Human oligodendrocyte progenitor cells (hOPCs)
persist into adulthood as an abundant precursor population capable of division and differentiation. The
transcriptional mechanisms that regulate hOPC homeostasis remain poorly defined. Herein, we identify
paired related homeobox protein 1 (PRRX1) in primary
PDGFaR+ hOPCs. We show that enforced PRRX1
expression results in reversible G1/0 arrest. While
both PRRX1 splice variants reduce hOPC proliferation, only PRRX1a abrogates migration. hOPC
engraftment into hypomyelinated shiverer/rag2
mouse brain is severely impaired by PRRX1a, characterized by reduced cell proliferation and migration.
PRRX1 induces a gene expression signature characteristic of stem cell quiescence. Both IFN-g and BMP
signaling upregulate PRRX1 and induce quiescence.
PRRX1 knockdown modulates IFN-g-induced quiescence. In mouse brain, PRRX1 mRNA was detected
in non-dividing OPCs and is upregulated in OPCs
following demyelination. Together, these data identify
PRRX1 as a regulator of quiescence in hOPCs and
as a potential regulator of pathological quiescence
Wang et al. investigate the role of transcription factor PRRX1 in human oligodendrocyte progenitor cells. PRRX1 induces reversible cell-cycle arrest (Stops oligos from dividing) , resulting in a quiescent-like state that prevents colonization and myelination of hypomyelinated (lack of myelin) shiverer mice. PRRX1 expression was regulated by interferon-gamma (a pro-inflammatory cytokine) and BMP and required for interferon induced quiescence.
PRRX1 is a DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription coactivator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. Alternative splicing yields two isoforms that differ in abundance and expression patterns
“Activation of a specific transcription factor that reads DNA induces in adult stem cells a phenomenon called pathological quiescence. This is when adult stem cells are rendered incapable of responding to injury by producing myelin-forming oligodendrocytes. The failure to remyelinate is the key feature of MS”.
“The paper defines the role of the previously undescribed transcription factor known as PRRX1 in human oligodendrocyte progenitor cells, the cells that generate myelin-forming oligodendrocytes”.
Like…Shimozaki K, Clemson GD Gage FH. Paired related homeobox protein 1 is a regulator of stemness in adult neural stem/progenitor cells. J Neuro-sci 2013;33:4066..unknown
Who reviews these papers?… Their Mates I suspect:-(
(Actually I doubt it as they were made to do a years work to address some issue)
However, the problem is what is the consequence of targeting this pathway as it is used by many cell types to do such things as control the generation of fat etc.
What to read more on Quiescence?
Current MS research focuses largely on drugs that induce the differentiation of human oligodendrocyte progenitors. In contrast, this research presents a concept for the development of new drugs based on blocking the pathological quiescence of progenitors
Yesterday ProfG told us how our life’s work was flushed done the toilet by a failed trial, a trial that we were never consulted on, before or after it was funded.
All and I mean all the experimental data showed that this should work and you had as many mechanisms of action that you want. Interogate the the data and the trial did work (partially).
Should we have done the trial at the time or waitied until we had more clues?
We are lucky that we have a clinical team that can translate our ideas. However, we were too slow to get the THC study done.
I won’t go into the reasons of why I think this happened, but as a basic scientist you put your ideas in publications, presentations and other things and clinicans can act on them, without any involvement or credit to you.
ProfG and I had discussed this one and we were of the opinion to enrich the trial with people most likely to progress and respond. Had this happened you would have had a treatment option.
So we are now at this crossroads again. This current study on remyelination and other studies may tell us were to go with regard to re-invigorating the oligodendrocyte.
Should we plough-on and do the study? The data and the idea is out there, if you know where to look and you are able to put two and two together.
Should we wait for the scientists to do more studies?…I think you will be waiting forever as there is always more science to done and remember once a trial is done the work will sink (if the trial fails) or swin (if trial succeeds) and everybody else will be doing it.
Should we make way for the scientist to try and get this off the ground…when they may not?
This will delay things as we could go now if the will was there
However the sad thing is that you seldom get a second bite of the cherry A trial fails and that is it you don’t get another go. Having spend sixteen years on our spasticity drug for it to miss the end-point, when we may have got the dose wrong, is abit of a killer. MY millions 🙂 down the pan
Ideas can be brought back from the dead, but it takes alot of efffort. Sodium channel blockers (Lamtorigine) failed, we resurrected the concept twice, you’ve heard of the phenytonin (sodium channel blocker) study,which suceeded and went nowhere and so failed….next we have the oxcarbazepine study to be reported soon.