Brain Cell Transplant Shows Promise, Raises Questions in Mouse Study

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by Steve Bryson, PhD |

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Transplanting human nerve cells into the brains of mice in a model of Parkinson’s disease to replace dopamine-producing cells — those lost in patients — improved the animals’ motor function over one year, a study demonstrated.

But longer studies into the grafted cells and their ability to mature are needed, its researchers said, as findings that include cell maturity at 12 months post-transplant have important implications for the design of clinical trials.

The study,” Long-Term Evaluation of Intranigral Transplantation of Human iPSC-Derived Dopamine Neurons in a Parkinson’s Disease Mouse Model,” was published in the journal Cells.

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Parkinson’s disease is associated with the progressive loss of dopaminergic neurons, nerve cells in the brain that communicate with other neurons by releasing the signaling molecule dopamine. Most treatment options focus on increasing dopamine levels.

However, none of these approaches halt or reverse the ongoing loss of dopaminergic neurons.

An alternative strategy is to transplant these neurons to replace the lost cells. One source of therapeutic neurons is induced pluripotent stem cells (hiPSCs) — a type of stem cell that can be reprogrammed to give rise to almost any cell in the human body, including dopaminergic neurons.

Researchers at the Université de Poitiers in France tested this approach in a mouse model of Parkinson’s.

Parkinson’s was chemically induced by injecting the dopaminergic neuron-destroying 6-OHDA into the substantia nigra pars compacta (SNpc), the midbrain area where dopamine-producing neurons are typically found.

hiPSCs were obtained by reprogramming healthy human fibroblasts, the most common cell type in connective tissue. These stem cells were then transformed into dopaminergic neuron precursor cells that, after being transplanted, are expected to mature into fully functioning neurons. Three weeks after the animals were exposed to 6-OHDA, the cells were injected into that midbrain area.

Researchers investigated the grafted cells’ survival and maturation at different times. The number of cells rose over one year, they reported, but not to a statistically significant degree. Further, more than a sixth of the transplanted cells were still immature at 12 months, and only half were fully mature neurons.

“Our results suggest that much longer survival times are needed to evaluate the development and maturation of neurons derived from human stem cells for safe application in cell therapy,” the team wrote.

The population of dopaminergic neurons was measured by the presence of tyrosine hydroxylase, the enzyme that generates dopamine. A gradual increase in the proportion of dopaminergic neurons was seen from one to eight months, which stabilized by one year.

An examination of the subtype of dopaminergic neurons typically found in the SNpc (midbrain area) showed that, between six months and one year, the number of tyrosine hydroxylase-containing cells increased, but the proportion of SNpc-subtype cells decreased. Experiments confirmed that the loss of these cell subtypes might be explained by a greater rate of apoptosis, or programmed cell death.

At three, six, and 10 months after the cell transplant, researchers also assessed the animals for motor function using the amphetamine rotation test — a common way to monitor the extent of motor impairment induced by 6-OHDA and to measure transplant-induced recovery. A higher number of rotations reflects more extensive brain damage (lesions).

The percentage of tyrosine hydroxylase-positive cells in the SNpc correlated with the number of rotations. At three months, there was no difference in turns between treated and untreated animals. But by six months, the grafted mice showed a significant reduction in the number of rotations than did ungrafted mice (0.09 vs. 3.03 turn/minute). These results were maintained at 10 months post-transplant.

As expected, after 6-OHDA-induced damage a positive correlation existed between the rotation score and the percentage of damage in the mice pre-transplant. Notably, 10 months after the cell transplant, this correlation was lost, “suggesting that the [dopaminergic] neurons of the transplant replaced the neurons lost by the lesion,” the researchers noted.

Researchers, in other words, found “long-term motor functional recovery after transplantation, which was correlated to the number of [dopaminergic] neurons within the graft.”

“Surprisingly,” however, “we found within the graft a decrease in the percentage of SNpc DA [midbrain dopaminergic] subtype [cells] from 6 to 12 mpt [months post-transplant] and the presence of immature neurons even 12 months after grafting,” the scientists added. “These observations have important implications for the design of human clinical trials. Accordingly, relying on short survival times could lead to misinterpretation of the results.”

Again, they advised that “much longer survival times are needed to evaluate the development and maturation of neurons derived from human stem cells for safe application of cell therapy not only for [Parkinson’s disease] but for other brain diseases.”