The protein, Netrin-1, could hold the key to boosting production of induced pluripotent stem cells.
For over 50 years, researchers have studied stem cells and their differentiation towards human cell end points. Whilst there has been much discussion over the ethics of using human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) provide a much simpler route towards developing disease-relevant human tissue for the development of treatments for disease states. This is particularly evident in the use of cardiovascular progenitors or differentiated cells from patients which have been applied to the modelling of cardiovascular disorders of genetic origin, such as long QT syndrome type I.
Human embryonic stem cells have their greatest application where they have been developed from a foetus with a genetic mutation associated with a disease, for example cystic fibrosis or Huntington’s disease, or where a genetic mutation can be introduced to them. A far more patient-centric approach has been through the route of induced pluripotent stem cell development; these stem cells are developed from consenting patients or healthy individuals through cellular reprogramming. The reprogramming of somatic cells to induced pluripotent stem (iPS) cells is accomplished by expressing pluripotency factors Oct4, Sox2, Klf4 and the oncogene c-Myc. Overexpression of oncogenes, such as c-Myc, activates the p53 pathway which reduces cancer initiation by inducing apoptosis or cell cycle arrest—leading to very low survival rates for reprogrammed cells. Yet this process of reprogramming differentiated cells to become pluripotent stem cells has been severely hampered by our limited understanding of the process.
Now, a recent study led by researchers from Université de Lyon has identified a secreted protein, Netrin-1, as a key regulator of survival for reprogrammed iPSCs. Specific receptors on neurons, DCC and UNC-5, act as attractors and repressors for axonal guidance, the process whereby neuronal connections are made to specific targets, in response to the presence of Netrin-1 in the developed and developing brain. In the absence of Netrin-1, these same receptors are pro-apoptic and lead to pronounced cell death.
The research from the French team found that stem cell reprogramming was accompanied by a transient repression of Netrin-1, leading to pronounced cell death during this reprogramming process. By supplementing their growth media with recombinant Netrin-1 they were able to boost their production of human iPSCs by around 15- fold. Such an increase in the ability to produce iPSCs from patient populations has huge potential to help increase our understandings of disease and to provide a larger population of cell lines worthy of investigation from healthy individuals and affected patients.
For instance, an increased pool of patient-derived iPSC lines would enable a more patient population focus for the research we currently perform targeting neurodegenerative disorders. This would hopefully lead to decreased efficacy failures for developing treatments and interventions in the clinic.
- Lavial, F. et al, Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance, Nature Communications 6 7398 (2015).
How to Cite
Aziz, Omar, Advancing Patient-Derived Stem Cell Research. Eureka blog. Sept 8, 2015. Available:https://eureka.criver.com/advancing-patient-derived-stem-cell-research/