Mouse cells and tissues created through nuclear transfer can be
rejected by the body because of a previously unknown immune response to
the cell's mitochondria, according to a study in mice by researchers at
the Stanford University School of Medicine and colleagues in Germany,
England and at MIT. The findings reveal a likely, but surmountable,
hurdle if such therapies are ever used in humans, the researchers said.
Stem cell therapies hold vast potential for repairing organs and
treating disease. The greatest hope rests on the potential of
pluripotent stem cells, which can become nearly any kind of cell in the
body. One method of creating pluripotent stem cells is called somatic
cell nuclear transfer, and involves taking the nucleus of an adult cell
and injecting it into an egg cell from which the nucleus has been
removed.
The promise of the SCNT method is that the nucleus of a patient's
skin cell, for example, could be used to create pluripotent cells that
might be able to repair a part of that patient's body. "One attraction
of SCNT has always been that the genetic identity of the new pluripotent
cell would be the same as the patient's, since the transplanted nucleus
carries the patient's DNA," said cardiothoracic surgeon Sonja
Schrepfer, MD, PhD, a co-senior author of the study, which will be
published online Nov. 20 in Cell Stem Cell.
"The hope has been that this would eliminate the problem of the
patient's immune system attacking the pluripotent cells as foreign
tissue, which is a problem with most organs and tissues when they are
transplanted from one patient to another," added Schrepfer, who is a
visiting scholar at Stanford's Cardiovascular Institute. She is also a
Heisenberg Professor of the German Research Foundation at the University
Heart Center in Hamburg, and at the German Center for Cardiovascular
Research.
Possibility of rejection
A dozen years ago, when Irving Weissman, MD, professor of pathology
and of developmental biology at Stanford, headed a National Academy of
Sciences panel on stem cells, he raised the possibility that the immune
system of a patient who received SCNT-derived cells might still react
against the cells' mitochondria, which act as the energy factories for
the cell and have their own DNA. This reaction could occur because cells
created through SCNT contain mitochondria from the egg donor and not
from the patient, and therefore could still look like foreign tissue to
the recipient's immune system, said Weissman, the other co-senior author
of the paper. Weissman is the Virginia and D.K. Ludwig Professor for
Clinical Investigation in Cancer Research and the director of the
Stanford Institute for Stem Cell Biology and Regenerative Medicine.
That hypothesis was never tested until Schrepfer and her colleagues
took up the challenge. "There was a thought that because the
mitochondria were on the inside of the cell, they would not be exposed
to the host's immune system," Schrepfer said. "We found out that this
was not the case."
Schrepfer, who heads the Transplant and Stem Cell Immunobiology
Laboratory in Hamburg, used cells that were created by transferring the
nuclei of adult mouse cells into enucleated eggs cells from genetically
different mice. When transplanted back into the nucleus donor strain,
the cells were rejected although there were only two single nucleotide
substitutions in the mitochondrial DNA of these SCNT-derived cells
compared to that of the nucleus donor. "We were surprised to find that
just two small differences in the mitochondrial DNA was enough to cause
an immune reaction," she said.
"We didn't do the experiment in humans, but we assume the same sort of reaction could occur," Schrepfer added.
Until recently, researchers were able to perform SCNT in many
species, but not in humans. When scientists at the Oregon Health and
Science University announced success in performing SCNT with human cells
last year, it reignited interest in eventually using the technique for
human therapies. Although many stem cell researchers are focused on a
different method of creating pluripotent stem cells, called induced
pluripotent stem cells, there may be some applications for which
SCNT-derived pluripotent cells are better suited.
Handling the reaction
The immunological reactions reported in the new paper will be a
consideration if clinicians ever use SCNT-derived stem cells in human
therapy, but such reactions should not prevent their use, Weissman said.
"This research informs us of the margin of safety that would be
required if, in the distant future, we need to use SCNT to create
pluripotent cells to treat someone," he said. "In that case, clinicians
would likely be able to handle the immunological reaction using the
immunosuppression methods that are currently available."
In the future, scientists might also lessen the immune reaction by
using eggs from someone who is genetically similar to the recipient,
such as a mother or sister, Schrepfer added.
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