Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

Laflamme, Michael A.; Chen, Kent Y; Naumova, Anna V.; Muskheli, Veronica; Fugate, James A.; Dupras, Sarah K.; Reinecke, Hans; Xu, Chunhui; Hassanipour, Mohammad; O’Sullivan, Chris; Collins, Lila R.; Chen, Yinhong; Minami, Elina; Gill, Edward A.; Ueno, Shu‐ichi; Yuan, Chun; Gold, Joseph K.; Murry, Charles E.

doi:10.1038/nbt1327

Cited by 2,020 publications

(2,146 citation statements)

References 68 publications

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“…Additionally, the typically very low yield of cardiac differentiation of hESCs also makes the harvesting of enough purified proteins from hESC-CMs even more difficult. Recent protocols to substantially improve the yield of CMs have been reported [35][36][37] but the heterogeneity of chamber-specific CMs have not been studied.…”

Section: Discussionmentioning

confidence: 99%

Distinct cardiogenic preferences of two human embryonic stem cell (hESC) lines are imprinted in their proteomes in the pluripotent state

Moore

Chan

et al. 2008

Biochemical and Biophysical Research Communications

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Although both the H1 and HES2 human embryonic stem cell lines (NIH codes: WA01 and ES02, respectively) are capable of forming all three germ layers and their derivatives, various lines of evidence including the need for using different protocols to induce cardiac differentiation hint that they have distinctive preferences to become chamber-specific heart cells. However, a direct systematic comparison has not been reported. Here we electrophysiologically demonstrated that the distributions of ventricular-, atrial-and pacemaker-like derivatives were indeed different (ratios=39:61:0 and 64:33:3 for H1 and HES2, respectively). Based on these results, we hypothesized the differences in their cardiogenic potentials are imprinted in the proteomes of undifferentiated H1 and HES2. Using the multiplexing, high-resolution 2-D Differential In Gel Electrophoresis (DIGE) to minimize gel-to-gel variations that are common in conventional 2D gels, a total of 2000 individual protein spots were separated. Of which, 55 were >2-fold differentially expressed in H1 and HES2 (p<0.05) and identified by mass spectrometery. Bioinformatic analysis of these protein differences further revealed candidate pathways that contribute to the H1 and HES2 phenotypes. We conclude that H1 and HES2 have predetermined preferences to become ventricular, atrial and pacemaker cells due to discrete differences in their proteomes. These results improve our basic understanding of hESCs and may lead to mechanism-based methods for their directed cardiac differentiation into chamber-specific cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Distinct cardiogenic preferences of two human embryonic stem cell (hESC) lines are imprinted in their proteomes in the pluripotent state

Moore

Chan

et al. 2008

Biochemical and Biophysical Research Communications

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“…Bioresponsiveness could be particularly relevant in studying and manipulating 'emergent' processes, such as stem cell differentiation, in which hydrogel properties that are appropriate in the early stages are likely to be dramatically different from those needed later on. For example, recent studies in standard cell culture indicate that human embryonic stem cell differentiation into spinal motor neurons 85 or cardiomyocytes 86 can be amplified by mimicking the timed soluble signalling regimen observed during early tissue development, and that the timing of signal delivery is critical. One can envision a more intelligent embodiment of this approach, in which a hydrogel responds to a change in stem cell phenotype (for example, initial lineage commitment) by changing local physical properties or by delivering a specific growth factor, thereby optimizing new tissue formation.…”

Section: Triggered Changes In Hydrogel Propertiesmentioning

confidence: 99%

Moving from static to dynamic complexity in hydrogel design

2012

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Hydrogels are water-swollen polymer networks that have found a range of applications from biological scaffolds to contact lenses. Historically, their design has consisted primarily of static systems and those that exhibit simple degradation. However, advances in polymer synthesis and processing have led to a new generation of dynamic systems that are capable of responding to artificial triggers and biological signals with spatial precision. These systems will open up new possibilities for the use of hydrogels as model biological structures and in tissue regeneration.H ydrogels are water-swollen polymer networks that have been used for many decades, with applications as varied as contact lenses and super-absorbant materials. As the field of biomedical engineering has developed, hydrogels have become a prime candidate for application as molecule delivery vehicles and as carriers for cells in tissue engineering, owing to their ability to mimic many aspects of the native cellular environment (for example, high water content, mechanical properties that match soft tissues). Traditional hydrogels, formed through the covalent and non-covalent crosslinking of polymer chains, were regarded as relatively inert materials, providing a simple biomimetic three-dimensional (3D) environment, either for tissue production by local resident cells or for positioning of cells delivered in vivo. However, the simplicity of these materials may have in fact hindered their application, restricting cellular interactions with the environment and preventing uniform extracellular matrix (ECM) production and proper tissue development. In addition, these materials were limited to modelling static environments and lacked the spatiotemporal dynamic properties relevant for complex tissue processes. Fortunately, during the last decade the concepts of hydrogel design and cellular interaction have evolved, shedding light on how they may control cell behaviour, particularly for tissue engineering applications.Hydrogels with a range of mechanical properties, and capable of incorporating a wide range of biologically relevant molecules, from individual functional groups to multidomain proteins, are currently in development 1 . In addition, hydrogels are being designed with spatial heterogeneity, to either replicate properties in native tissue structures or to produce constructs with distinct regionally specific cell behavior 2 . As a result, studies to date have clearly demonstrated the possibility of creating well-defined microenvironments with control over the 3D presentation of signals to cells 3 . However, recently there has been a focus on the concept of hydrogels that exhibit dynamic complexity. These materials should evolve with time and in response to

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“…It is therefore tempting to suggest that the brain may be a tumor-privileged site. When hESC-derived osteocytes or cardiomyocytes were transplanted into the bone or heart of SCID mice, there was also no teratoma production within 1 month after injection [Bielby et al, 2004;Laflamme et al, 2007]. The longer hESCs are differentiated in vitro, the risk of teratoma formation seems to be reduced.…”

Section: Immunorejectionmentioning

confidence: 99%

Taking stem cells to the clinic: Major challenges

Bongso

Fong

Gauthaman

2008

J of Cellular Biochemistry

167

111

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Stem cell therapy offers tremendous promise in the treatment of many incurable diseases. A variety of stem cell types are being studied but human embryonic stem cells (hESCs) appear to be the most versatile as they are pluripotent and can theoretically differentiate into all the tissues of the human body via the three primordial germ layers and the male and female germ lines. Currently, hESCs have been successfully converted in vitro into functional insulin secreting islets, cardiomyocytes, and neuronal cells and transfer of such cells into diabetic, ischaemic, and parkinsonian animal models respectively have shown successful engraftment. However, hESC-derived tissue application in the human is fraught with the problems of ethics, immunorejection, tumorigenesis from rogue undifferentiated hESCs, and inadequate cell numbers because of long population doubling times in hESCs. Human mesenchymal stem cells (hMSC) though not tumorigenic, also have their limitations of multipotency, immunorejection, and are currently confined to autologous transplantation with the genuine benefits in allogeneic settings not conclusively shown in large controlled human trials. Human Wharton's jelly stem cells (WJSC) from the umbilical cord matrix which are of epiblast origin and containing both hESC and hMSC markers appear to be less troublesome in not being an ethically controversial source, widely multipotent, not tumorigenic, maintain ''stemness'' for several serial passages and because of short population doubling time can be scaled up in large numbers. This report describes in detail the hurdles all these stem cell types have to overcome before stem cell-based therapy becomes a genuine reality.

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Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

Cited by 2,020 publications

References 68 publications

Distinct cardiogenic preferences of two human embryonic stem cell (hESC) lines are imprinted in their proteomes in the pluripotent state

Distinct cardiogenic preferences of two human embryonic stem cell (hESC) lines are imprinted in their proteomes in the pluripotent state

Moving from static to dynamic complexity in hydrogel design

Taking stem cells to the clinic: Major challenges

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