hiPSCs readily meets the requirements of cell-based therapies and brings their clinical potential closer to fruition.

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Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair

Cited by 117 publications

References 206 publications

In vitro cardiac tissue models: Current status and future prospects

In vitro cardiac tissue models: Current status and future prospects

Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes

Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single‐use bioreactors

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