Some of the genes of ordinary human cells reprogrammed as induced pluripotent stem cells may be mutated, researchers wrote in the journal Nature. They believe extensive genetic screening of these stem cells, known as hiPSCs should be carried out routinely before using them to treat patients.
New and varied treatments tailored for individual patients may become feasible by using ordinary human cells reprogrammed as hiPSCs, the authors explained. However, many questions remain unanswered regarding the safety of such cells. We still do not understand whether and/or how their genetic material changes during the reprogramming process.
Kun Zhang, PhD, assistant professor of bioengineering, UC, San Diego, and team looked at 22 different hiPSC lines gathered from seven different research groups that used varying methods to create pluripotent stem cells from skin cells.
They found protein-coding point mutations – six mutations per exome – in every cell line they examined. The genetic instructions for making proteins and other gene products lie within the exome.
Zhang said:
“Every single stem cell line we looked at had mutations. Based on our best knowledge, we expected to see 10 times fewer mutations than we actually observed.”
The authors said their study showed that reprogramming adult human (mammalian) cells into hiPSCs does affect the overall genome at the fundamental level of single nucleotides. They are “permanent genome scars.”
Some of the mutations seemed to be silent, but most of them altered specific protein functions, including cancer causing ones.
Lawrence S.B. Goldstein, PhD, said:
“Reprogrammed stem cells provide an important new tool in the fight against human disease, but to use these cells directly in the clinic, we must ensure that they are safe and that we are able to define their structure and behavior in the most precise terms.
Our studies open a new window into the genetic behavior of these important types of stem cells and begin to define some new and straightforward safety standards that may help accelerate their use in clinical settings.
We covered cell lines derived from seven different labs because we wanted to make sure our conclusions are general enough to make realistic extrapolations.”
The San Diego team found that approximately half of all mutations discovered in stem cell lines lay in starting cells at very low levels. They were present in a few cells sometime during the individual’s life, or during cell culture in the lab – they were not inherited.
The reprogramming-associated mutations came from:
- Mutations that were already in the skin cells before reprogramming occurred
- Mutations that occurred during reprogramming
- Mutations that occurred after reprogramming, when the pluripotent cells started to proliferate
Athurva Gore, Zhe Li, Ho-Lim Fung, Jessica E. Young, Suneet Agarwal, Jessica Antosiewicz-Bourget, Isabel Canto, Alessandra Giorgetti, Mason A. Israel, Evangelos Kiskinis, Je-Hyuk Lee, Yuin-Han Loh, Philip D. Manos, Nuria Montserrat, Athanasia D. Panopoulos, Sergio Ruiz, Melissa L. Wilbert, Junying Yu, Ewen F. Kirkness, Juan Carlos Izpisua Belmonte, Derrick J. Rossi, James A. Thomson, Kevin Eggan, George Q. Daley, Lawrence S. B. Goldstein & Kun Zhang et al.
Nature Volume: 471, Pages: 63-67 March 2011 doi:10.1038/nature09805
Written by Christian Nordqvist