UK researchers have developed two synthetic molecules that coax stem cells to differentiate into either neurons or epithelial cells for use in drug discovery applications.
The new molecules, dubbed EC23 and EC19, should enable researchers to more efficiently produce stem cell-derived cell lines for use in drug discovery and development programs that will help reduce the need for animal testing experiments.
The latest research, published by a collaborative team of scientists from Durham University, the North East England Stem Cell Institute (NESCI) and ReInnervate in the latest issue of the journal Organic and Biomolecular Chemistry, describes the design, synthesis and testing of the new molecules that are analogues of the notoriously unstable all-trans-retinoic acid (ATRA).
A major challenge in stem cell biology is controlling the development of cells and tissues in a predictable and reproducible way.
Retinoids such as ATRA are naturally occurring derivatives of vitamin A, which plays a major role in the mammalian development process, and is commonly used to induce differentiation of stem cells.
ATRA is currently sold in various topical formulations as a treatment for acne and follicular keratosis as well as being marketed by Roche under the brand name Vesanoid as a treatment for acute promyelocytic leukemia.
However the molecules are very sensitive to light and degrade quickly during routine use in a laboratory, with the degradation products hampering the control of the differentiation process and the subsequent reliability of screening experiments.
“The key thing about these synthetic molecules is that they remain stable and are exactly the same every time you use them, ensuring more reliable scientific experiments compared to those which use ATRA,” said Dr Stefan Przyborski, one of the co-authors of the report, Reader in the School of Biological and Biomedical Sciences at Durham University and chief scientific officer of ReInnervate.
“Because the results will be more scientifically robust, this will accelerate drug development using human stem cell-derived tissues and potentially reduce the numbers of animals used in such research.”
The researchers tested the effectiveness of EC23 and EC19 on four types of stem cell and found that EC23 was particularly effective at causing cells to differentiate into neurons which could be used to test the efficacy and mode of action of drug candidates on conditions such as Alzheimer’s and Parkinson’s.
EC19 was found to induce the stem cells to form epithelial cells, the cells that line the inner and outer surfaces of the body.
"We've set out to make stable mimics of natural compounds which control cell development, but in this case, not only have we uncovered a compound which is not only stable and does what the natural system does, but it actually seems to be better as well,” said Dr Andrew Whiting, one of the co-authors of the report and a Reader at Durham University’s Chemistry Department.
“It’s a real bonus and shows the validity of the approach."
EC23 is now being marketed by ReInnervate and the scientists are in the process of developing a complete ‘molecular toolkit’ of synthetic compounds tailor-made to induce stem cells to form different cell lines.