TDP-43 and Paraspeckle: Key Factor to Determine Stem Cells Differentiated or Remain Pluripotent

Induced pluripotent stem cells (iPS cells) can be transformed into any cells in the body or maintain their original form. In a new study, researchers from research institutions such as the Helmholtz Center in Germany described how cells decide which of these two directions to choose. In their research, they identified a protein and a ribonucleic acid (RNA) that played a very important role in this process. Their findings also allow for a better understanding of amyotrophic lateral sclerosis (ALS), a progressive neurological disease that affects motor neurons. Related research results recently published online in the journal of Molecular Cell.


Since iPS cells can be transformed into any type of cell in the body, they have the potential to make an important contribution to regenerative medicine. For example, in order to produce artificial beta cells for the treatment of type 1 diabetes, understanding their cellular differentiation mechanisms is indispensable. In this new study, Dr. Micha Drukker of the Stem Cell Institute at the Helmholtz Center in Munich and his team demonstrated how this process is controlled at the molecular level. It all starts with a structure that can be observed by means of a fluorescence microscope in the nucleus.



Dr. Miha Modic, the first author of the paper and a member of the Drukker team, said, “We noticed that the nuclear domain called paraspeckle does not occur in iPS cells, but it forms soon during differentiation. This is independent of the type of cells we use to produce iPS cells.” Drukker and Modic speculate that this phenomenon is related to the ability of stem cells to differentiate into somatic cells. The researchers found that two key molecules in the nucleus coordinate the appearance of paraspeckle and how they regulate differentiation.


Drukker said, “There are two factors that play a key role in determining whether stem cells differentiate or maintain pluripotency. We identified an RNA called NEAT1 and an RNA-binding protein called TDP-43.” NEAT1 comes in two forms. The shorter form of NEAT1 can be stabilized by TDP-43, in which case paraspeckle will not form. Stem cells remain pluripotent and will not change. Conversely, a decrease in TDP-43 produces a longer form of NEAT1, when paraspeckle is formed and iPS cells begin to differentiate. Modic added, “This control system may be a common mechanism for stem cell selection when to differentiate.”


Modic said, “Dr. Silvia Schirge and Professor Heiko Lickert of the Helmholtz Center for Diabetes and Regeneration in Munich have helped us to confirm that paraspeckle is also essential for efficient differentiation in mouse embryonic development. In short, their research has made breakthroughs in understanding differentiation and development processes.”


In Drukker’s view, these findings not only contribute to basic research. He explained, “Paraspeckle is associated with many diseases, but so far they have rarely been studied in the context of developmental and stem cell biology.” In amyotrophic lateral sclerosis (ALS), the role of TDP-43 and the appearance of paraspeckle are particularly evident. In motoneurons, cells that manipulate our muscles, which are affected in ALS, TDP-43 is abnormally regulated and forms toxic aggregates; and the appearance of longer forms of NEAT1 increases, more paraspeckle is detectable. These mechanisms are also considered early signs of ALS, even before the patient has clinically relevant symptoms. In the next phase, Drukker and his team hope to study paraspeckle, RNA and their interactions in other cell types. By that time, it will be obvious whether newly discovered molecules will provide suitable targets for drug therapy.




Miha Modic et al, Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition, Molecular Cell (2019). DOI: 10.1016/j.molcel.2019.03.041.

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