The term stem cell includes a large class of cells defined by their ability to give rise to various mature progeny while maintaining the capacity to self-renew. Embryonic stem cells (ESCs) were first isolated from the inner mass of late blastocysts in mice by Sir Martin J. Evans and Matthew Kaufman (Evans & Kaufman, 1981) and independently by Gail R. Martin (Martin, 1981). Later, it became possible to obtain ESCs from non-human primates and humans. In 1998, James Thomson and his team reported the first successful derivation of human ESC lines (Thomson
Embryonic stem cells are pluripotent, a term that defines the ability of a cell to differentiate into cells of all three germ layers. There are different types of mammalian pluripotent stem cells: embryonic stem cells derived from pre-implantation embryos (Evans & Kaufman, 1981), embryonic carcinoma (EC) cells, the stem cells of testicular tumors (Stevens, 1966; Evans, 1972), epiblast stem cells (EpiSCs) derived from the late epiblast layer of post-implantation embryos (Brons
Besides isolating pluripotent cells from different embryonic tissues, various experimental methods are available nowadays for inducing pluripotency
By using various biological reagents (e.g. growth factors) (Schuldiner
2. Treatment of eye diseases
Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Age-related macular degeneration (AMD) is a late-onset, complex disorder of the eye with a multi-factorial etiology in elderly (Katta
Restoration of vision has focused up to now on transplantation of neural progenitor cells (NPCs) and retinal pigmented epithelium (RPE) to the retina. The retinal pigment epithelium (RPE) is a monolayer of pigmented cells forming a part of the blood/retina barrier and plays crucial roles in the maintenance and function of the retina and its photoreceptors (Strauss, 2005). The apical membrane of the RPE is associated with the rod and cone photoreceptors of the retina. The basal side of the RPE faces Bruch’s membrane, thereby separating the NR from the blood. The RPE absorbs light energy to increase visual sensitivity and protect against photooxidation, transports nutrients and ions between the photoreceptors at its apical surface and the choriocapillaries at its basal surface, phagocytoses photoreceptor outer segments, according to a daily circadian cycle, to relieve the photoreceptors of light-induced free radicals. The RPE secretes a variety of growth factors, such as the neuroprotective-antiangiogenic pigment epithelium-derived factor (PEDF) which is released to the neural retina, and the vasoprotective-angiogenic vascular endothelial growth factor (VEGF) that is secreted to the choroid (Layer
2.1. Preclinical work
Cell transplantation is a novel therapeutic strategy to restore visual responses. Human embryonic stem cells (hESCs) may serve as an unlimited source of RPE cells and photoreceptors for transplantation in different blinding conditions.
hESC studies have focused on the derivation of subsets of retinal cell populations (Meyer
Several groups have demonstrated that differentiating hESCs mimic the stepwise development of retinal cells
So far, it has been shown that transplanted postmitotic photoreceptor precursors are able to functionally integrate into the adult mouse neural retina. However, photoreceptors are neurons and they need to form synaptic connections in order to be functional. This makes the cell therapy with photoreceptors more challenging when compared to RPE cells. Interestingly, a group from Japan (Eiraku
2.2. Clinical trial
Until shortly, the most relevant clinical studies currently being conducted in patients with retinal degeneration were fetal retinal sheet transplants (Radtke
Advanced Cell Technology and Jules Stein Eye Institute at UCLA started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of human ESC-derived retinal pigment epithelium (RPE) in patients with Stargardt’s macular dystrophy (clinical trial identifier-NCT01469832) and dry age-related macular degeneration (clinical trial identifier-NCT01344993) — the leading cause of blindness in the developed world (Schwartz
One of the rationales behind using the eye for cell therapy is that the eye represents an immunoprivileged site. The failure of the immune system to elicit an immune response in this and other such sites constitutes the hallmark of the immune privilege status (Hori
Two patients enrolled in the clinical trial in order to test the safety of such cell transplantations. 50 000 viable RPE cells differentiated from the hESC line MA09 (Klimanskaya
This is the first peer reviewed study that uses human ESCs for cell therapy. Although their report is preliminary, in only two patients, and with a short-term follow-up, the results are impressive - especially considering the progressive nature of both diseases (Atala, 2012).
3. Treatment of spinal cord injury
More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical care. Published incidence rates for traumatic spinal-cord injury in the USA range between 28 and 55 per million people, with about 10 000 new cases reported every year. Causes include motor vehicle accidents (36–48%), violence (5–29%), falls (17–21%), and recreational activities (7–16%) (McDonald & Sadowsky, 2002). The primary injury (the initial insult) is usually due to the mechanical trauma and includes traction and compression forces. Neural elements are compressed by fractured and displaced bone fragments, disc material, and ligaments and leads to injuries on both the central and peripheral nervous systems. Blood vessels are damaged, axons disrupted and cell membranes broken. Micro-haemorrhages occur within minutes in the central grey matter and spread out over the next few hours. Within minutes, the spinal cord swells to occupy the entire diameter of the spinal canal at the injury level. Secondary ischaemia results when cord swelling exceeds venous blood pressure. The more destructive phase of secondary injury is, however, more responsible for cell death and functional deficits. Hemorrhage, edema, ischaemia, release of toxic chemicals from disrupted neural membranes, and electrolyte shifts trigger a secondary injury cascade that substantially compounds initial mechanical damage by harming or killing neighbouring cells (McDonald & Sadowsky, 2002). Glutamate plays a key part in a highly disruptive process known as excitotoxicity. It was demonstrated that glutamate, released during injury, damages oligodendocytes (Domercq
There are many repair strategies in spinal cord injury, as prevention of cell death by anti-glutamatergic drugs, promotion of axonal regeneration, compensation of the lost myelination or cell replacement therapy (McDonald
3.1. Differentiation to oligodendrocytes
As mentioned before in the case of spinal cord injury, diseases of the nervous system involve proliferation of astrocytes and loss of oligodendrocytes (OLN) and the protective myelin sheath they produce. Transplantation of oligodendrocyte precursors in different animals systems show that these precursors can myelinate axons (Groves
Oligodendrocytes were first efficiently derived from mouse ESCs (Brustle
The first detailed protocol for directed differentiation of oligodendrocytes from human ESCs was published in 2005 and involved the induction of neural lineage by retinoic acid treatment, followed by expansion and selection in various media containing the differentiation factors triiodothyroidin hormone, FGF2, EGF, and insulin (Nistor
3.2. Clinical trial
In October 2010 the world's first clinical trial using human embryonic stem cells began, using ESCs converted into OLN precursor cells. The feasibility of the treatment was proofed by a wide range of pre-clinical studies that have shown that human oligodendrocyte progenitor cells implanted after spinal cord injury in rodent models show functional improvement (Keirstead, 2005; Keirstead
The trial was planned to involve treating ten patients who have suffered a complete thoracic-level spinal cord injury in a phase 1 multicenter trial. The pioneering therapy is Geron's 'GRNOPC1 product', which contains hES cell–derived oligodendrocyte progenitor cells that have demonstrated remyelinating and nerve growth–stimulating properties. In the human SCI lesion site, it is hoped that OLN precursors will work as a "combination therapy" - phenotypically replacing lost oligodendrocytes and hence remyelinating axons that have become demyelinated during injury, as well as secreting neurotrophic factors to establish a repair environment in the lesion (Hatch
4. Embryonic stem cells and tumorigenesis
The major safety concerns for the use of hESCs are related to the achievement of xenobiotic-free culture conditions, avoidance of genetic abnormalities, development of good differentiation and selection protocols, and the avoidance of the immune rejection. Moreover, the unlimited proliferative capacity of ESCs is a disadvantage in clinical applications because this could cause tumor formation upon transplantation. When implanted in an undifferentiated state, ESCs cause teratoma, a tumor type that consists of different kinds of differentiated cells. Teratomas are encapsulated, usually benign tumors that can occur naturally, but there is the fear, based on some animal studies, that some proportion of the cells derived from ESCs injected into the body could drift from their intended developmental pathway. Teratoma formation was reported in various cases when mouse ESCs-derived cells like insulin producing islets (Fujikawa
The simplest way to slow or even eliminate the tumorigenicity of normal stem cells prior to transplantation may be to take advantage of pluripotency by partially differentiating them into progenitors. Therefore, a promising proposed method for making stem cell-based regenerative medicine therapies safer may seem paradoxical: to not transplant stem cells at all into patients. The idea is to use the stem cells to produce progenitor or precursor cells of the desired lineage and then transplant progenitors purified by sorting (Knoepfler, 2009). This approach was presented in this chapter and is actually used in the clinical trial with oligodendrocyte progenitor cells. However, not only the embryonic stem cells, but also the implanted precursor cells seem to form teratoma in some cases. A group of Israeli researchers reported that a boy with ataxia telangiectasia who had received several fetal neural stem cell transplants developed teratomas in his brain and spinal cord four years after treatment (Amariglio
Currently, the only way to ensure that teratomas do not form is to differentiate the ESCs in advance, enrich for the desired cell type, and screen for the presence of undifferentiated cells. The elimination of undifferentiated hESCs may best be achieved by (1) destroying the remaining undifferentiated hESCs in the differentiated tissue population with specific agents or antibodies, (2) separating or removing the undifferentiated hESCs from the differentiated cell population, (3) eliminating pluripotent cells during the differentiation process, and (4) inducing further differentiation of left-over rogue undifferentiated hESCs (Bongso
5. Embryonic stem cells versus induced pluripotent stem cells in clinics
Induced pluripotent cells (iPS) are generated by re-engineering mature, fully differentiated cells (e.g. human skin fibroblasts) by modifying the cells with a set of transgenes (Takahashi & Yamanaka, 2006; Takahashi
During the last years various studies reported the differentiation of iPS cells to various types of cells in vitro and these cells were used for cellular therapy in various mouse models (Wernig
However, before bringing these cells into the clinics, their safety should be tested. For example, the initial enthusiasm related to bringing iPS cells into clinics dampened when it was shown that these cells develop teratoma more efficiently than ESCs (Gutierrez-Aranda
There is no doubt that after the hurdles are overcome, hESC-derived cells have a promising future for transplantation therapy given the versatility of these cells. It is very encouraging to see that clinical trials involving the use of hESCs have begun, and that extensive efforts are underway to efficiently, and safely differentiate hESCs into specific cell types.
I would like to thank Paul G. Layer for carefully reading the manuscript.
Alge, C.S., Suppmann, S., Priglinger, S.G., Neubauer, A.S., May, C.A., Hauck, S., Welge-Lussen, U., Ueffing, M. & Kampik, A. (2003) Comparative proteome analysis of native differentiated and cultured dedifferentiated human RPE cells. , 44, 3629-3641.
Alper, J. (2009) Geron gets green light for human trial of ES cell-derived product. , 27, 213-214.
Amariglio, N., Hirshberg, A., Scheithauer, B.W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., Paz, N., Koren-Michowitz, M., Waldman, D., Leider-Trejo, L., Toren, A., Constantini, S. & Rechavi, G. (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. , 6, e1000029.
Atala, A. (2012) Human embryonic stem cells: early hints on safety and efficacy. , 379, 689-690.
Banin, E., Obolensky, A., Idelson, M., Hemo, I., Reinhardtz, E., Pikarsky, E., Ben-Hur, T. & Reubinoff, B. (2006) Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. , 24, 246-257.
Ben-Hur, T., Idelson, M., Khaner, H., Pera, M., Reinhartz, E., Itzik, A. & Reubinoff, B.E. (2004) Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. , 22, 1246-1255.
Bielby, R.C., Boccaccini, A.R., Polak, J.M. & Buttery, L.D. (2004) In vitro differentiation and in vivo mineralization of osteogenic cells derived from human embryonic stem cells. , 10, 1518-1525.
Bongso, A., Fong, C.Y. & Gauthaman, K. (2008) Taking stem cells to the clinic: Major challenges. , 105, 1352-1360.
Bracken, M.B., Shepard, M.J., Collins, W.F., Holford, T.R., Young, W., Baskin, D.S., Eisenberg, H.M., Flamm, E., Leo-Summers, L., Maroon, J. & et al. (1990) A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. , 322, 1405-1411.
Brons, I.G., Smithers, L.E., Trotter, M.W., Rugg-Gunn, P., Sun, B., Chuva de Sousa Lopes, S.M., Howlett, S.K., Clarkson, A., Ahrlund-Richter, L., Pedersen, R.A. & Vallier, L. (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. , 448, 191-195.
Brustle, O., Jones, K.N., Learish, R.D., Karram, K., Choudhary, K., Wiestler, O.D., Duncan, I.D. & McKay, R.D. (1999) Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 285, 754-756.
Cao, F., Lin, S., Xie, X., Ray, P., Patel, M., Zhang, X., Drukker, M., Dylla, S.J., Connolly, A.J., Chen, X., Weissman, I.L., Gambhir, S.S. & Wu, J.C. (2006) In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. , 113, 1005-1014.
Do, J.T., Han, D.W. & Scholer, H.R. (2006) Reprogramming somatic gene activity by fusion with pluripotent cells. , 2, 257-264.
Domercq, M., Etxebarria, E., Perez-Samartin, A. & Matute, C. (2005) Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition. , 52, 36-46.
Domercq, M., Sanchez-Gomez, M.V., Areso, P. & Matute, C. (1999) Expression of glutamate transporters in rat optic nerve oligodendrocytes. , 11, 2226-2236.
Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., Sekiguchi, K., Adachi, T. & Sasai, Y. (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. , 472, 51-56.
Evans, M.J. (1972) The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. , 28, 163-176.
Evans, M.J. & Kaufman, M.H. (1981) Establishment in culture of pluripotential cells from mouse embryos. , 292, 154-156.
Fehlings, M.G. & Vawda, R. (2011) Cellular treatments for spinal cord injury: the time is right for clinical trials. , 8, 704-720.
Fong, C.Y., Gauthaman, K. & Bongso, A. (2010) Teratomas from pluripotent stem cells: A clinical hurdle. , 111, 769-781.
Fujikawa, T., Oh, S.H., Pi, L., Hatch, H.M., Shupe, T. & Petersen, B.E. (2005) Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. , 166, 1781-1791.
Gamm, D.M. & Meyer, J.S. (2010) Directed differentiation of human induced pluripotent stem cells: a retina perspective. , 5, 315-317.
Groves, A.K., Barnett, S.C., Franklin, R.J., Crang, A.J., Mayer, M., Blakemore, W.F. & Noble, M. (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. , 362, 453-455.
Gutierrez-Aranda, I., Ramos-Mejia, V., Bueno, C., Munoz-Lopez, M., Real, P.J., Macia, A., Sanchez, L., Ligero, G., Garcia-Parez, J.L. & Menendez, P. (2010) Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. , 28, 1568-1570.
Hatch, M.N., Nistor, G. & Keirstead, H.S. (2009) Derivation of high-purity oligodendroglial progenitors. , 549, 59-75.
Hori, J., Vega, J.L. & Masli, S. (2010) Review of ocular immune privilege in the year 2010: modifying the immune privilege of the eye. , 18, 325-333.
Idelson, M., Alper, R., Obolensky, A., Ben-Shushan, E., Hemo, I., Yachimovich-Cohen, N., Khaner, H., Smith, Y., Wiser, O., Gropp, M., Cohen, M.A., Even-Ram, S., Berman-Zaken, Y., Matzrafi, L., Rechavi, G., Banin, E. & Reubinoff, B. (2009) Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. , 5, 396-408.
Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H. & Benvenisty, N. (2000) Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. , 6, 88-95.
Karadottir, R. & Attwell, D. (2007) Neurotransmitter receptors in the life and death of oligodendrocytes. , 145, 1426-1438.
Karadottir, R., Cavelier, P., Bergersen, L.H. & Attwell, D. (2005) NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. , 438, 1162-1166.
Katta, S., Kaur, I. & Chakrabarti, S. (2009) The molecular genetic basis of age-related macular degeneration: an overview. , 88, 425-449.
Kawasaki, H., Mizuseki, K., Nishikawa, S., Kaneko, S., Kuwana, Y., Nakanishi, S., Nishikawa, S.I. & Sasai, Y. (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. , 28, 31-40.
Keirstead, H.S. (2005) Stem cells for the treatment of myelin loss. , 28, 677-683.
Keirstead, H.S., Nistor, G., Bernal, G., Totoiu, M., Cloutier, F., Sharp, K. & Steward, O. (2005) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. , 25, 4694-4705.
Klimanskaya, I., Chung, Y., Becker, S., Lu, S.J. & Lanza, R. (2006) Human embryonic stem cell lines derived from single blastomeres. , 444, 481-485.
Klimanskaya, I., Hipp, J., Rezai, K.A., West, M., Atala, A. & Lanza, R. (2004) Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. , 6, 217-245.
Knoepfler, P.S. (2009) Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. , 27, 1050-1056.
Laflamme, M.A., Zbinden, S., Epstein, S.E. & Murry, C.E. (2007) Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. , 2, 307-339.
Layer P.G., Araki, M. & Vogel-Höpker, A. (2010) New concepts for reconstruction of retinal and pigment epithelial tissues. Expert Review of Ophthalmology, 5, No. 4, 523-543.
Lamba, D.A., Karl, M.O., Ware, C.B. & Reh, T.A. (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. , 103, 12769-12774.
Learish, R.D., Brustle, O., Zhang, S.C. & Duncan, I.D. (1999) Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin. , 46, 716-722.
Martin, G.R. (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 78, 7634-7638.
Matsui, Y., Zsebo, K. & Hogan, B.L. (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. , 70, 841-847.
McDonald, J.W., Becker, D., Sadowsky, C.L., Jane, J.A., Sr., Conturo, T.E. & Schultz, L.M. (2002) Late recovery following spinal cord injury. Case report and review of the literature. , 97, 252-265.
McDonald, J.W. & Sadowsky, C. (2002) Spinal-cord injury. , 359, 417-425.
Meyer, J.S., Shearer, R.L., Capowski, E.E., Wright, L.S., Wallace, K.A., McMillan, E.L., Zhang, S.C. & Gamm, D.M. (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. , 106, 16698-16703.
Murry, C.E. & Keller, G. (2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. , 132, 661-680.
Neman, J. & de Vellis, J. (2012) A method for deriving homogenous population of oligodendrocytes from mouse embryonic stem cells. , 72, 777-788.
Niederkorn, J.Y. (2002) Immune privilege in the anterior chamber of the eye. , 22, 13-46.
Nistor, G.I., Totoiu, M.O., Haque, N., Carpenter, M.K. & Keirstead, H.S. (2005) Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. , 49, 385-396.
Noggle, S., Fung, H.L., Gore, A., Martinez, H., Satriani, K.C., Prosser, R., Oum, K., Paull, D., Druckenmiller, S., Freeby, M., Greenberg, E., Zhang, K., Goland, R., Sauer, M.V., Leibel, R.L. & Egli, D. (2011) Human oocytes reprogram somatic cells to a pluripotent state. , 478, 70-75.
Osakada, F., Ikeda, H., Mandai, M., Wataya, T., Watanabe, K., Yoshimura, N., Akaike, A., Sasai, Y. & Takahashi, M. (2008) Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. , 26, 215-224.
Prokhorova, T.A., Harkness, L.M., Frandsen, U., Ditzel, N., Schroder, H.D., Burns, J.S. & Kassem, M. (2009) Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel. , 18, 47-54.
Radtke, N.D., Aramant, R.B., Petry, H.M., Green, P.T., Pidwell, D.J. & Seiler, M.J. (2008) Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. , 146, 172-182.
Reubinoff, B.E., Itsykson, P., Turetsky, T., Pera, M.F., Reinhartz, E., Itzik, A. & Ben-Hur, T. (2001) Neural progenitors from human embryonic stem cells. , 19, 1134-1140.
Richards, M., Fong, C.Y., Chan, W.K., Wong, P.C. & Bongso, A. (2002) Human feeders support prolonged undifferentiated growth of human inner cell masses and embryonic stem cells. , 20, 933-936.
Rowland, T.J., Buchholz, D.E. & Clegg, D.O. (2012) Pluripotent human stem cells for the treatment of retinal disease. , 227, 457-466.
Roy, N.S., Cleren, C., Singh, S.K., Yang, L., Beal, M.F. & Goldman, S.A. (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. , 12, 1259-1268.
Saha, K. & Jaenisch, R. (2009) Technical challenges in using human induced pluripotent scells to model disease. , 5, 584-595.
Schuldiner, M., Eiges, R., Eden, A., Yanuka, O., Itskovitz-Eldor, J., Goldstein, R.S. & Benvenisty, N. (2001) Induced neuronal differentiation of human embryonic stem cells. , 913, 201-205.
Schuldiner, M., Yanuka, O., Itskovitz-Eldor, J., Melton, D.A. & Benvenisty, N. (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. , 97, 11307-11312.
Schwartz, S.D., Hubschman, J.P., Heilwell, G., Franco-Cardenas, V., Pan, C.K., Ostrick, R.M., Mickunas, E., Gay, R., Klimanskaya, I. & Lanza, R. (2012) Embryonic stem cell trials for macular degeneration: a preliminary report. , 379, 713-720.
Sharp, J., Frame, J., Siegenthaler, M., Nistor, G. & Keirstead, H.S. (2010) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. , 28, 152-163.
Shih, C.C., Forman, S.J., Chu, P. & Slovak, M. (2007) Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice. , 16, 893-902.
Stevens, L.C. (1966) Development of resistance to teratocarcinogenesis by primordial germ cells in mice. , 37, 859-867.
Stewart, C.L., Gadi, I. & Bhatt, H. (1994) Stem cells from primordial germ cells can reenter the germ line. , 161, 626-628.
Strauss, O. (2005) The retinal pigment epithelium in visual function. , 85, 845-881.
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. & Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. , 131, 861-872.
Takahashi, K. & Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. , 126, 663-676.
Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. & Jones, J.M. (1998) Embryonic stem cell lines derived from human blastocysts. , 282, 1145-1147.
Turovets, N., Semechkin, A., Kuzmichev, L., Janus, J., Agapova, L. & Revazova, E. (2011) Derivation of human parthenogenetic stem cell lines. , 767, 37-54.
Watson, R.A. & Yeung, T.M. (2011) What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury? , 11, 113.
Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., Broccoli, V., Constantine-Paton, M., Isacson, O. & Jaenisch, R. (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. , 105, 5856-5861.
Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J. & Campbell, K.H. (1997) Viable offspring derived from fetal and adult mammalian cells. , 385, 810-813.
Zhang, S.C., Wernig, M., Duncan, I.D., Brustle, O. & Thomson, J.A. (2001) In vitro differentiation of transplantable neural precursors from human embryonic stem cells. , 19, 1129-1133.