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| Status |
Public on Oct 21, 2018 |
| Title |
The integrated stress response regulates cell health of cardiac progenitors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The discovery of mammalian cardiac progenitor cells has suggested that the heart consists of not only terminally differentiated beating cardiomyocytes, but also a population of self-renewing stem cells with the potential to generate new cardiomyocytes (Anderson, Self et al. 2007; Bearzi, Rota et al. 2007; Wu, Chien et al. 2008). A consequence of longevity is continual exposure to environmental and xenobiotic stresses, and recent literature suggests that hematopoietic stem cell pools tightly control cell health through upregulation of the integrated stress response and consequent cellular mechanisms such as apoptosis. However, whether or not this biological response is conserved in progenitor cells for later lineages of tissue specific stem cells is not well understood. Using human induced pluripotent stem cells (iPSC) of both cardiac progenitor and mature cardiomyocyte lineages, we found that the integrated stress response was upregulated in the iPSC cardiac progenitors leading to an increased sensitivity for apoptosis relative to the mature cardiomyocytes. Of interest, C/EBP homologous protein (CHOP) signaling plays a mechanistic role in the cell death phenotype observed in iPSC progenitors, by which depletion of CHOP prevents cell death following cellular stress by thapsigargin exposure. Our studies suggest that the integrated stress response plays a unique role in maintaining iPSC cardiac progenitor cellular integrity by removing unhealthy cells via apoptosis following environmental and xenobiotic stresses, thus preventing differentiation and self-renewal of damaged cells.
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| Overall design |
IPSC cardiomyocytes (Cellular Dynamics) were cultured for 24hrs (progenitors) or 2 weeks (mature), followed by compound treatment for 24hrs. All treatments were performed in triplicate. Compound treatments were 1uM thapsigargin, 2uM tunicamycin, or 0.1uM halifuginone. RNA was hybridized to Affymetrix Human Genome U133_Plus_2.0 arrays. Data was analyzed using the MAS 5.0 algorithm, with global scaling to 1500.
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| Contributor(s) |
Searfoss GH, Paisley BM, Goldstein KM, Baker TK, Willy JA |
| Citation(s) |
30215789 |
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| Submission date |
Sep 06, 2018 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Keith M Goldstein |
| E-mail(s) |
goldsteinkm@lilly.com
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| Organization name |
Eli Lilly & Co.
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| Department |
Investigative Toxicology
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| Lab |
Keith Goldstein
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| Street address |
Lilly Corporate Center
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| City |
Indianapolis |
| State/province |
IN |
| ZIP/Postal code |
46285 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA489576 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE119559_RAW.tar |
120.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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