Introduction
From time immemorial, humans have been obsessed with the concept of longevity and immortality. Most civilizations, from the Spanish Conquistadors to the Ancient Greek and Roman empires, have tales of an ancient fruit or fountain that gave them the key to eternal life. While this seemed like a plausible idea then, we certainly now know that there is no such mystical item. However, one organism does have such a gift: a gift that gives them the trait of immortality.
The Immortal Jellyfish
Turritopsis dohrnii, also known as T.Dohrnii, is a hydrozoan species of jellyfish that was first discovered in the Mediterranean sea and has since spread to many research facilities and laboratories worldwide. Like its counterpart jellyfish, T.Dohrnii starts its life as a planula, a special type of larva. The planulae settle at the bottom of the sea, where they split into multiple genetically identical medusae. These medusae fully mature into grown, adult jellyfish in a matter of weeks. However, unlike the other species of jellyfish, T.Dohrnii possesses a special defense mechanism known as ‘Transdifferentiation.’ This cellular mechanism allows T.Dohrnii to revert back into its polyp or juvenile stage when in physical danger. This process looks remarkably similar to what we define as “immortality” and has many promising medical applications as well.
Potential Medical Applications of Transdifferentiation
Unlike dedifferentiation, a process where cells can differentiate or revert back to a less-differentiated stage within its own lineage, transdifferentiation allows cells to differentiate back to a stage where cells can switch lineages. The pioneering work by Takashi and Yamanaka showed that the overexpression of four transcription factors (Oct4, Sox2, KLF4, and cMyc) could induce somatic cells to form pluripotent stem cells. These induced pluripotent stem cells (iPSCs) are capable of infinite regeneration and can differentiate into any somatic cell type while still retaining the same genetic background. This groundbreaking discovery was instrumental in opening multiple doors in regenerative medicine, disease modeling, and drug discovery, especially in cardiology and neurology.
It is common knowledge that neurons are by far the most difficult cells to regrow and produce. However, through the use of transdifferentiation, we may be able to re-populate thousands of lost neuronal cells caused by neurodegenerative disorders such as Alzheimer’s and Parkinson’s. Using transdifferentiation, phenotypes of cells can be altered and changed. Cells found commonly throughout the body, such as skin fibroblasts and peripheral blood mononuclear cells, can be reverted into a stage where the cell can proliferate into glial and neuronal cells. This proves especially effective in the critical stages of late-onset diseases. In a study done on rats, it was found that the skin fibroblasts injected into mouse brains were able to survive up to 6 months and had very minimal risk of tumorigenesis. These cells can also be used to model neurodegenerative disorders such as ALS and have been shown as a potential therapy for spinal cord trauma.
Cardiovascular diseases such as ischemic heart disease, heart failure, stroke, and peripheral arterial disease are the leading causes of death in the United States. The reversal of these heart diseases requires an orthopedic heart transplant. However, this requires the mass use of immunosuppressants in the body, leading to side effects such as dyslipidemia and hypertension, which continue to exacerbate the progression of heart disease. These flaws lead to the need for more advanced forms of treatment such as regenerative medicine. However, there is one major problem with the development of regenerative medicine therapies: the lack of “suitable cell sources.” An ideal cell source would be an autologous somatic stem cell to avoid the possibility of immune rejection. Mesenchymal Stroma cells are suitable cell sources; however, there are very minute amounts of these cells in the body. Advances in the study of transdifferentiation in somatic cells may help alleviate the issue. Through the use of specific transcription factors, transdifferentiation can be used to differentiate resident somatic cells into the desired cell type. For example, with ischemic trauma in the myocardium, transdifferentiation proves to be an effective therapeutic treatment. Cardiac Fibroblasts can be differentiated into cardiomyocytes that the body can use to repair the injury, reduce scar formation, and improve the overall ventricular function.
Conclusion
Since its inception by Yamanaka, the technology surrounding the study of transdifferentiation of iPCS cells has advanced tenfold and has found use in disease modeling, drug discovery, and regenerative medicine. Transdifferentiation has given us the ability to model disease in a petri dish, screen various drugs without ever giving them to patients, and regenerate cells on a large scale in vivo without the fear of activating inflammatory pathways. This concept is very promising and holds great potential, but it is still complicated, time-consuming, and needs more standardization. The study of T.Dohrnii may help in advancing it. Maybe one day, we would see the first human being past the age of 150.
Shreyas Gupta, Youth Medical Journal 2022
References
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