As the brain's population of dopamine cells dwindle, they are not replaced. One great hope is that stem cell engineering may offer a way to transplant a pool of progenitor cells into the brains of patients so they make new supplies of dopamine cells.
In fact, one of the teams behind the new studies thought they had got very close to such a solution. In a breakthrough study published in 2014, they
showed how it is possible to make dopamine cells from embryonic stem cells and transplant them into the brains of rats with Parkinson's disease, to replace the lost cells.
Malin Parmar, professor in the faculty of medicine at Lund, led the earlier study and is also one of the leaders of the new research. She explains the unexpected delay that followed their high hopes from the first breakthrough:
"In our preclinical assessments of stem cell-derived dopamine neurons we noticed that the outcome in animal models varied dramatically, even though the cells were very similar at the time of transplantation. This has been frustrating and puzzling, and has significantly delayed the establishment of clinical cell production protocols."
In one of the papers, the
researchers discuss how a particular complication in the use of stem cells to treat brain diseases like Parkinson's is that you cannot just produce a population of working dopamine cells in a dish and transplant them into the brain.
While some stem cell treatments - such as those undergoing trial for the treatment of
macular degeneration - can use cells fully matured in the lab, in the case of brain diseases like Parkinson's, you have to implant immature cells that only differentiate and mature after they are transplanted into the brain.
Animal models of Parkinson's and other brain diseases show it can take months for the cells to mature and start working properly after transplant.
Ensuring quality of stem cells before transplant
The challenge is how to ensure that the cells are of the right quality before transplant, since it is going to be very difficult to keep an eye on their development once they are inside the brain.
In the first study, the researchers used modern global gene expression techniques and undertook experiments in over 30 batches of grafted human embryonic stem cell (hESC)-derived progenitors to look at predictive markers of high quality dopamine cell yield.
They found that many of the commonly used markers did not accurately predict the yield of the desired mature dopamine cells following transplants into live animal brains. Instead, they identified a specific set of markers that offer much higher predictive power.
"Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs," the authors note.
In the second study, the researchers undertook - using transcriptome-wide single-cell RNA sequencing techniques - a
detailed investigation of how dopamine cells develop in the brains of mice.
Among other things, they found a marker that can distinguish between developing dopamine cells and other similar neighboring cells. They suggest this should help refine current stem cell engineering methods to increase the proportion of desired dopamine precursor cells. The finding, they conclude, should "have important implications for cell replacement therapy" in Parkinson's disease.
"We have identified a specific set of markers that correlate with high dopaminergic yield and graft function after transplantation in animal models of Parkinson's disease. Guided by this information, we have developed better and more accurate methods for producing dopamine cells for clinical use in a reproducible way."
First author Dr. Agnete Kirkeby, Lund University
http://www.medicalnewstoday.com/articles/313805.php
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