U.S. Department of Health and Human Services

Induced Pluripotent Stem Cells Hold on to Past Identity

Researchers have found genomic marks in human induced pluripotent stem (iPS) cells that currently limit their scientific and therapeutic potential, but also suggest opportunities to improve the development of these cells. 

Researchers initially developed iPS cells with the hope of overcoming challenges posed by other types of stem cells. Human embryonic stem (ES) cells, for example, hold promise in the treatment of disease because they are “pluripotent,” meaning that unlike most other cells, they have the ability to form virtually any cell type and thus could generate cells for repair of human tissues and organs. The use of human ES cells, however, is controversial because their isolation entails the destruction of early-stage human embryos; ES cells have other limitations as well. In recent years, scientists developed strategies to reprogram cells, such as blood or skin cells, to revert from their specific cell types back to an ES cell-like state, with the potential to form not only new cells of their original type, but also stem cells and a multitude of different cell types. These pluripotent, reprogrammed cells, called iPS cells, could potentially be used to study diseases and to generate cells to treat specific diseases, potentially with a tissue match for the recipient (avoiding transplant rejection).

For reasons that have been poorly understood, iPS cells generated to date are significantly less pluripotent than ES cells; they are more easily able to form the cell type from which they were originally derived than to form cells of other types. To understand why this might be the case in human iPS cells, researchers analyzed the cells’ DNA, building on previous findings in mouse cells. Mouse iPS cells retain a pattern of chemical modifications on their DNA characteristic of their past cell type, rather than a pattern characteristic of ES cells. Although this modification does not alter the sequence of the genetic code, it can affect the cell’s ability to turn genes on or off. The combination of genes that are active and inactive characterizes a cell type; therefore this important modification has the effect of helping a cell to “remember” its identity. In this new research, scientists sought to determine whether human iPS cells retained the chemical modifications of their past cell type, like the mouse iPS cells did. They produced iPS cells from both blood and skin cells. The researchers found, as expected, that blood-derived iPS cells were more likely to form blood cells and skin-derived iPS cells were more likely to become skin cells. By comparing the patterns of chemical modifications of iPS cells to ES cells, the researchers determined that the iPS cells retained patterns characteristic of their original cell types. Current techniques to generate iPS cells, therefore, do not fully erase the cell’s memory, limiting its potential to become another cell type. 

Scientists will continue research to develop new techniques that may be able to erase the residual patterns more fully. In the meantime, scientists may be able to take advantage of the bias of iPS cells toward their original cell type in the study of and development of therapies for diseases associated with those cell types. Cautious optimism continues for the eventual, wider use of iPS cells.

Kim K, Zhao R, Doi A, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotech 29: 1117-1119, 2011.