Differentiation of Human Embryonic Stem Cells to Cardiomyocytes

Mummery, Christine L.; Oostwaard, Dorien Ward‐van; Doevendans, Pieter A.; Spijker, René; Brink, Stieneke van den; Hassink, Rutger J.; Heyden, M. van der; Opthof, Tobias; Pera, Martin F.; Rivière, Aart Brutel de la; Passier, Robert; Tertoolen, Leon L.

doi:10.1161/01.cir.0000068356.38592.68

Cited by 981 publications

(407 citation statements)

References 29 publications

Supporting

Mentioning

387

Contrasting

Unclassified

Order By: Relevance

“…For the induction of specific cell lineages from ES cells, purified growth and/or differentiation factors or factorproducing feeder or stromal cells have been used (Chadwick et al, 2003;Cohen et al, 2007;Green et al, 2003;Kaufman et al, 2001;Kehat et al, 2001;Lavon et al, 2006;Levenberg et al, 2002;Mummery et al, 2003;Rambhatla et al, 2003;Sottile et al, 2003;Vodyanik and Slukvin, 2007;Zhang et al, 2001). In some cases, very complex culture strategies have been used, including the sequential addition and withdrawal of factors and purification of specific cell populations during the culture period (Fang et al, 2006;Wang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

Aoki

Hara

Niwa

et al. 2009

Developmental Dynamics

View full text Add to dashboard Cite

Correctly inducing the differentiation of pluripotent hESCs to a specific lineage with high purity is highly desirable for regenerative cell therapy. Our first effort to perform in vitro differentiation of hESCs resulted in a limited recapitulation of the ocular tissue structures. When undifferentiated hESCs were placed in vivo into the ocular tissue, in this case into the vitreous cavity, 3-dimensional retina-like structures reminiscent of the invagination of the optic vesicle were generated. Immunohistochemical analysis confirmed the presence of both a neural retina-like cell layer and a retinal pigmented epithelium-like cell layer, possibly equivalent to the developing E12.5 mouse retina. Furthermore, mouse epiblast-derived stem cells, which are reported to share some characteristics with hESCs, but not with mouse ESCs, also generated retinal anlage-like structures in vivo. hESC-derived retina-like structures present a novel therapeutic possibility for retinal diseases and also provide a novel experimental system to study early human eye development.

show abstract

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

Aoki

Hara

Niwa

et al. 2009

Developmental Dynamics

View full text Add to dashboard Cite

show abstract

“…In hESC-differentiating multi-lineage aggregates (EBs), only a very small fraction of cells (< 4 %) spontaneously differentiate into cardiomyocytes [3,26]. Immune-selection, co-culturing, and morphogens have been used to isolate and enrich populations of immature cardiomyocytes from hESC-differentiating EBs [26,116–119]. Enriched hESC-derived cardiomyocytes could generate small grafts and function as the biological pacemaker in animal infarcted models [27].…”

Section: Transform Pluripotent Human Embryonic Stem Cells Into Carmentioning

confidence: 99%

Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine

Parsons¹

2013

BBJ

View full text Add to dashboard Cite

To date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost CNS structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Given the limited capacity of the CNS and heart for self-repair, there is a large unmet healthcare need to develop stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Derivation of human embryonic stem cells (hESCs) provides a powerful in vitro model system to investigate molecular controls in human embryogenesis as well as an unlimited source to generate the diversity of human somatic cell types for regenerative medicine. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. Retinoic acid was identified as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger a cascade of neuronal lineage-specific progression to human neuronal progenitors and neurons of the developing CNS in high efficiency, purity, and neuronal lineage specificity by promoting nuclear translocation of the neuronal specific transcription factor Nurr-1. Similarly, nicotinamide was rendered sufficient to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs by promoting the expression of the earliest cardiac-specific transcription factor Csx/Nkx2.5 and triggering progression to cardiac precursors and beating cardiomyocytes with high efficiency. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-ba...

show abstract

“…Moreover, visceral endoderm-like cells can induce the differentiation of the epiblast to undergo hematopoiesis and vasculogenesis and respecify prospective neuroectodermal cell fates [25]. Mummery et al previously demonstrated that coculture of hESC lines with visceral endoderm-like cells induce epithelia through formation of large cystic structures that stain positively for a-fetoprotein and are presumably extraembryonic layers [29]. Therefore, we propose that SD-hESCs are not just an artifact cell produced during in vitro hESC culture, but that they may represent an important intermediate cell state related to appropriate germinal layer formation in the ICM during human blastocyst development.…”

Section: Fig 5 Cystic Ebs and Noncysticmentioning

confidence: 99%

Spontaneously DifferentiatedGATA6-Positive Human Embryonic Stem Cells Represent an Important Cellular Step in Human Embryonic Development; They Are Not Just an Artifact of In Vitro Culture

Lee

Hong

Mantel

et al. 2013

Stem Cells and Development

View full text Add to dashboard Cite

In this study, we isolated and characterized spontaneously differentiated human embryonic stem cells (SDhESCs) found in hESC colonies in comparison to the morphologically premature ESCs in the colonies to investigate the potential role of SD-hESCs in embryogenesis. SD-hESCs were distinguished from undifferentiated hESCs by their higher expression of GATA6, a marker for primitive endoderm and transthyretin, a marker visceral endoderm in embryoid bodies (EBs). SD-hESCs expressed OCT4 and NANOG, markers for pluripotent stem cells, at significantly lower levels than undifferentiated hESCs. EBs derived from isolated SD-hESCs were morphologically distinct from cells directly derived from the undifferentiated hESCs; they contained higher number of cysts compared to EBs from undifferentiated hESC-derived EBs (42% vs. 20%). Furthermore, the extracellular signal molecule, BMP2/4, induced a higher GATA4/6 expression and cystic EB formation than control and noggin-treated EBs. Since cystic formation in EBs play a role in primitive endoderm formation during embryogenesis, the SD-hESC may be a relevant cell type equipped to differentiate into primitive endoderm. Our results suggest that SD-ESCs generated during routine hESC culture are not just an artifact of in vitro culture and these cells could serve as a useful model to study the process of embryogenesis.

show abstract

Differentiation of Human Embryonic Stem Cells to Cardiomyocytes

Abstract: Background-Cardiomyocytes derived from human embryonic stem (hES) cells could be useful in restoring heart function after myocardial infarction or in heart failure.

Cited by 981 publications

References 29 publications

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine

Spontaneously DifferentiatedGATA6-Positive Human Embryonic Stem Cells Represent an Important Cellular Step in Human Embryonic Development; They Are Not Just an Artifact of In Vitro Culture

Contact Info

Product

Resources

About