Dedifferentiation

Dedifferentiation is a term used to suggest that differentiated epithelial cells revert to a previous developmental stage before their subsequent differentiation into an alternative cell fate. Hereby we discuss about the phenomenon and their impact in medical applications.

1. Dedifferentiation Presented by Hang Jie Justin Izz Hariz Por K wang Jeff Zoe

2. Introduction Dedifferentiation is an important biological phenomenon: Cells regress from a specialized function to a simpler state reminiscent of stem cells Stem cells that are derived by dedifferentiation could be a new resource for regenerative medicine (poses no risk of genetic incompatibility or immune rejection) It also offers an ethically acceptable alternative route to obtain an abundant source of stem cells compare than the use of stem cells derived from embryonic tissue - ( CAI et al. 2007 )

3. How to reprogram stem cells? E xperiment ed by - Takahashi and Yamanaka Introduce four genes ( Oct-3/4, Sox2, c- Myc , and  KLF4 ) into an adult mouse fibroblast population G enerate colonies with the characteristics of ESCs C olonies were capable of differentiation to endodermal, ectodermal, and mesodermal lineages after transplant in immunodeficient mice - ( Friedmann-Morvinski & Verma 2014)

4. - ( EuroStemCell 2012)

5. Phenomenon of Dedifferentiation The phenomenon can be observed at the level of : Genetic - cell undergoes reversion to progenitor cell gene expression profile Protein - evidenced by the up-regulation of progenitor & down-regulation of differentiated cell rel a ted proteins Morphology - dedifferentiated cells are smaller, fewer organelles and have high karyoplasmic ratio Functional - cells regains the capacity to proliferate - ( CAI et al. 2007 )

6. Medical Application & Research 1. To study neurological diseases Obtain the neurons from patient through dedifferentiation of their skin cells and reprogram them into affected neurons Thus able to further work on the affected neurons by searching and testing new drugs to treat or protect patients against the disease - ( EuroStemCell 2012)

7. 2 . Dedifferentiation of epithelial cells for corneal maintenance : Stem cells in corneal limbus forming a ring of tissue around the central cornea, and epithelial cells in the central areas After proliferating, stem cells differentiate into terminal corneal epithelial cells that replace the cells shed in the central cornea - (Yoon et al. 2014 )

8. 3. Treatment of Osteoarthritis Technique developed by - Dr Paul Genever To revitalize cells from older people with osteoarthritis to repair worn or damaged cartilage, therefore reducing pain Cultivated spheroid clusters of cells in tiny cavities, by using pharmaceutical to induce cell-self-eating effects and consequently reduce in size, which stimulate dedifferentiation and the cells revert to embryonic state - ( Alexandra Thompson 2015)

9. Current Medical development -Clinical Stages Masayo Takahashi, has been using induced pluripotent stem ( iPS ) cells to prepare a treatment for age-related macular degeneration . Skin cells taken from people with the disease and converted them to iPS cells. Coax these cells to become retinal pigment epithelium cells, and then to grow into thin sheets that can be transplanted to the damaged retina. - ( Cyranoski 2014)

10. Safety test Researches has been done on iPS cells in monkey and there is no immune reaction found. There have been concerns that iPS cells could cause tumours, but Takahashi's team has found that to be unlikely in mice and monkeys. - ( Cyranoski 2014)

11. Future Application Cartilage injury remains a challenge in orthopedic surgery due to the fact that articular cartilage has limited capacity for intrinsic healing. The main cells in the cartilage are the chondrocytes. When they dedifferentiate, the tend to lose their bone like characteristics. To generate more chondrocytes for studies, there will have to be a dedifferentiation of chondrocytes . - (Wei et al. 2012)

12. Future Application Therefore through the dediffrentiation of chondrocytes , studies on redifferentiation of chondrocytes can be carried out. Successful redifferentiation of chondrocytes can be used in replacing the dedifferentiated chondrocytes in the bones to improve the rate of cartilage healing. - ( Lin et al. 2008)

13. Limitation in Dedifferentiation Process High medical cost Lack of large-scale culture technologies Longer timeframe needed to prepare the cells for transplantation ( eg : crucial spinal cord injuries ) Impractical to isolate neurons directly from a patient’s brain C ells isolated from the patient will be affected and have a little therapeutic value

14. Low quality of cells which derived from somatic cells of aged individuals (incidence of spontaneously occurring tumors ) I ntegration site of retroviral vectors and also the use of undefined serum-containing media to support I PSC generation will increase the risk of insertional mutagenesis and the risk of tumorigenicity The use of oncogenic transgenes, such as MYC gene (code for transcription factor), can also increase the risk of tumour development Limitation in Dedifferentiation Process

15. Conclusion Cell dedifferentiation is an important part of the life of a cell and is an important part of medical research More research towards the dedifferentiation of cells are needed to be carried out to ensure that the dedifferentiation pathways are fully understood

16. References Alexandra Thompson 2015, Researchers develop dedifferentiation technique to help treat osteoarthritis , viewed on 26 th September 2015, <https://www.regmednet.com/users/1034-alexandra-thompson/posts/2947-researchers-develop-dedifferentiation-technique-to-help-treat-osteoarthritis#> CAI, S., FU, X. & SHENG, Z., 2007. Dedifferentiation: A New Approach in Stem Cell Research. BioScience , 57(8), p.655, viewed on 26 th September 2015, <http://bioscience.oxfordjournals.org/content/57/8/655> Cyranoski , D 2014, Next-generation stem cells cleared for human trial , Nature, viewed on 26 th September 2015, <http://www.nature.com/news/next-generation-stem-cells-cleared-for-human-trial-1.15897> EuroStemCell 2012, IPS cells and reprogramming: turn any cell of the body into a stem cell , viewed on 26 th September 2015, <http://www.eurostemcell.org/factsheet/ips-cells-and-reprogramming-turn-any-cell-body-stem-cell> Friedmann-Morvinski , D. & Verma , I.M., 2014. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO reports , 15(3), pp.244–53, viewed on 26 th Semptember 2015, <http :// www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3989690&tool=pmcentrez&rendertype=abstract>

17. Lin, Z. et al., 2008. Gene expression profiles of human chondrocytes during passaged monolayer cultivation. Journal of Orthopaedic Research , 26(9), pp.1230–1237 Wei, Y. et al., 2012. Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. European cells & materials , 23, pp.1–12, viewed on 26 th September 2015, <http :// www.ncbi.nlm.nih.gov/pubmed/22241609> Yoon, J.J., Ismail, S. & Sherwin, T., 2014. Limbal stem cells: Central concepts of corneal epithelial homeostasis. World journal of stem cells , 6(4), pp.391–403, viewed on 26 th September 2015, <http :// www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4172668&tool=pmcentrez&rendertype=abstract> References

18. Thank You 