Growing better human neural stem cells: the role of HIF1a

“HIF1a is an interesting target for drug development, not only from the stand point of improving dopamine neuron differentiation for cell transplantation (as this study demonstrates), but also potentially for neuroprotective treatments for Parkinson’s. It will be interesting to see if compound A in this study is able to cross the blood brain barrier and enter the brain. If so, it would be very advantageous to test the compound in models of Parkinson’s (which perhaps the researchers are already doing).”

Transplanting neurons directly into the brain as a therapeutic strategy for Parkinson’s has generated much enthusiasm but trials have so far been inconclusive. One of the obstacles is developing a standardized method and improving on existing procedures by which these neurons are grown in the lab before transplantation. It is essential that the quality and number of these neurons are as high as can possibly be achieved.

To this end, the Danish team focused on HIF1a (or Hypoxia Inducible Factor 1a): this is a substance inside all cells which under conditions of low oxygen, becomes activated and causes a number of downstream changes, all of which are designed to help the cell survive and grow. Under normal oxygen conditions, HIF1a is broken down as its function is no longer necessary. Another interesting observation is that although neuronal stem cells destined for transplantation are grown in the lab in normal room air which contains approx. 20% oxygen, neurons in the brain are exposed to only less than half of this. This opens up the following possibility: might stabilizing HIF1a, not through low oxygen conditions (which would be impractical for a surgical context) but through a drug, help promote the survival and growth of dopamine cells for transplantation?

The researchers used human neuronal stem cells which they grew under different conditions in dishes in the lab. They grew these cells in conditions of both high and low oxygen, and also treated them with one of three drugs, which stabilize HIF1a and prevent it from being degraded in slightly different ways. They also had a control group which was grown without any of these additions, and compared how well all the cells survived, and grew into more mature dopamine cells at the end of 10 days.

Neurons grow better in conditions of low oxygen. The team also found that stabilizing HIF1a with these drugs did not actually increase the final number of cells compared to controls. However, given that stem cells have the ability to grow into different kinds of cells, the important question was whether targeting HIF1a increased their ability to grown specifically into dopaminergic neurons. Indeed, this was the case. Although all three of these drugs used to stabilize HIF1a had this effect, one of these, FG41, appeared to be slightly more potent.

Further work, including replication by other labs around the world, will ultimately help determine whether targeting HIF1a in this way could be incorporated into a future standardized protocol.

https://www.cureparkinsons.org.uk/regenerative-medicine-transeuro