UCLA. US: Research could have broad, long-term impact in improving disease modeling and devising new therapies for patients. In a study that provides scientists with a critical new understanding
of stem cell development and its role in disease, UCLA researchers led
by Kathrin Plath, have established a first-of-its-kind methodology that
defines the stages by which specialized cells are reprogrammed into stem
cells resembling those found in embryos.
The study, conducted by researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was published this month in the journal Cell.
Induced pluripotent stem cells, known as iPSCs, are cells that can be
generated from adult cells and then, like embryonic stem cells, be
directed to become any cell in the human body. Adult cells can also be
reprogrammed in the lab to change from a specialized cell back to an
iPSC (and thus becoming a cell similar to that of an embryonic stem
cell).
Reprogramming takes one to two weeks and is a largely inefficient
process, with typically less than one percent of the starting cells
successfully becoming an iPSC. The exact stages a cell goes through
during the reprogramming process are not well understood. This knowledge
is important, as iPSCs hold great promise in the field of regenerative
medicine, as they can reproduce indefinitely and provide a single source
of patient-specific cells to replace those lost to injury or disease.
They can also be used to create novel disease models from which new
drugs and therapies can be developed.
Vincent Pasque and Jason Tchieu, postdoctoral fellows in Plath’s lab
and co-first authors of the study, developed a roadmap of the
reprogramming process using detailed time-course analyses. They induced
the reprogramming of specialized cells (that could only make more of
themselves, and not other cell types), then observed and analyzed on a
daily basis or every other day the process of transformation at the
single-cell level. The data was collected and recorded during a period
of up to two weeks.
Plath’s
team found that the changes that happen in cells during reprogramming
occur in sequentially, and that importantly, the stages of the sequence
were the same across the different reprogramming systems and different
cell types analyzed.
“The exact stage of reprogramming of any cell can now be determined,”
Pasque said. “This study signals a big change in thinking, because it
provides simple and efficient tools for scientists to study stem cell
creation in a stage-by-stage manner. Most studies to date ignore the
stages of reprogramming, but we can now seek to better understand the
entire process on both a macro and micro level.”
Plath’s team further discovered that the stages of reprogramming to
iPSC are different from what was expected. They found that it is not
simply the reversed sequence of stages of embryo development. Some steps
are reversed in the expected order; others do not actually happen in
the exact reverse order and resist a change until late during
reprogramming to iPSCs.
“This reflects how cells do not like to change from one specialized
cell type to another and resist a change in cell identity,” Pasque said.
“Resistance to reprogramming also helps to explain why reprogramming
takes place only in a very small proportion of the starting cells.”
With these findings, Plath’s lab plans future studies to actively
isolate specific cell types during specific stages of reprogramming.
They also hope the research will encourage further investigation into
the characteristics of iPSC development.
“This research has broad impact, because by understanding cell
reprogramming better we have the potential to improve disease modeling
and the generation of better sources of patient-specific specialized
cells suitable for replacement therapy,” said Plath, who is a professor
of biological chemistry. “This can ultimately benefit patients with new
and better treatments for a wide range of diseases.”
The research was supported by grants from the California Institute
for Regenerative Medicine, the state’s stem cell agency. Additional
funding was provided by the UCLA Broad Stem Cell Research Center through
philanthropy and other sources.