Abstract
Human embryonic stem cells (hESCs) are highly sensitive to DNA damage and have low survival ability relative to differentiated cells. We investigated the source of this difference by comparing damage response pathways in hESCs and differentiated cells. We found that hESCs undergo more rapid p53-dependent apoptosis after DNA damage than differentiated cells do. However, p53 localization and function are similar between hESCs and differentiated cells, suggesting that p53 alone cannot explain the difference in sensitivity. Instead, we show that mitochondrial readiness for apoptosis, known as mitochondrial priming, differs between hESCs and differentiated cells. Specifically, the balance between proapoptotic and antiapoptotic proteins is shifted closer to the apoptotic threshold in hESCs than in differentiated cells. Altering this balance in differentiated cells increases their sensitivity and results in cell death, suggesting that manipulation of mitochondrial priming could potentially alter the sensitivity of other stem cells, including cancer stem cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 483-491 |
| Number of pages | 9 |
| Journal | Cell Stem Cell |
| Volume | 13 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 3 2013 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank R. Agami for the p53shRNA construct; G. Daley for the CHB8 cell line; D. Melton for the HUES9 cell line; Y. Xu for the HUES9 p53 −/− cell line; A. Baccei, B. Gorman, and K. Karhohs for assistance with IF imaging and analysis; J. Moore and J. Stewart-Ornstein for assistance with flow cytometry and analysis; J. Reyes for assistance with illustration; and E. Batchelor and all members of our laboratory for comments and discussions. J.C.L. was supported by the Molecular Biophysics Training Grant (NIH/NIGMS T32008313) and the National Science Foundation Graduate Research Fellowship. A.G.R. was supported by the Harvard College Program for Research in Science and Engineering and the FAS Center for Systems Biology. P.H.L. was supported by the Charles H. Hood Foundation and NIH/NICHD HD061981.
