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

sendiri sel-sel stem juga ada batasnya. Hal ini disebabkan karena terjadinya
mutasi pada gen-gen pada sel stem yang diakibatkan karena pengaruh nutrisi
dalam medium kultur.
3. mempunyai karyotipe yang normal
4. dapat bersifat tumorigenik artinya setiap kontaminasi dengan sel yang tak
berdifferensiasi dapat menimbulkan kanker
5. selalu bersifat allogenik sehingga berpotensi menimbulkan terjadinya rejeksi
imunitas. Untuk mencegah terjadinya reaksi penolakan jaringan dapat digunakan
metoda somatic cell nuclear transfer atau terapi kloning.

Gambar-5 Metoda Somatic Cell Nuclear Transfer

Therapeutic cloning atau disebut Somatic Cell Nuclear Transfer (SCNT) adalah
suatu teknik yang bertujuan untuk menghindari resiko penolakan atau rejeksi. Pada teknik
ini inti sel telur donor dikeluarkan dan diganti dengan inti sel resipien. Sel yang telah
dimanipulasi ini kemudian akan membelah diri dan setelah menjadi blastokista maka

inner cell massnya akan diambil sebagai embryonic stem cells. Stem cells ini kemudian
akan dimasukkan kembali kedalam tubuh resipien dan stem cells ini kemudian akan
berdifferensiasi menjadi sel organ (sel beta pankreas, sel otot jantung dan lain-lain).
Tanpa reaksi penolakan karena sel tersebut mengandung materi genetik resipien.

Gambar-6 Terapi Kloning (Therapeutic Cloning)

APPLIKASI / PENGGUNAAN KULTUR STEM CELLS
Stem cells dapat digunakan untuk keperluan baik dalam bidang riset maupun
pengobatan. Adapun penggunaan kultur stem cells adalah sebagai berikut
1. Terapi gen
Stem cells khususnya hematopoetic stem cells digunakan sebagai pembawa
transgen kedalam tubuh pasien dan selanjutnya dilacak apakah jejaknya apakah
stem cells ini berhasil mengekspresikan gen tertentu dalam tubuh pasien. Adanya
sifat self renewing pada stem cell menyebabkan pemberian stem cells yang
mengandung transgen tidak perlu dilakukan berulang-ulang. Selain itu

hematopoetic stem cells juga dapat berdifferensiasi menjadi bermacam-macam sel

sehingga transgen tersebut dapat menetap diberbagai macam sel.
2. Penelitian untuk mempelajari proses-proses biologis yang terjadi pada organisma
termasuk perkembangan organisma dan perkembangan kanker
3. Penelitian untuk menemukan dan mengembangkan obat-obat baru terutama untuk
mengetahui efek obat terhadap berbagai jaringan
4. Terapi sel (cell based therapy)
Stem cell dapat hidup diluar tubuh manusia, misalnya di cawan Petri. Sifat ini
dapat digunakan untuk melakukan manipulasi pada stem cells yang akan
ditransplantasikan ke dalam organ tubuh untuk menangani penyakit-penyakit
tertentu tanpa mengganggu organ tubuh.

Gambar-7 Berbagai peran Stem Cells

PENGGUNAAN STEM CELLS DALAM PENGOBATAN PENYAKIT

Para ahli saat ini sedang giat melakukan berbagai penelitian untuk menggunakan
stem cell dalam mengobati berbagai penyakit. Penggunaan stem cells untuk mengobati
penyakit dikenal sebagai Cell Based Therapy. Prinsip terapi adalah dengan melakukan
transplantasi stem cells pada organ yang rusak. Tujuan dari transplantasi stem cells ini
adalah
1. Mendapatkan pertumbuhan dan perkembangan sel-sel baru yang sehat pada jaringan
atau organ tubuh pasien
2. Menggantikan sel-sel spesifik yang rusak akibat penyakit atau cidera tertentu dengan
sel-sel baru yang ditranspalantasikan.
Sel stem embryonic sangat plastik dan mempunyai kemampuan untuk dikembangkan
menjadi berbagai macam jaringan sel seperti neuron, kardiomiosit, osteoblast, fibroblast,
sel-sel darah dan sebagainya, sehingga dapat dipakai untuk menggantikan jaringan yang
rusak. Sel stem dewasa juga dapat digunakan untuk mengobati berbagai penyakit
degeneratif, tetapi kemampuan plastisitasnya sudah berkurang. Keuntungan dari
penggunaan sel stem dewasa yaitu tidak atau kurang menimbulkan masalah dan
kontroversi etika.
Penggunaan sel punca embrionik untuk mengobati cidera pada medula spinalis
(spinal cord)
Cidera pada medula spinalis disertai demielinisasi menyebabkan hilangnya fungsi
neuron. Sel punca dapat mengembalikan fungsi yang hilang dengan cara melakukan
remielinisasi . Percobaan dengan sel punca embrionik tikus dapat menghasilkan
oligodendrosit yang kemudian dapat menyebabkan remielinisasi akson yang rusak
Penggunaan sel punca pada penyakit stroke
Pada penyakit stroke dicoba untuk menggunakan sel punca mesenkim
(mesenchymal stem cells (MSC) dari sumsum tulang autolog. Penelitian ini didasarkan
pada hasil penelitian yang telah dilakukan sebelumnya. Mesenchymal stem cells
diperoleh dari aspirasi sumsum tulang. Setelah disuntikkan perifer MSC akan melintas
sawar darah otak pada daerah otak yang rusak.

Pemberian MSC intravenous akan

mengurangi terjadinya apoptosis dan menyebabkan proliferasi sel endogen setelah

terjadinya stroke
Penggunaan sel punca pada infark miokardium
Bartinek telah melakukan intracoronary infusion bone marrow stem cells otolog
pada 22 pasien dengan AMI dan mendapatkan hasil yang baik. Penelitian terkini
menunjukkan bukti awal bahwa adult stem cells dan embryonic stem cells dapat
menggantikan sel otot jantung yang rusak dan memberikan pembuluh darah baru. Strauer
et al. mencangkok mononuclear bone marrow cell autolog ke dalam arteri yang
menimbulkan infark pada saat PTCA 6 hari setelah infark miokard. Sepuluh pasien yang
diberi stem cells area infarkya menjadi lebih kecil dan indeks volume stoke, left
ventricular end systolic volume, kontraktilitas area infark dan perfusi miokard
menunjukkan perbaikan dibandingkan dengan kelompok kontrol.
Bioetika Pada Penelitian Stem Cells
Manfaat yang diperoleh dari penggunaan sel punca embrionik (embryonic stem
cell) dalam bidang kedokteran amat besar, namun sumber sel punca embrionik ini
merupakan masalah etika yang perlu mendapat perhatian.
Berkembangnya penelitian stem cell dan penggunaan stem cell dalam upaya
untuk mengobati penyakit pada manusia akan mengakibatkan timbulnya masalah dalam
hal etik. Hal utama terkait dengan masalah etik adalah sumber stem cell tersebut.
Berbagai masalah etika yang perlu dipikirkan adalah
1. Apakah penelitian embrio manusia secara moral dapat dipertanggung jawabkan?
2. Apakah penelitian embrio yang menyebabkan kematian embrio merupakan
pelanggaran terhadap hak azasi manusia (HAM) dan berkurangnya penghormatan
terhadap mahluk hidup?
3. Apakah penyalah gunaan dapat diketahui dan dikendalikan?
4. Apakah penggunaan embrio sisa proses bayi tabung pada penelitian diperbolehkan?
5. Apakah penelitian khusus membuat embrio untk digunakan diperbolehkan?
Isu bioetika utama dalam penelitian dan penggunaan stem cell adalah penggunaan
stem cell embrio terutama tentang sumber sel tersebut yaitu embrio. Sumber embrio

adalah hasil abortus, zigot sisa IVF dan hasil pengklonan. Pengklonan embrio manusia
untuk memperoleh stem cell merupakan isu yang sangat menimbulkan kontroversi. Hal
ini terkait dengan isu awal kehidupan dan penghormatan terhadap kehidupan.
Pengklonan embrio manusia untuk memperoleh stem cell menimbulkan kontroversi
karena berhubungan dengan pengklonan manusia yang ditentang oleh semua agama.
Dalam proses pemanenan stem cell embrio terjadi kerusakan pada embrio dan
menyebabkan embrio tersebut mati. Adanya anggapan bahwa embrio berstatus sama
dengan manusia menyebabkan hal tersebut tidak dapat diterima
Perdebatan yang cukup ramai adalah mengenai status moral embrio, apakah embrio
harus diperlakukan sebagai manusia atau sebagai sesuatu yang berpotensi untuk menjadi
manusia atau sebagai jaringan hidup tubuh lainnya. Lebih jauh lagi apakah embrio yang
berkembang dianggap sebagai mahluk hidup.
Penggunaan stem cell yang berasal dari surplus zigot pembuatan bayi tabung sendiri.
juga menimbulkan kontroversi. Pendapat yang moderat mengatakan ketimbang surplus
zigot itu dibuang, sebaiknya dipakai saja untuk penelitian. Sebaliknya ada juga yang
berpendapat bahwa sisa itu harus dipelihara hingga zigot itu mati.
KEPUSTAKAAN
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neural phenotypes and ameliorate neurological deficits after grafting into the
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CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery
after recent myocardial infarction. Circulation 2005; 112 (9 suppl): 78-83
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degeneratif. Cermin Dunia Kedokteran 2006; 153: 5-8
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2006; 153: 9-12.
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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.
back to article

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.
back to article

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.
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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. 215233.
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.

25. Thomas, K.R., Capecchi, M.R. (1987) Site-directed Mutagenesis by Gene

Targeting in Mouse Embryo-derived Stem Cells. Cell 51, 503-512.; Koller, B.H.,
Hageman, L.J., Doetschman, T.C., Hagaman, J.R., Huang, S., Williams, P.J., et. al.
(1989) Proc. Natl. Acad. Sci. USA 86, 8924-8931.
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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. 347379.
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.
37. http://stemcells.nih.gov/info/scireport/chapter7.asp; Street, C.N., Sipione, S.,
Helms, L., Binette, T., Rajotte, R.V., Bleackley, R.C., Korbutt, G.S. (2004) Stem

Cell-based Approaches to Solving the Problem of Tissue Supply for Islet

Transplantation in Type I Diabetes. Intl. J. Biochem. Cell Biol. 36, 667-683.
38. Bouwens, L. (2004) Islet Cells. Stem Cell Handbook ed. by Sell, S. 429-438.
39. Seaberg, R.M., Smukler, S.R., Kieeffer, T.J., Enikolopov, G., Asghar, Z., Wheeler
M.B., Korbutt, G., van der Kooy, D. (2004) Clonal Identification of Multipotent
Precursors from Adult Mouse Pancreas that Generate Neural and Pancreatic
Lineages. Nat. Biotechnol. 22, 1115-1124.; SeNakajima-Nagata, N., Sakurai, T.,
Mitaka, T., Katakai, T., Yamaot, E., Miyazaki, J., Tabata, Y., Sugai, M., Shimzu,
A.. (2004) In vitro Induction of Adult Hepatic Progenitor Cells into Insulinproducing Cells. Biochem. Biophys. Res. Commun. 318, 625-630.
40. http://www.parkinson.org/site/pp.asp?c=9dJFJLPwB&b=71125
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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 6Hydroxy-Dopamine Lesioned Rats after Transplantation of Differentiated Mouse
Embryonic Stem Cells without Morphological Integration. Stem Cells 22, 396404.
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.,
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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,
pp. A01.

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 embryoapproximately four to five days old in humans and
consisting of 50150 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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