PENDAHULUAN Pada dekade terakhir perhatian dan penelitian dalam bidang sel punca (stem cells) mengalami kemajuan yang amat pesat. Para peneliti menggunakan sel punca untuk mengetahui dan mempelajari proses pertumbuhan dan perkembangan jaringan tubuh manusia serta patogenesis penyakit-penyakit yang diderita. Disamping itu penggunaan sel punca dalam perngobatan penyakit-penyakit yang sudah tidak mungkin untuk diobati lagi baik secara konservatif maupun operatif khususnya penyakit degeneratif maupun kelainan lainnya seperti trauma, keganasan dan sebagainya juga meningkat pesat. Dalam bidang farmakologi para peneliti juga menggunakan sel punca untuk menguji obat-obat baru. Tentu saja penggunaan sel punca dalam bidang penelitian dan pengobatan penyakit ini tidak terlepas dari potensi nilai bisnis yang akan diraih manakala sel punca ini sudah dapat digunakan untuk mengobati penyakit-penyakit atau kelainan-kelainan pada manusia. Penggunaan dan pengembangan sel punca dalam bidang penelitian dan aplikasinya diklinik dalam rangka mengobati penyakit tidak terlepas dari masalah etik yang mungkin membayanginya, khususnya penggunaan dan pemanfaatan sel punca yang berasal dari embrio (embryonic stem cells). Tanggal 12 Pebruari 2004 sejumlah peneliti di Korea telah mengumumkan pembuatan stem cell manusia pertama dengan cara transplantasi sel somatik. Walaupun pernyataan ini kemudian ditarik kembali dengan alasan manipulasi data atau perilaku tidak etis para penelitinya, hal ini telah mendorong para peneliti untuk menggiatkan penelitian sel punca dan pengkolnan embrio guna pemakaian dalam pengobatan penyakit-penyakit degeneratif.
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PENDAHULUAN
Pada dekade terakhir perhatian dan penelitian dalam bidang sel punca (stem cells)
mengalami kemajuan yang amat pesat. Para peneliti menggunakan sel punca untuk mengetahui
dan mempelajari proses pertumbuhan dan perkembangan jaringan tubuh manusia serta
patogenesis penyakit-penyakit yang diderita. Disamping itu penggunaan sel punca dalam
perngobatan penyakit-penyakit yang sudah tidak mungkin untuk diobati lagi baik secara
konservatif maupun operatif khususnya penyakit degeneratif maupun kelainan lainnya seperti
trauma, keganasan dan sebagainya juga meningkat pesat. Dalam bidang farmakologi para peneliti
juga menggunakan sel punca untuk menguji obat-obat baru. Tentu saja penggunaan sel punca
dalam bidang penelitian dan pengobatan penyakit ini tidak terlepas dari potensi nilai bisnis yang
akan diraih manakala sel punca ini sudah dapat digunakan untuk mengobati penyakit-penyakit
atau kelainan-kelainan pada manusia.
Penggunaan dan pengembangan sel punca dalam bidang penelitian dan aplikasinya
diklinik dalam rangka mengobati penyakit tidak terlepas dari masalah etik yang mungkin
membayanginya, khususnya penggunaan dan pemanfaatan sel punca yang berasal dari embrio
(embryonic stem cells). Tanggal 12 Pebruari 2004 sejumlah peneliti di Korea telah
mengumumkan pembuatan stem cell manusia pertama dengan cara transplantasi sel somatik.
Walaupun pernyataan ini kemudian ditarik kembali dengan alasan manipulasi data atau perilaku
tidak etis para penelitinya, hal ini telah mendorong para peneliti untuk menggiatkan penelitian sel
punca dan pengkolnan embrio guna pemakaian dalam pengobatan penyakit-penyakit degeneratif.
Penelitian dengan menggunakan embrio dan pengklonan embrio telah menyulut kontroversi dan
menjadi bahan perdebatan dibanyak negara, seperti Inggris, Amerika Serikat, Swedia dan
sebagainya.
Uraian dibawah ini akan membahas tentang pengertian, aspek biomedik dan potensi
penggunaannya di klinik serta masalah etik yang membayanginya
DEFINISI
Sel Punca atau stem cell adalah sel yang tidak/belum terspesialisasi dan
mempunyai kemampuan/potensi untuk berkembang menjadi berbagai jenis sel-sel yang
spesifik yang membentuk berbagai jaringan tubuh.
Gambar-1 Sifat/karakter sel punca yaitu differentiate dan self regenerate/renew
Sel Punca mempunyai 2 sifat yang khas yaitu
1. Differentiate yaitu kemampuan untuk berdifferensiasi menjadi sel lain. Sel Punca mampu
berkembang menjadi berbagai jenis sel yang khas (spesifik) misalnya sel saraf, sel otot
jantung, sel otot rangka, sel pankreas dan lain-lain
2. Self regenerate/self renew yaitu kemampuan untuk memperbaharui atau meregenerasi
dirinya sendiri. Stem cells mampu membuat salinan sel yang persis sama dengan dirinya
melalui pembelahan sel.
Berdasarkan pada kemampuannya untuk berdifferensiasi sel punca dikelompokkan menjadi
1. Totipoten yaitu sel punca yang dapat berdifferensiasi menjadi semua jenis sel. Yang
termasuk dalam sel punca totipoten adalah zigot dan morula. Sel-sel ini merupakan sel
embrionik awal yang mempunyai kemampuan untuk membentuk berbagai jenis sel
termasuk sel-sel yang menyusun plasenta dan tali pusat. Karenanya sel punca kelompok
ini mempunyai kemampuan untuk membentuk satu individu yang utuh.
Gambar-2 Sel Punca totipoten dan pluripoten
2. Pluripoten yaitu sel punca yang dapat berdifferensiasi menjadi 3 lapisan germinal
(ektoderm, mesoderm, dan endoderm) tetapi tidak dapat menjadi jaringan
ekstraembrionik seperti plasenta dan tali pusat. Yang termasuk sel punca pluripoten
adalah sel punca embrionik (embryonic stem cells).
3. Multipoten yaitu sel punca yang dapat berdifferensiasi menjadi berbagai jenis sel
misalnya sel punca hemopoetik (hemopoetic stem cells) yang terdapat pada sumsum
tulang yang mempunyai kemampuan untuk berdifferensiasi menjadi berbagai jenis sel
yang terdapat di dalam darah seperti eritrosit, lekosit dan trombosit. Contoh lainnya
adalah sel punca saraf (neural stem cells) yang mempunyai kemampuan berdifferensiasi
menjadi sel saraf dan sel glia.
4. Unipotent yaitu sel punca yang hanya dapat berdifferensiasi menjadi 1 jenis sel. Berbeda
dengan non sel punca, sel punca mempunyai sifat masih dapat memperbaharui atau
meregenerasi diri (self-regenerate/self renew) Contohnya erythroid progenitor cells
hanya mampu berdifferensiasi menjadi sel darah merah.
Gambar-3 Multipotent dan unipotent stem cells pada sumsum tulang
ASPEK BIOMEDIK SEL PUNCA EMBRIONIK (EMBRYONIC STEM CELLS)
Sel punca embrionik (embryonic stem cells) adalah sel yang diambil dari inner
cell mass (suatu kumpulan sel yang terletak di satu sisi blastokista) embrio berumur 5
hari dan terdiri dari 100 sel. Sel ini mempunyai sifat dapat berkembang biak secara terus
menerus dalam media kultur optimal dan dalam keadaan tertentu dapat diarahkan untuk
berdifferensiasi menjadi berbagai sel yang terdifferensiasi seperti sel jantung, sel kulit,
neuron, hepatosit dan sebagainya, sehingga dapat dipakai untuk transplantasi jaringan
yang rusak.
Gambar -4 Embryonic Stem Cells
Inner cell mass ini mempunyai kemampuan untuk menjadi berbagai jaringan
embrio dan tubuh kecuali membentuk plasenta. Inner cell mass ini disebut sel pluripotent
karena dapat berkembang lebih lanjut menjadi berbagai jaringan dan organ tubuh. Secara
alami sel pluripotent yang telah berkembang dan melakukan spesialisasi dikenal sebagai
sel multipoten dan merupakan sel punca dewasa. Sel punca dewasa ini dapat berkembang
menjadi berbagai sel dan jaringan. Tantangan bagi peneliti sebenarnya adalah cara
memanipulasi sel punca dewasa ini sehingga berkembang menjadi sel atau produk yang
diinginkan yang dapat digunakan untuk pengobatan.
Sel punca embrionik (Embryonic Stem Cell) mempunyai sifat sebagai berikut
1. pluripoten, artinya sel punca ini mempunyai kemampuan berdifferensiasi menjadi
sel-sel yang merupakan turunan dari 3 lapis germinal, tetapi tidak dapat
membentuk membran embrio (tali pusat dan plasenta)
2. immortal artinya dapat berumur panjang sehingga dapat memperbanyak diri
ratusan kali pada media kultur. Mereka merupakan sumber sel-sel yang belum
berdifferensiasi. Sel punca embrionik dulu dipikirkan dapat memperbanyak diri
sendiri secara tak terbatas, tetapi kini diketahui bahwa usia dan perbanyakan diri
20. Islam MS, Terapi sel stem pada cedera medulla spinalis. Cermin Dunia
Kedokteran 2006; 153: 17-19
21. Ibrahim N, Aplikasi terapi stem cell pada luka bakar. Cermin Dunia Kedoketran
2006; 153: 20
22. Saputra V, Dasar-dasar stem cell dan potensi apilkasinya dalam ilmu kedokteran.
Cermin Dunia Kedoketran 2006; 153: 21-25
23. Prayogo R, Wijaya MT, Kultur dan potensi stem cells dari darah tali pusat.
Cermin Dunia Kedoketran 2006; 153: 26-28
ES cells from mouse embryos have been cultured since the 1980s by various groups of researchers working independently.10 These pioneers established murine embryonic stem cells lines that could differentiate into several different cell types.11 ES cell lines have been established from other mammals (hamsters, rats, pigs, and cows). Thompson and colleagues at the University of Wisconsin reported isolation of primate ES cells in 1995 and human ES cells in 1998.12
B. Research and Clinical Applications of Cultured Stem Cells
What are the uses of Cultured Stem cells? The most prominent is cell therapy for treating conditions such as spinal cord injuries and for curing disease. Stem cells are used to investigate questions to further basic and clinical research. Here are the major applications to date:
1. Functional Genomic studies In 1986, Gossler et al. reported using mouse ES cells to produce transgenic animals.24 Soon after, two landmark papers in the field of mouse genetics demonstrated the ability to manipulate a specific gene of ES cells.25 Combining these techniques, a specific gene can be introduced into ES cells to produce transgenic mice. This gene can be transmitted to their offspring through the germline. Today these techniques enable the study of the function of mammalian genes and proteins in the mouse (through introducing human histocompatibility genes into mice).26
2. Study of biological processes Studies of biological processes, namely development of the organism and progress of cancer, are facilitated by the ability to trace stem cell fate. The spleen colony assay developed by Till and McCulloch is an example study of the development of blood cells. In this method single cells were injected into heavily irradiated mice so that all the hematopoietic cells in these mice originated from the original colony. Studies of this nature helped decipher the clonal origin of cancer,
3. Drug discovery and development The combination of isolation and purification of mouse ES cells and genetic engineering techniques has led to the use of murine ES cells in drug discovery. With the sequencing of the human genome many potential targets of new drugs have been identified. Studies using human ES may follow those of murine ES cells.27 Interest in using stem cells as models for toxicology has also grown recently.28
4. Cell-based therapy Cultured ES cells spontaneously form embryoid bodies containing different cell types from all three germ layers. The desired cells are isolated and cultured and the differentiated cells are then used for therapy. ES cells have been induced to differentiate into neurons, cardiomyocytes and endoderm cells.
1. For ethical issues and stem cell research refer to http://stemcells.nih.gov/info/ethics.asp; http://athome.harvard.edu/programs/psc/index.html; http://www.aaas.org/spp/sfrl/projects/stem/main.htm Ethical Issues Associated with Pluripotent Stem Cells. Human Embryonic Stem Cells (2003) ed. by Chiu A.Y., Rao, M.S, 3-25.
2. Sell, S. (2004) Stem cells. Stem Cell Handbook ed. by Sell, S. 1-18. 3. http://stemcells.nih.gov/info/scireport/chapter4.asp 4. Forbes, S.J., Vig, P., Poulsom, R., Wright, N.A., Alison, M.R. (2002) Adult Stem
Cell Plasticity: New Pathways of Tissue Regeneration become Visible. Clin. Sci. 103, 355-369.
5. Asahara T., Isner, J.M. (2004) Endothelial Progenitor Cells. Stem Cell Handbook ed. by Sell, S. 221-227.
6. Lindblad, W.J. (2004) Stem cells in Dermal Wound Healing. Stem Cell Handbook ed. by Sell, S. 101-105.
7. McCulloch, E.A. (2004) Normal and Leukemic Hematopietic Stem cells and Lineages. Stem Cell Handbook ed. by Sell, S. 119-131.
8. Tsai, R.Y.L. (2004) A Molecular View of Stem Cell and Cancer Cell Self-renewal. Intl. J. Biochem. Cell Biol. 36, 684-694.
9. Cai, J., Weiss M.L., Rao, M.S. (2004) In Search of "stemness". Exp. Hematol. 32, 585-598.
10. Roach, M.L., McNeish, J.D. (2002) Methods for the Isolation and Maintenance of Murine Embryonic Stem Cells. Embryonic Stem Cells Methods and Protocols ed. by Turksen K. 1-16.
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11. Evans, M.J., Kaufman, M.H. (1981) Establishment in Culture of Pluripotenial Cells from Mouse Embryos. Nature 292, 154-156; Axelrod, H.R. (1984) Embryonic Stem Cell Lines Derived from Blastocysts by a Simplified Technique. Dev. Biol. 101, 225-228; Wobus, A.M., Holzhausen H., Jakel, P., Schneich, J. (1984) Characterization of a Pluripotent Stem Cell Line Derived from a Mouse Embryo. Exp. Cell Res. 152, 212-219; Doetschman, T.C. Eistattaer, H., Katz, M., Schmidt, W., and Kemler, R. (1985) The in vitro development of Blastocyst Derived Embryonic Stem Cell Lines: formation of Yolk Sac, Blood Islands and Myocardium. J. Embryol. Exp. Morphol. 87, 27-45.
12. Thompson, J.A., Kalishman, J., Golos, T.G., Durning, M., Harris, C.P., Becker, R.A., Hearn, J.P. (1995) Isolation of a Primate Embryonic Stem Cell Line. Proc. Natl. Acad. Sci. USA 86, 7844-7848; Thomson, J.A, Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshal, V.S., Jones, J.M. (1998) Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 282, 1145-1147.
13. Amit, M., Segev, H., Manor, D., Itskovitz-Eldor, J. (2003) Subcloning and Alternative Methods for the Derivation and Culture of Human Embryonic Stem Cells. Human Embyronic Stem Cells ed. by Chiu, M., Rao, M.S. 127-141.
14. Carpenter, M.K., Xu, C., Daigh, C.A., Antosiewicz, J.E., Thomson, J.A. (2003) Protocols for the Isolation and Maintenance of Human Embryonic Stem Cells. Human Embyronic Stem Cells ed. by Chiu, M., Rao, M.S.
15. Drukker M., Benvenisty, N. (2003) Genetic Manipulation of Human Embryonic Stem Cells. Human Embryonic Stem Cells ed. by Chiu, A.Y., Rao, M.S. 265-284.
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16. Shamblott, M.J., Axelman, J., Wang, S., Bugg, E.M., Littlefield, J.W., Donovan, P.J., Blumenthal, P.D., Huggins, G. R., Gearhart J.D., (1998) Derivation of Pluripotent Stem Cells from Cultured Human Primordial Germ CellS. Proc. Natl. Acad. Sci.USA 95, 13726-13731.
17. Doyonnas, R., Blau, H.M. (2004) What is the Future of Stem Cell Research? Stem Cell Handbook ed. by Sell, S. 491-499.
18. Draper, J.S. Moore, H., Andrews, P.W. (2003) Embryonal Carcinoma Cells. Human Embryonic Stem Cells ed. Chiu, A. Y., Rao, M.S. 63-87.
19. Adult Stem Cells ed. Turksen, K. (2004) For reviews of hematopoietic stem cells: http://stemcells.nih.gov/info/scireport/chapter5.asp; http://www.stemcell.com/technical/Hema%20SC%20MiniReview.pdf; for mesenchymal stem cells: http://www.stemcell.com/technical/MSC%20MiniReview.pdf; for neural stem cells: http://www.stemcell.com/technical/Neurocult%20MiniReview.pdf
20. Nosrat, I.V., Smith, C. A., Mullally, P., Olson, L., Nosrat C.A. (2004) Dental Pulp Cells Provide Neurotrophic Support for Dopaminergic Neurons and Differentiate into Neurons in vitro; implications for Tissue Engineering and Repair in the Nervous System. Eur. J. of Neurosci. 19, 2388-2398.
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21. Shen, C-N., Horb, M.E., Slack, J.M.W., Tosh,D. (2003) Transdifferentiation of Pancreas to Liver. Mech. Dev.120, 107-116.
22. Priller, J. (2004) From Marrow to Brain. Adult Stem Cells ed. by Turksen, K. 215-233.
23. de Wynter, E.A. (2003) What is the future of Cord blood stem cells? Cytotech. 41, 133-138.
24. Gossler, A., Doetschman, T.C., Eistattaer, H., Katz, M., Schmidt, W., Kemler, R. (1986) Transgenesis by means of Blastocyst Derived Embryonic Stem Cell Lines. Proc. Natl. Acad. Sci. USA 83, 9065-9069.
26. For review: Floss,T., Wurst, W. (2002) Functional Genomics by Gene-trapping in ES cells. Embryonic Stem Cells Methods and Protocols ed. by Turksen, K. 347-379.
27. McNeish, J. (2004) Embryonic Stem Cells in Drug Discovery Nat. Rev. Drug Discov. 3, 70-80.
28. Davila, J.C., Cezar, G.G., Thiede, M., Strom, S., Miki, T., Trosko J. (2004) Use and Application of Stem Cells in Toxicology. Toxicol. Sci. 79, 214-223.
29. Till, J.E., McCulloch, E.A. (1961) A Direct Measurement of the Radiation Sensitivity of Normal Mouse Bone Marrow Cells. Radiat. Res. 14, 2213-222.
30. Thomas, E.D. (1999) Bone Marrow Transplantation: a Review. Semin. Hematol. 36, 95-103.
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31. Barker, R.A., Jain, M., Armstrong, R.J.E., Caldwell, M.A. (2003) Stem Cells and Neurological Disease. J. Neurol. Neurosurg. Psychiat. 74, 553-557.
32. http://www.who.int/cardiovascular_diseases/resources/atlas/en/ 33. Jackson, K.A., Goodell, M.A. (2004) Generation and Stem Cell Repair of Cardiac
Tissue. Stem Cell Handbook, edited by Sell, S. 259-266. 34. Kehat, I., Khimovich, L., Caspi, O., Gepstein, A., Shofti, R., Arbel, G., Huber, I.,
Satin, J., Itskovitz-Eldor, J., Gepstein, L. (2004) Electromechanical Integration of Cardiomyocytes Derived from Human Embryonic Stem Cells . Nature Biotechnol. 22, 1282-1289.
35. Fraser, J.K., Schreiber, R.E., Zuk, P.A., Hedrick, M.H. (2004) Adult Stem Cell Therapy for the Heart. Intl. J. Biochem. Cell Biol. 36, 658-666.
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36. Cohen, S., Leor, J. (2004) Rebuilding Broken Hearts. Scientific American Nov. 2004, 45-51.
41. http://stemcells.nih.gov/info/scireport/chapter8.asp 42. Baier, P.C., Schindehutte HJ., Thinane, K., Flugge G., Fuchs, E., Mansouri, A.,
Paulus, W., Gruss, P.,Trenwalder, C.(2004) Behavioral Changes in Unilaterally 6-Hydroxy-Dopamine Lesioned Rats after Transplantation of Differentiated Mouse Embryonic Stem Cells without Morphological Integration. Stem Cells 22, 396-404.
43. Lindvall O., Bjorklund, A. (2004) Cell Therapy in Parkinson's Disease. NeuroRx. 1, 382-393.
44. Zheng, X., Cai, J., Chen, J., Luo, Y., Zhi-Bing Y., Fotter, E., Wang, Y., Harvey, B., Miura, T., Backman, C., Chen, G-J., Rao, M.S., Freed. W.J. (2004) Dopaminergic Differentiation of Human Embryonic Stem Cells. Stem Cells 22, 925-940; Wilmut, I., Paterson, L.A. (2004) Stem cells and Cloning. Stem Cell Handbook ed. by Sell, S. 75-80.
Barker, R.A., Widner, H. (2004). Immune Problems in the Central Nervous System Cell
Therapy. NeuroRx. 1, 472-481.
Embryonic stem cells (ES cells) were first derived from mouse embryos in 1981 by Martin Evans and Matthew Kaufman and independently by Gail R. Martin. Gail R. Martin is credited with coining the term 'Embryonic Stem Cell'.[3][4] A breakthrough in human embryonic stem cell research came in November 1998 when a group led by James
Thomson at the University of Wisconsin-Madison first developed a technique to isolate and grow the cells when derived from human blastocysts.[5]
[edit] Potential method for new cell line derivation
On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.[9] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding. Federal funding is currently limited to research using embryonic stem cell lines derived prior to August 2001.
See also: Induced pluripotent stem cell
Professor Yamanaka had a recent breakthrough[10] in which the skin cells of laboratory mice were genetically manipulated back to their embryonic state. This work was confirmed by two other groups, demonstrating that the addition of just 4 genes (Oct3/4, Sox2, Klf4, and c-Myc) could reprogram mouse skin cells into embryonic stem like cells. The ability to reproduce such findings are very important in science and the stem cell field, especially after Hwang Woo-Suk from Korea fabricated data, claiming to have generated human ES cells from cloned embryos. These cells produced by Yamanaka as well as the other laboratories demonstrated all the hallmarks of embryonic stem cells including the ability to form chimeric mice and contribute to the germ-line. One issue with this work is that the mice generated from these ES lines were prone to develop cancer due to the use of Myc, which is a known oncogene.
On 20th of November, 2007, two research teams, one of which was headed by Professor Yamanaka and the other by James Thomson[11] announced a similar breakthrough with ordinary human skin cells that were transformed into batches of cells that look and act like embryonic stem cells. This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.
While this work is a huge accomplishment for science, there is still much work to be done before this technology can be used for the treatments of disease. First, the genes used to reprogram the skin cells into ES-like cells were added by the use of retroviruses that can cause mutations and lead to the risk of possible cancers, although recent research by professor Yamanaka's research group has made advances in avoiding this particular problem.[12]
In addition, as shown with the mouse work, one of the genes used to reprogram, Myc, can also cause cancer. The group led by Thomson did not use Myc to reprogram and may not have this difficulty. Future work is aimed at attempting to reprogram without permanent genetic manipulation of the cells with viruses. This could be accomplished by either small molecules or other methodologies to express these reprogramming genes.
However, as a first indication that the induced pluripotent stem (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on 6th of December.[13]
On January 16, 2008, a California based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells.[14]
1. Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto (August 25, 2006). "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors". Cell.
2. Andrews P, Matin M, Bahrami A, Damjanov I, Gokhale P, Draper J (2005). "Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin.". Biochem Soc Trans 33 (Pt 6): 1526-30. PMID 16246161.
3. Evans M, Kaufman M (1981). "Establishment in culture of pluripotential cells from mouse embryos.". Nature 292 (5819): 154-6. doi:10.1038/292154a0. PMID 7242681.
4. Martin G (1981). "Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.". Proc Natl Acad Sci U S A 78 (12): 7634-8. doi:10.1073/pnas.78.12.7634. PMID 6950406.
5. Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V, Jones J (1998). "Embryonic stem cell lines derived from human blastocysts.". Science 282 (5391): 1145-7. doi:10.1126/science.282.5391.1145. PMID 9804556.
6. "Derivation of embryonic germ cells and male gametes from embryonic stem cells" (January 8, 2004). Nature 427: 148-154. doi:10.1038/nature02247.
7. Access to articles : Nature Medicine 8. Lancet Medical Journal 9. Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R. (2006). "Human embryonic stem
cell lines derived from single blastomeres.". Nature 444 (7118): 481-5. PMID 16929302. 10. "Human stem cells may be produced without embryos ‘within months’", Zangani, July
17, 2007. 11. "Embryonic stem cells made without embryos", Reuters, November 21, 2007. 12. "Researchers get closer to safe stem cell treatments", AFP, February 14, 2008. 13. Rick Weiss. "Scientists Cure Mice Of Sickle Cell Using Stem Cell Technique: New
Approach Is From Skin, Not Embryos", Washington Post, December 7, 2007, pp. A02. 14. Helen Briggs. "US team makes embryo clone of men", BBC, January 17, 2008,
Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast
tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos.[6] A
blastocyst is an early stage embryo—approximately four to five days old in humans and
consisting of 50–150 cells.
Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF).[7] Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2).[8] Without optimal culture conditions or genetic manipulation,[9] embryonic stem cells will rapidly differentiate.
A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and SOX2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[10] The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[11]
The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include several transcription factors including the oncogene c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent.[24] However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.
There exists a widespread controversy over human embryonic stem cell research that emanates from the techniques used in the creation and usage of stem cells. Human embryonic stem cell research is controversial because, with the present state of technology, starting a stem cell line requires the destruction of a human embryo and/or therapeutic cloning. However, recently, it has been shown in principle that embryonic stem cell lines can be generated using a single-cell biopsy similar to that used in
preimplantation genetic diagnosis that may allow stem cell creation without embryonic destruction.[29] It is not the entire field of stem cell research, but the specific field of human embryonic stem cell research that is at the centre of an ethical debate.
Opponents of the research argue that embryonic stem cell technologies are a slippery slope to reproductive cloning and can fundamentally devalue human life. Those in the pro-life movement argue that a human embryo is a human life and is therefore entitled to protection.
Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created for in vitro fertilisation could be donated with consent and used for the research.
The ensuing debate has prompted authorities around the world to seek regulatory frameworks and highlighted the fact that stem cell research represents a social and ethical challenge.
Key stem cell research events 1960s - Joseph Altman and Gopal Das present scientific evidence of adult
neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
1968 - Bone marrow transplant between two siblings successfully treats SCID. 1978 - Haematopoietic stem cells are discovered in human cord blood. 1981 - Mouse embryonic stem cells are derived from the inner cell mass by
scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
1992 - Neural stem cells are cultured in vitro as neurospheres. 1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first
direct evidence for cancer stem cells. 1998 - James Thomson and coworkers derive the first human embryonic stem cell
line at the University of Wisconsin-Madison. 2000s - Several reports of adult stem cell plasticity are published. 2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell
stage) human embryos for the purpose of generating embryonic stem cells.[30] 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in
children's primary teeth.[31] 2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several
human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
2005 - Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
October 2006 - Scientists in England create the first ever artificial liver cells using umbilical cord blood stem cells.[32][33]
January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid.[5] This may potentially provide an alternative to embryonic stem cells for use in research and therapy.[34]
June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice.[35] In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer [36]
October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.[37]
November 2007 - Human Induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors", and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
January 2008 - Human embryonic stem cell lines were generated without destruction of the embryo[38]
January 2008 - Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts[39]
February 2008 - Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach: these iPS cells seem to be more similar to embryonic stem cells than the previous developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages the development of non-viral reprogramming techniques. [40][41]
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FOXNews.com - New Stem-Cell Procedure Doesn't Harm Embryos, Company Claims - Biology | Astronomy | Chemistry | Physics
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Result The Niche: Adult cell types besides skin are reprogrammed Dispatches: The Politics of Stem Cells PBS Dispatches: The Politics of Stem Cells PBS Full-text of Missouri Constitution Amendment 2 Calif. Awards $45M in Stem Cell Grants Associated Press, Feb. 17, 2007.