Embryonic stem cell transplantation represents an attractive method for restoring vision to patients with degenerative retinal diseases. Researchers in this field face many challenges in obtaining perfect stem cells and inducing the transplanted cells to differentiate into synaptically connected photoreceptors. Lessons from the embryo may yield answers to some of those issues.
Baltimore-Lessons from the embryo may help guide researchers in their efforts to develop stem cell transplantation as a method for restoring vision to patients with degenerative retinal diseases, said Ruben Adler, MD, at the Current Concepts in Ophthalmology meeting held here.
Dr. Adler told attendees the hope is that embryonic stem cells transplanted into the eye would become photoreceptors synaptically connected to the rest of the retina. However, studies performed to date in animal models of retinal disease have failed to achieve anatomic or functional restoration of vision.
"Because of the embryo we know it should be possible to induce transplanted stem cells to make mature, synaptically connected photoreceptors, and the embryo may help teach us how to achieve that goal," said Dr. Adler, who is the Arnall Patz Distinguished Professor of Ophthalmology, professor of neuroscience, and director, Retinal Degenerations Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
Quest for the perfect cell
Although there was much initial enthusiasm for using adult stem cells as an alternative to embryonic stem cells, Dr. Adler said studies suggesting the promise of that approach have fallen into disrepute. Therefore, it remains an open question whether adult stem cells function the same as embryonic stem cells.
Meanwhile, the embryonic stem cell lines now available for research are imperfect. They have oncogenic and immunogenic potential and may introduce the possibility of murine retroviral infection. Furthermore, they may have "aging" consequences as a result of prolonged culture.
"There are no perfect stem cell lines available, and a lot of work needs to be done to overcome that problem," Dr. Adler continued.
He credited Viktor Hamburger, PhD, famed biologist and molecular geneticist, with the concept of turning to the embryo for clues to success in developing stem cell transplantation for therapeutic purposes.
"Dr. Hamburger said, 'Our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right,' " Dr. Adler quoted.
In attempting to drive stem cell differentiation into photoreceptors, researchers need to recognize that the embryo operates in sequence, he said. In other words, the differentiation process from embryonic stem cell to mature photoreceptor needs to occur through a progressive series of transformations, one step at a time, without "cutting corners."
It is also important to consider that the embryo recycles and uses the same molecules repeatedly for different purposes and in different places.
"So, it is not only what you do, but also when you do it," Dr. Adler commented.
He added that researchers need to learn how to fight repression because activation is usually the repression of a repressor. Researchers also need to appreciate that the embryo uses combinations of signaling molecules and transcription factors.
"The embryo teaches us the secret of life is how to make a good cocktail, and so it seems obvious that a complex system cannot be replaced with a single magic bullet," Dr. Adler said.
Inducing transplanted stem cells to form synapses with host retina requires attention to the fact that "it takes two to tango."
"Synapses are made of a presynaptic and a postsynaptic component and a series of molecules that brings the two together, of which more than one hundred have been identified," Dr. Adler said.
"Not only do we need to manipulate the stem cell, but also the host, to make sure that it has the necessary molecules and is devoid of repulsive molecules, which seem to appear especially as a result of photoreceptor degeneration," Dr. Adler said.