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Breakthrough in the production of dopamine neurons for Parkinson’s disease.

Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon.  One major task en route to the clinic is to generate standardized good manufacturing practice (GMP)-grade human-pluripotent stem cell derived neural-progenitors which will mature and function in the adult brain after transplantation.  However, it remains a challenge for researchers to control stem cells accurately in the lab in order to achieve successful and functional stem cell therapies for patients.

Now, a set of studies from Lund University shows, firstly, that assessments of stem cell-derived dopamine neurons in animal models varied dramatically, even though the cells were similar at the time of transplantation.  Whilst the second study sheds new light on how dopamine neurons are formed during development, and what makes them different from other similar and neighbouring neurons.  The team state that their new insights enable the manufacturing of pure populations of dopamine neurons of high quality.  The studies, one of which is opensource, are published in the journal Cell Stem Cell.

Previous studies show that most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, making prediction of the long-term graft outcome a challenge.  This has been further marred by the fact human-pluripotent stem cell derived neural-progenitors’ differentiation protocols have relied on markers which are shared between the two lineages.  The new studies found, firstly, that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned human-pluripotent stem cell derived neural- progenitors.  They also take an unbiased approach to identify predictive markers expressed in dopamine neuron-progenitors which correlate with graft outcome in an animal model of Parkinson’s disease through gene expression.

The first study uses transcriptome-wide single-cell RNA sequencing of mouse neural progenitors to resolve the differentiation of human-pluripotent stem cell derived neural-progenitors and the neighbouring neuronal lineages.  Results show a remarkably close relationship between developing human-pluripotent stem cell derived neural-progenitors, and subthalamic nucleus neurons, whilst also highlighting a distinct transcription factor set which can distinguish between them.

The second study identifies a specific set of markers associated with the caudal midbrain which correlate with high dopaminergic yield after transplantation in-vivo.  The lab investigated predictive markers expressed in dopamine neuron-progenitors which correlate with graft outcome in an animal model of Parkinson’s disease through gene-expression analysis. Results show that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation.  The team state that, using the new markers they identified, they have developed a GMP-differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from human pluripotent stem cells.

The team surmise that they have successfully identified a specific set of markers which correlates with high dopaminergic yield and graft function after transplantation in animal models of Parkinson’s disease.  For the future, the researchers state that guided by this information, they have developed a better and more accurate method for producing dopamine cells for clinical use in a reproducible way.

Source: Lund University

Induced stem cells, adult skin cells that have been genetically reprogrammed to mimic embryonic stem cells, have been made potentially safer by removing the introduced genes and the viral vector used to ferry the genes into the cells. These cells were reprogrammed to an embryonic like state with the aid of a plasmid, a loop of DNA, which prompts the reprogramming but is not integrated into the genome of the cells. The work was accomplished by geneticist Junying Yu in the laboratory of James Thomson, a UW-Madison School of Medicine and Public Health professor and the director of regenerative biology for the Morgridge Institute for Research. ©UW-Madison University Communications 608/262-0067 Photo by: unknown Date:  unknown    File#:   digital frame

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