Transdifferentiation-Exploring Biological Alchemy

How to turn lead into gold may still remain a mystery, but the discovery of what is equivalent to alchemy at a cellular level opens up a new range of possibilities. Contrary to previous belief that cellular differentiation is a permanent process, recent work has shown that differentiated cells under specific defined factors have the capacity to change into other cell types through the process of transdifferentiation, also known as lineage reprogramming. In other words, cells are no longer locked into their differentiated state, and if the factors that cause transdifferentiation are found, any type of cell will be able to take up another cell’s characteristics.

But how is transdifferentiation possible? Every cell has a complete set of genes, and once a cell becomes mature and specialized, its characteristics stabilize. This is caused by epigenetic modifications, which only control gene expression, not genetic information. Since gene expression determines the interpretation of the genetic material, changes in gene expression alter cell fate. Appropriate mechanisms and reprogramming factors can reverse gene expression and induce differentiation from a certain cell type to another. In the process of transdifferentiation, the cells first dedifferentiate into a more general state within its own lineage; then, the natural developmental program activates to enable the cells to enter a new lineage1 .

Transdifferentiation may sound like a simple process, but it actually depends on many factors, such as the cell culture conditions and exposure to certain proteins and chemicals, which are very difficult to control at a molecular level. More common ways of reprogramming cells involve inducing pluripotency, which means changing mature cells into stem cells. However, transdifferentiation avoids this step. During the process, specialized cells are directly changed into other cell types. The absence of the intermediate step challenges a lot of biological orthodoxies, and since the body is programmed to keep differentiated cells in their predetermined posts, spontaneous transdifferentiation is a relatively rare process2.

Red-spotted NewtOnly a few cases of spontaneous transdifferentiation are observed in nature. A classic example is lens regeneration in newts. When the lens of an adult newt is removed, the specialized pigmented epithelial cells from the dorsal iris dedifferentiate. The cells lose their defining characteristics such as pigmentation and revert to an earlier developmental stage still within its lineage. To regenerate the missing tissue, the cells then differentiate into lens vesicles, completing the cycle of naturally occurring transdifferentiation1. Lens regeneration is also observed when these pigmented epithelial cells are grown in vitro, but it does not occur frequently in nature3.

Natural transdifferentiation has never been observed in humans. Regenerative capabilities range across different organisms and organs, and humans are limited in this scope. New tissue cells only arise from stem cells in particular body parts, such as in bone marrow or the liver. Stem cells are the core essentials of the human body as they provide raw materials for new, healthy cells to replace diseased or damaged cells. Stem cell research includes transforming stem cells into various other cell types by expressing and repressing certain gene expressions4.

If stem cell differentiation and transdifferentiation are similar in their end results (the new cells possess completely different functions and characteristics than the originals), then why don’t we just resort to this simpler way to replace transdifferentiation research? While stem cell research is an important field of regenerative medicine, there are many challenges and limitations to future development. Embryonic stem cells are commonly used in stem cell regeneration, but they pose problems such as the risk of tumor formation and cellular rejection in adults. The treatment of unused embryonic cells even sparks heated debate on the ethical problems of stem cell research. On top of that, once a patient’s stem cells lose the self-regenerative properties, transplantation must be performed, and difficulties in finding compatible stem cell donors arise. Therefore, the discovery of transdifferentiation reinvigorates the development of regenerative medicine as it addresses the above problems by providing alternative raw materials that can be directly retrieved from the target more easily and safely.

As technology advances, the possibility of controlling transdifferentiation in human cells emerges. A recent groundbreaking study in 2010 performed at McMaster University, Canada, found ways to directly transform skin cells into blood cells, bypassing the middle step of reprogramming the cells into a pluripotent state5. By using a specific cell culture supplemented with transcription and growth factors, reprogramming was induced in human fibroblasts. Human fibroblasts directly generated cells capable of differentiating into other cell types. As a result, healthy adult blood cells were produced and could be used for transplantation in adults in treatment of anemia and leukemia6.

More research has provided cases of different types of transdifferentiation. After proper culturing, fibroblast cells are found to acquire a wide array of different phenotypes, including blood cells, neurons and cardiac muscle cells5,6,7. This suggests that mature differentiated cells are able to alter developmental fate by controlling environmental and epigenetic signals. Although the exact mechanisms that dictate the process of lineage programming are still under examination, scientists have found several ways to manipulate transdifferentiation in vitro. If the reprogramming factor and the culture medium are identified, artificial cell fate transitions can be performed for future study2.

The discovery of transdifferentiation has the potential to expand the field of regenerative medicine. The ability to alter cell identity represents a powerful method to restore damaged biological function, and developing this new technology can benefit medicine by introducing new therapeutic strategies. In the future, it may be possible for cells to be generated in vivo by changing the gene expressions of nearby cells. Multiple sources of cells can then be provided for medical treatment or development of cell products9. Despite the fact that more work has to be done to map out definitive methods of long-lasting transdifferentiation with therapeutic values, lineage reprogramming provides a promising future in cell therapy and regenerative medicine2.

References

  1. Chris Jopling, Stephanie Boue and Juan Carlos Izpisua Belmonte. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Feb 2011. Nature Reviews, Molecular Cell Biology Vol 12.
  2. Macarena Peran, Juan Antonio Marchal, Fernando Rodrıguez-Serrano, Pablo A Lvarez and Antonia Aranega. Mar 2011. Transdifferentiation: why and how? Cell Biology International 2 Mar 2011; Vol 35, 373-379
  3. Panagiotis A. Tsonis, Katia Del Rio-Tsonis. 24 Oct 2003. Lens and retina regeneration: transdifferentiation, stem cells and clinical applications.  Experimental Eye Research 78 (2004) 161–172.
  4. Amy Ralston and Kenna Shaw. 2008. Gene Expression Regulates Cell Differentiation.  Nature Education.
  5. Eva Szabo, Shravanti Rampalli, Ruth M. Risueño, Angelique Schnerch, Ryan Mitchell, Aline Fiebig-Comyn, Marilyne Levadoux-Martin and Mickie Bhatia. Direct conversion of human fibroblasts to multilineage blood progenitors. 25 Nov 2010. Nature 468, 521–526
  6. Scientists turn skin cells directly into blood cells, bypassing middle pluripotent step. Nov 8 2010. Science Daily.
  7. Thomas Vierbuchen, Austin Ostermeier, Zhiping P. Pang, Yuko Kokubu, Thomas C. Südhof, and Marius Wernig. Feb 2010 25. Direct conversion of fibroblasts to functional neurons by defined factors. Nature.; 463(7284): 1035–1041.
  8. Masaki Ieda, Ji-Dong Fu, Paul Delgado-Olguin,Vasanth Vedantham, Yohei Hayashi, Benoit G. Bruneau,Deepak Srivastava. 6 Aug 2010. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell, Volume 142, Issue 3, 375-386.
  9. Wagner BK. Dec 2010. Grand challenge commentary: Chemical transdifferentiation and regenerative medicine. Nat Chem Biol 6(12):877-9.
  10. Image credit (Creative Commons): Becky Gregory. 27 May 2009. Red-spotted Newt, Notophthalmus viridescens, eastern news, red eftFlickr.

Annie Zhang is a first-year student at the University of Chicago majoring in biological sciences. Follow The Triple Helix Online on Twitter and join us on Facebook.

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