Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA.
Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes.
Nat Med. 2006 Nov;12(11):1259-68.
PubMed.
Curt Freed University of Colorado School of Medicine
Posted:
Steve Goldman’s lab has reported that they can differentiate dopamine neurons from human embryonic stem cells and use those cells to modify a chemically induced form of Parkinson disease in rats. They’ve shown that if the embryonic stem cells are grown together with astrocytes, some of the cells become dopamine neurons. This finding is similar to what my laboratory published in 2004 when we found that brain astrocytes could make stem cells become dopamine neurons. Dr. Goldman’s lab has now found that these cells can survive in rat brain and change animal behavior. They point out that the cells are also forming large masses of non-dopamine cells. Of course, these unwanted cells will have to be eliminated before any human therapy can be done.
Human ES cells are evolving as a source of cells to treat humans. First, the cells had to be converted in tissue culture to dopaminergic neurons. Over the past few years, that has been accomplished in several laboratories. Next, the cells have to be shown to survive transplantation and modify animal behavior. Dr. Goldman’s lab, Ole Isacson’s lab, and our lab have all reported success in this phase. The next step will be to refine the whole process to maximize the number of dopamine neurons produced and to eliminate cells that could cause harm. This evolution will continue for a few more years as we move beyond success of the principle to actually being able to treat patients.
For Parkinson disease, we have treated patients successfully using fetal dopamine neurons recovered from early-stage abortions. Those cells have survived for more than a decade without immunosuppression. Very few patients have received such transplants, however, because it is very difficult to recover tissue after abortion. About 200 to 300 patients in the world have gotten transplants. Human embryonic stem cells offer the potential to create an unlimited supply of dopamine neurons to treat everyone who could benefit. I am optimistic that the technical issues can be solved in the next few years to make stem cell therapy a reality.
Although caution is always warranted in any therapy, particularly cellular therapies, this is not, by any means, a setback for the embryonic stem cell field. We have always known that we need to “lock” the cells into their commitment state. This problem flagged by Steve Goldman and colleagues simply indicates that the recipe he used, while moving them from the pluripotent state to the neuroectodermal state, did not advance their lineage sufficiently. It is simply a matter of tweaking the recipe as well as identifying the more committed cells and separating them from the more undifferentiated cells. I am confident that this is possible because, in preliminary studies, we have already achieved it and have very safe and effective long-term engraftment in a mouse model of a neurodegenerative disease. Also, other investigators have had success (their work may be published soon) in using modifications of the protocol Steve used to get successful and safe results.
One other consideration is that the human embryonic stem cells (hESCs) Steve had to use were the “presidential” hESCs which are known to be old and somewhat unstable. It is possible that better hESC lines, which reflect twenty-first-century insights—rather than 1990s insights—would not have this problem.
Comments
University of Colorado School of Medicine
Steve Goldman’s lab has reported that they can differentiate dopamine neurons from human embryonic stem cells and use those cells to modify a chemically induced form of Parkinson disease in rats. They’ve shown that if the embryonic stem cells are grown together with astrocytes, some of the cells become dopamine neurons. This finding is similar to what my laboratory published in 2004 when we found that brain astrocytes could make stem cells become dopamine neurons. Dr. Goldman’s lab has now found that these cells can survive in rat brain and change animal behavior. They point out that the cells are also forming large masses of non-dopamine cells. Of course, these unwanted cells will have to be eliminated before any human therapy can be done.
Human ES cells are evolving as a source of cells to treat humans. First, the cells had to be converted in tissue culture to dopaminergic neurons. Over the past few years, that has been accomplished in several laboratories. Next, the cells have to be shown to survive transplantation and modify animal behavior. Dr. Goldman’s lab, Ole Isacson’s lab, and our lab have all reported success in this phase. The next step will be to refine the whole process to maximize the number of dopamine neurons produced and to eliminate cells that could cause harm. This evolution will continue for a few more years as we move beyond success of the principle to actually being able to treat patients.
For Parkinson disease, we have treated patients successfully using fetal dopamine neurons recovered from early-stage abortions. Those cells have survived for more than a decade without immunosuppression. Very few patients have received such transplants, however, because it is very difficult to recover tissue after abortion. About 200 to 300 patients in the world have gotten transplants. Human embryonic stem cells offer the potential to create an unlimited supply of dopamine neurons to treat everyone who could benefit. I am optimistic that the technical issues can be solved in the next few years to make stem cell therapy a reality.
The Burnham Institute
Although caution is always warranted in any therapy, particularly cellular therapies, this is not, by any means, a setback for the embryonic stem cell field. We have always known that we need to “lock” the cells into their commitment state. This problem flagged by Steve Goldman and colleagues simply indicates that the recipe he used, while moving them from the pluripotent state to the neuroectodermal state, did not advance their lineage sufficiently. It is simply a matter of tweaking the recipe as well as identifying the more committed cells and separating them from the more undifferentiated cells. I am confident that this is possible because, in preliminary studies, we have already achieved it and have very safe and effective long-term engraftment in a mouse model of a neurodegenerative disease. Also, other investigators have had success (their work may be published soon) in using modifications of the protocol Steve used to get successful and safe results.
One other consideration is that the human embryonic stem cells (hESCs) Steve had to use were the “presidential” hESCs which are known to be old and somewhat unstable. It is possible that better hESC lines, which reflect twenty-first-century insights—rather than 1990s insights—would not have this problem.
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