Skin cells converted directly into beating heart cells
16 Feb 2011
The Scripps Research Institute has developed a technique to
convert adult skin cells directly into beating heart cells efficiently
without having to first go through the laborious, time consuming and
highly inefficient process of generating embryonic-like stem cells.
The powerful general technology platform could lead to new
treatments for a range of diseases and injuries involving cell loss
or damage, such as heart disease, Parkinson’s, and Alzheimer’s
The work has been published in Nature Cell Biology .
"This work represents a new paradigm in stem cell reprogramming,"
said Scripps Research Associate Professor Sheng Ding PhD who led the
study. "We hope it helps overcome major safety and other technical
hurdles currently associated with some types of stem cell
Mature heart muscle cells created directly from
Making stem cells
As the human body develops, embryonic-like stem cells multiply and
transform themselves into more mature cell types through a process
known as differentiation, producing all of the body’s different cell
types and tissues. Past the embryonic stage, however, the human body
has limited capacity to generate new cells to replace ones that have
been lost or damaged.
Thus, scientists have been trying to develop ways to “reprogram”
adult human cells back to a more embryonic-like, or pluripotent,
state, from which they are able to divide and then change into any
of the body’s cell types. Using these techniques, scientists aim to
someday be able to take a patient’s own cells, say skin cells,
change them into heart or brain cells, and then insert them back
into the patient to fix damaged tissues. In 2006, Japanese
scientists reported that they could reprogram mouse skin cells to
become pluripotent simply by inserting a set of four genes into the
Although the technology to generate these cells, dubbed induced
pluripotent stem (iPS) cells, represents a major advance, there are
some hurdles to overcome before it can be adapted to therapies.
“It takes a long time to generate iPS cells and then differentiate
them into tissue-specific functional cell types," said Ding, "and
it’s a tedious process. Also, what you generate is not ideal.”
Specifically, it takes some two to four weeks for scientists to
create iPS cells from skin cells and the process is far from
efficient, with only one cell out of thousands making the complete
transformation. Furthermore, once scientists obtain iPS cells, they
then have to go through the tricky procedure of inducing the iPS
cells to differentiate into desired types of cells, which takes an
additional two to four weeks.
In addition, the process of generating mature cells from iPS cells
is not foolproof. When, for example, scientists induce iPS cells to
become heart cells, the resulting cells are a mix of heart cells and
some lingering iPS cells. Scientists are concerned that giving these
new heart cells (along with the remaining pluripotent cells) to
patients might be dangerous. When pluripotent cells are injected in
mice, they cause cancer-like growths.
Because of these concerns, Ding and colleagues decided to try to
tweak the process by completely bypassing the iPS stage and going
directly from one type of mature cell (a skin cell) to another (a
Bypassing the stem cell stage
The team introduced the same four genes initially used to make iPS
cells into adult skin fibroblast cells, but instead of letting the
genes be continuously active in cells for several weeks, they
switched off their activities just after a few days, long before the
cells had turned into iPS cells. Once the four genes were switched
off, the scientists gave a signal to the cells to make them turn
into heart cells.
“In 11 days, we went from skin cells to beating heart cells in a
dish,” said Ding. “It was phenomenal to see.”
Ding points out the protocol is fundamentally different from what
has been done by other scientists in the past and notes that giving
the cells a different kind of signal could turn them into brain
cells or pancreatic cells.
“It is like launching a rocket," he said. "Until now, people thought
you needed to first land the rocket on the moon and then from there
you could go to other planets. But here we show that just after the
launch you can redirect the rocket to another planet without having
to first go to the moon. This is a totally new paradigm.”
In addition to better understanding the basic biology of stem cells,
the next step will be to modify this technique further to remove the
need for inserting the four genes, which have been linked to the
development of cancer.
As a result, many scientists, including Ding, have been working on
new techniques to develop iPS cells without use of these genes. That
has proven difficult. But with the new protocol, which bypasses the
iPS cell stage, the genes are needed for a much shorter time.
“Action for such a short period of time is a lot easier to replace,”
1. Jem A. Efe, Simon Hilcove, Janghwan Kim, Hongyan Zhou,
Kunfu Ouyang, Gang Wang, Ju Chen, and Sheng Ding. Conversion of
mouse fibroblasts into cardiomyocytes using a direct reprogramming
Date: Published online January 30, 2011.