Transdifferentiation

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Transdifferentiation, also known as lineage reprogramming,[1] is a process where one mature somatic cell transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type.[2] It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine.[3] The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.[4]

Contents

Discovery [edit]

Davis et al. 1987 reported the first instance of transdifferentiation where a cell changed from one adult cell type to another. Mouse embryonic fibroblasts forced to express MyoD was found to be sufficient in turning those cells into myoblasts.[5]

Natural Examples of Transdifferentiation [edit]

There are no known instances where adult cells change directly from one lineage to another except Turritopsis nutricula . Rather, cells dedifferentiate and then redifferentiate into the cell type of interest. In newts when the lens is removed, pigmented epithelial cells dedifferentiate and then redifferentiate into the lens cells.[6]

While it was previously believed that oesophageal cells were developed from the transdifferentiation of smooth muscle cells, that has been shown to be false.[7]

Methods [edit]

Lineage-Instructive Approach [edit]

In this approach transcription factors from progenitor cells of the target cell type are transfected into a somatic cell to induce transdifferentiation.[8] There exists two different means of determining which transcription factors to use: by starting with a large pool and narrowing down factors one by one[9] or by starting with one or two and adding more.[10] One theory to explain the exact specifics is that ectopic TFs directs the cell to an earlier progenitor state and then redirects it towards a new cell type. Rearrangement of the chromatin structure via DNA methylation or histone modification may play a role as well.[11] Here is a list of in vitro examples and in vivo examples. In vivo methods of transfecting specific mouse cells utilize the same kinds of vectors as in vitro experiments, except that the vector is injected into a specific organ. Zhou et al. (2008) injected Ngn3, Pdx1 and Mafa into the dorsal splenic lobe (pancreas) of mice to reprogram pancreatic exocrine cells into β-cells in order to ameliorate hyperglycaemia.[12]

Initial Epigenetic Activation Phase approach [edit]

Somatic cells are first transfected with pluripotent reprogramming factors temporarily (Oct4, Sox2, Nanog, etc.) before being transfected with the desired inhibitory or activating factors.[13] Here is a list of examples in vitro.

Issues [edit]

Evaluation [edit]

When examining transdifferentiated cells, it is important to look for markers of the target cell type and the absence of donor cell markers which can be accomplished using green fluorescent protein or immunodetection. It is also important to examine the cell function, epigenome, transcriptome, and proteome profiles. Cells can also be evaluated based upon their ability to integrate into the corresponding tissue in vivo[14] and functionally replace its natural counterpart. In one study, transdifferentiating tail-tip fibroblasts into hepatocyte-like cells using transcription factors Gata4, Hnf1α and Foxa3, and inactivation of p19(Arf) restored hepatocyte-like liver functions in only half of the mice using survival as a means of evaluation.[15]

Transition from mouse to human cells [edit]

Generally transdifferentiation that occurs in mouse cells does not translate in effectiveness or speediness in human cells. Pang et al. found that while transcription factors Ascl1, Brn2 and Myt1l turned mouse cells into mature neurons, the same set of factors only turned human cells into immature neurons. However, the addition of NeuroD1 was able to increase efficiency and help cells reach maturity.[16]

Order of Transcription Factor Expression [edit]

The order of expression of transcription factors can direct the cell fate. Iwasaki et al. (2006) showed that in hematopoietic lineages, the expression timing of Gata-2 and (C/EBPalpha) can change whether or not a lymphoid-committed progenitors can differentiate into granulocyte/monocyte progenitor, eosinophil, basophil or bipotent basophil/mast cell progenitor lineages.[17]

Immunogenicity [edit]

It has been found for induced pluripotent stem cells that when injected into mice, the immune system of the synergeic mouse rejected the teratomas forming. Part of this may be because the immune system recognized epigenetic markers of specific sequences of the injected cells. However, when embryonic stem cells were injected, the immune response was much lower. Whether or not this will occur within transdifferentiated cells remains to be researched.[18]

Method of Transfection [edit]

In order to accomplish transfection, one may use integrating viral vectors such as lentiviruses or retroviruses, non-integrating vectors such as Sendai viruses or adenoviruses, microRNAs and a variety of other methods including using proteins and plasmids;[19] one example is the non-viral delivery of transcription factor-encoding plasmids with a polymeric carrier to elicit neuronal transdifferentiation of fibroblasts.[20] When foreign molecules enter cells, one must take into account the possible drawbacks and potential to cause tumorous growth. Integrating viral vectors have the chance to cause mutations when inserted into the genome. One method of going around this is to excise the viral vector once reprogramming has occurred, an example being Cre-Lox recombination[21] Non-integrating vectors have other issues concerning efficiency of reprogramming and also the removal of the vector.[22] Other methods are relatively new fields and much remains to be discovered.

Pluripotent Reprogramming vs Transdifferentiation [edit]

  • Almost all factors that reprogram cells into pluripotency have been discovered and can turn a wide variety of cells back into induced pluripotent stem cells (iPSCs) . However, many of the reprogramming factors that can change a cell's lineage have not been discovered and these factors apply only for that specific lineage.[23]
  • The final products of transdifferentiated cells are capable of being used for clinical studies, but iPSCs must be differentiated.[24]
  • It may become possible in the future to use transdifferentiation in vivo where as pluripotent reprogramming may cause teratomas in vivo.[25]
  • Transdifferentiated cells will require less epigenetic marks to be reset where as pluripotent reprogramming requires nearly all to be removed, which may become an issue during redifferentiation.[26]
  • Transdifferentiation is geared towards moving between similar lineages where as pluripotent reprogramming has unlimited potential.[27]
  • Pluripotent cells are capable of self-renewal and often go through many cell passages, which increases the chance of accumulating mutations. Cell culture may also favor cells that are adapted for surviving under those conditions, as opposed to inside an organism. Transdifferentiation requires fewer cell passages and would reduce the chance of mutations.[28]
  • Transdifferentiation can also be much more efficient than pluripotency reprogramming due to the extra step involved in the latter process.[29]
  • Both pluripotent and transdifferentiated cells use adult cells, thus starting cells are very accessible, whereas human embryonic stem cells require that one navigate legal loopholes and delve into the morality of stem cell research debate.

See also [edit]

References [edit]

  1. ^ Orkin, S. H.; Zon, L. I. (2008). "Hematopoiesis: An Evolving Paradigm for Stem Cell Biology". Cell 132 (4): 631–644. doi:10.1016/j.cell.2008.01.025. PMC 2628169. PMID 18295580.  edit
  2. ^ Graf, T.; Enver, T. (2009). "Forcing cells to change lineages". Nature 462 (7273): 587–594. doi:10.1038/nature08533. PMID 19956253.  edit
  3. ^ Pournasr, B.; Khaloughi, K.; Salekdeh, G. H.; Totonchi, M.; Shahbazi, E.; Baharvand, H. (2011). "Concise Review: Alchemy of Biology: Generating Desired Cell Types from Abundant and Accessible Cells". Stem Cells 29 (12): 1933–1941. doi:10.1002/stem.760. PMID 21997905.  edit
  4. ^ Selman, K.; Kafatos, F. C. (1974). "Transdifferentiation in the labial gland of silk moths: Is DNA required for cellular metamorphosis?". Cell differentiation 3 (2): 81–94. PMID 4277742.  edit
  5. ^ Davis, R. L.; Weintraub, H.; Lassar, A. B. (1987). "Expression of a single transfected cDNA converts fibroblasts to myoblasts". Cell 51 (6): 987–1000. PMID 3690668.  edit
  6. ^ Jopling, C.; Boue, S.; Belmonte, J. C. I. (2011). "Dedifferentiation, transdifferentiation and reprogramming: Three routes to regeneration". Nature Reviews Molecular Cell Biology 12 (2): 79–89. doi:10.1038/nrm3043. PMID 21252997.  edit
  7. ^ Rishniw, M.; Xin, H. B.; Deng, K. Y.; Kotlikoff, M. I. (2003). "Skeletal myogenesis in the mouse esophagus does not occur through transdifferentiation". Genesis 36 (2): 81–82. doi:10.1002/gene.10198. PMID 12820168.  edit
  8. ^ Graf, T.; Enver, T. (2009). "Forcing cells to change lineages". Nature 462 (7273): 587–594. doi:10.1038/nature08533. PMID 19956253.  edit
  9. ^ Ieda, M.; Fu, J. D.; Delgado-Olguin, P.; Vedantham, V.; Hayashi, Y.; Bruneau, B. G.; Srivastava, D. (2010). "Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors". Cell 142 (3): 375–386. doi:10.1016/j.cell.2010.07.002. PMC 2919844. PMID 20691899.  edit
  10. ^ Vierbuchen, T.; Ostermeier, A.; Pang, Z. P.; Kokubu, Y.; Südhof, T. C.; Wernig, M. (2010). "Direct conversion of fibroblasts to functional neurons by defined factors". Nature 463 (7284): 1035–1041. doi:10.1038/nature08797. PMC 2829121. PMID 20107439.  edit
  11. ^ Ang, Y. S.; Gaspar-Maia, A.; Lemischka, I. R.; Bernstein, E. (2011). "Stem cells and reprogramming: Breaking the epigenetic barrier?". Trends in Pharmacological Sciences 32 (7): 394–401. doi:10.1016/j.tips.2011.03.002. PMC 3128683. PMID 21621281.  edit
  12. ^ Zhou, Q.; Brown, J.; Kanarek, A.; Rajagopal, J.; Melton, D. A. (2008). "In vivo reprogramming of adult pancreatic exocrine cells to β-cells". Nature 455 (7213): 627–632. doi:10.1038/nature07314. PMID 18754011.  edit
  13. ^ Efe, J. A.; Hilcove, S.; Kim, J.; Zhou, H.; Ouyang, K.; Wang, G.; Chen, J.; Ding, S. (2011). "Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy". Nature Cell Biology 13 (3): 215–222. doi:10.1038/ncb2164. PMID 21278734.  edit
  14. ^ Ieda, M.; Fu, J. D.; Delgado-Olguin, P.; Vedantham, V.; Hayashi, Y.; Bruneau, B. G.; Srivastava, D. (2010). "Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors". Cell 142 (3): 375–386. doi:10.1016/j.cell.2010.07.002. PMC 2919844. PMID 20691899.  edit
  15. ^ Huang, P.; He, Z.; Ji, S.; Sun, H.; Xiang, D.; Liu, C.; Hu, Y.; Wang, X. et al. (2011). "Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors". Nature 475 (7356): 386–389. doi:10.1038/nature10116. PMID 21562492.   edit
  16. ^ Pang, Z. P.; Yang, N.; Vierbuchen, T.; Ostermeier, A.; Fuentes, D. R.; Yang, T. Q.; Citri, A.; Sebastiano, V. et al. (2011). "Induction of human neuronal cells by defined transcription factors". Nature 476 (7359): 220–223. doi:10.1038/nature10202. PMC 3159048. PMID 21617644.   edit
  17. ^ Iwasaki, H.; Mizuno, S. -I.; Arinobu, Y.; Ozawa, H.; Mori, Y.; Shigematsu, H.; Takatsu, K.; Tenen, D. G. et al. (2006). "The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages". Genes & Development 20 (21): 3010–3021. doi:10.1101/gad.1493506. PMC 1620021. PMID 17079688.   edit
  18. ^ Pournasr, B.; Khaloughi, K.; Salekdeh, G. H.; Totonchi, M.; Shahbazi, E.; Baharvand, H. (2011). "Concise Review: Alchemy of Biology: Generating Desired Cell Types from Abundant and Accessible Cells". Stem Cells 29 (12): 1933–1941. doi:10.1002/stem.760. PMID 21997905.  edit
  19. ^ Patel, M.; Yang, S. (2010). "Advances in Reprogramming Somatic Cells to Induced Pluripotent Stem Cells". Stem Cell Reviews and Reports 6 (3): 367–380. doi:10.1007/s12015-010-9123-8. PMC 2924949. PMID 20336395.  edit
  20. ^ Adler, A. F.; Grigsby, C. L.; Kulangara, K.; Wang, H.; Yasuda, R.; Leong, K. W. (2012). "Nonviral Direct Conversion of Primary Mouse Embryonic Fibroblasts to Neuronal Cells". Molecular Therapy — Nucleic Acids 1 (7): e32–. doi:10.1038/mtna.2012.25. PMC 3411320. PMID 23344148.  edit
  21. ^ Sommer, C. A.; Gianotti Sommer, A.; Longmire, T. A.; Christodoulou, C.; Thomas, D. D.; Gostissa, M.; Alt, F. W.; Murphy, G. J. et al. (2009). "Excision of Reprogramming Transgenes Improves the Differentiation Potential of iPS Cells Generated with a Single Excisable Vector". Stem Cells 28 (1): 64–74. doi:10.1002/stem.255. PMID 19904830.   edit
  22. ^ Zhou, W.; Freed, C. R. (2009). "Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells". Stem Cells 27 (11): 2667–2674. doi:10.1002/stem.201. PMID 19697349.  edit
  23. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  24. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  25. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  26. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  27. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  28. ^ Zhou, Q.; Melton, D. A. (2008). "Extreme Makeover: Converting One Cell into Another". Cell Stem Cell 3 (4): 382–388. doi:10.1016/j.stem.2008.09.015. PMID 18940730.  edit
  29. ^ Passier, R.; Mummery, C. (2010). "Getting to the Heart of the Matter: Direct Reprogramming to Cardiomyocytes". Cell Stem Cell 7 (2): 139–141. doi:10.1016/j.stem.2010.07.004. PMID 20682439.  edit
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