|
|
Blood, 15 May 2007, Vol. 109, No. 10, pp. 4518-4527.
Prepublished online as a Blood First Edition Paper on February 8, 2007; DOI 10.1182/blood-2006-10-054247.
 Previous Article | Next Article 
Submitted October 25, 2006
Accepted January 23, 2007
Checkpoint-Apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability
Charlie R Mantel, Ying Guo, Man Ryul Lee, Min-Kyoung Kim, Myung-Kwan Han, Hirohiko Shibayama, Seiji Fukuda, Mervin C. Yoder, Louis M. Pelus, Kye-Seong Kim, and Hal E. Broxmeyer*
Department of Microbiology & Immunology, & Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, IN, United States
Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea, Republic of
Department of Medical Genetics, Hanyang University College of Medicine, Seoul, Korea, Republic of
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
* Corresponding author; email: hbroxmey{at}iupui.edu.
Karyotypic abnormalities in cultured embryonic stem cells (ESC), especially near-diploid-aneuploidy, are potential obstacles to ESC use in regenerative medicine. Events causing chromosomal abnormalities in ESC may be related to events in tumor cells causing chromosomal instability (CIN) in human disease. However, the underlying mechanisms are unknown. Using multiparametric permeabilized-cell flow-cytometric analysis, we found that the mitotic-spindle-checkpoint, which helps maintain chromosomal integrity during all cell divisions, functions in human and mouse ESC, but does not initiate apoptosis as it does in somatic cells. This allows an unusual tolerance to polyploidy resulting from failed mitosis, common in rapidly proliferating cell populations and which is reduced to near-diploid-aneuploidy, which is also common in human neoplastic disease. Checkpoint activation in ESC-derived early-differentiated cells results in robust apoptosis without polyploidy/aneuploidy similar to somatic cells. Thus, the spindle checkpoint is "uncoupled" from apoptosis in ESC and is a likely source of karyotypic abnormalities. This natural behavior of ESC to tolerate/survive varying degrees of ploidy change could complicate genome-reprogramming studies and stem cell plasticity studies, but could also reveal clues about mechanisms of CIN in human tumors.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. M. Majka, M. Skokan, L. Wheeler, J. Harral, S. Gladson, E. Burnham, J. E. Loyd, K. R. Stenmark, M. Varella-Garcia, and J. West
Evidence for cell fusion is absent in vascular lesions associated with pulmonary arterial hypertension
Am J Physiol Lung Cell Mol Physiol,
December 1, 2008;
295(6):
L1028 - L1039.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ambartsumyan and A. T. Clark
Aneuploidy and early human embryo development
Hum. Mol. Genet.,
April 15, 2008;
17(R1):
R10 - R15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
