Induced pluripotent stem cells and regenerative medicine

  • Abstract
  • Full Text
  • References

Abstract

Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke, and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells, reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases.

Keywords:

Stem cells, Embryonic stem cell, Induced pluripotent stem cell, Regenerative medicine

Article Outline

  1. Introduction
  2. Comparison of iPS cells with ES cells
  3. Advances in reprogramming techniques
  4. Reactive oxygen species and stem cells differentiation
  5. Clinical application of iPS cells
  6. Summary
  7. References

Abstract

Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke, and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells, reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases.

Keywords:

Stem cells, Embryonic stem cell, Induced pluripotent stem cell, Regenerative medicine

1. Introduction

Stem cells are classified into three types according to their abilities to differentiate. The first type is totipotent stem cells, which can be implanted in the uterus of a living animal and give rise to a full organism. The second type is pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. They can give rise to every cell of an organism except extraembryonic tissues, such as placenta. This limitation restricts pluripotent stem cells from developing into a full organism. The third type is multipotent stem cells. They are adult stem cells, which only generate specific lineages of cells.1 ES cells are pluripotent stem cells derived from the inner cell mass of mammalian blastocysts. They have remarkable abilities to proliferate indefinitely under appropriate in vitro culture system and to differentiate into any cell types of all three germ layers.2,3 Since isolation of human ES in 1998, ES cells have been regarded as a powerful platform or tool for developmental studies, drug screening, diseases treatment, tissue repair engineering, and regenerative medicine. However, two main limitations have impeded the application of ES cell-based therapy. First, ethical dilemma regarding the human embryo donation and destruction. Second, ES cells are incompatible with the immune system of patients. To circumvent these deficiencies, scientists worldwide have devoted to developing a variety of reprogramming techniques to reverse somatic cells into a stem cell-like state.4 In 2006, Takahashi and Yamanaka5 published a landmark discovery that reprogramming of somatic cells back to iPS cells could be achieved by retroviral transduction of four pluripotency-associated transcription factors—Oct3/4, Sox2, c-Myc, and Klf4. These iPS cells possessed morphological and molecular features that resemble those of ES cells, as well as gave rise to teratoma and germline-competent chimeras on injection into blastocysts. This amazing finding showed that cell fate could be manipulated by certain genes and was recently honored by many awards, including 2009’s Albert Lasker Basic Medical Research Award and 2010’s International Balzan Prize. Since this astonishing report, iPS cells are now generated by various ways, including kinds of exogenous genes delivery methods,6,7,8,9,10 choosing multiple somatic cell sources,11,12,13,14,15 and even by small compounds16 to improve the efficiency of the reprogramming process.

2. Comparison of iPS cells with ES cells

Generally, fully reprogrammed iPS cells display numerous properties similar to those of ES cells. First of all, iPS cells are morphologically identical to ES cells and show infinite proliferation and self-renewal abilities. Several molecular and functional assays were set to evaluate the similarity of iPS cells to ES cells, including reactivation of self-renewal and pluripotency-associated genes, telomerase activity, X chromosome, and stage-specific embryonic surface antigens, suppression of somatic genes associated with cell of origin, silencing of exogenous factors, capabilities of in vitro differentiation, demethylation of promoters of pluripotency genes, and in vivo teratoma formation, chimera contribution, germline transmission, and tetraploid complementation.7,17 A recent study demonstrated that patient-specific iPS cells from dermal fibroblasts of patients with long QT syndrome can differentiate into functional cardiac myocytes but still recapitulated the electrophysiological features of the disorder.18 Therefore, the major advantage of iPS cells over ES cells is that iPS cells can be derived from a patient’s own somatic cells, thereby avoiding immune rejection after transplantation and the ethical concerns raised by using ES cells.

3. Advances in reprogramming techniques

Based on their pluripotent capability of differentiating into any functional cell type, iPS cells possess great potential for regenerative and therapeutic applications. However, the group led by Dr. Yamanaka also reported that these chimeras derived from mouse iPS cells and their progeny often develop tumors mainly because of reactivation of c-Myc transgene.19 Thus, numerous approaches to generate iPS cells with lower tumorigenicity have been established. Several studies have shown that iPS cells generated without c-Myc virus demonstrated reduced tumor incidence in chimeric mouse, but the efficiency of iPS creation is significantly reduced.20,21 To overcome this dilemma, Nakagawa et al.22 found another member of Myc, L-Myc, which possessed stronger activity to generate iPS cells and less tumorigenic activity.

The use of genome-integrating retroviruses that are closely related with tumor formation was another major limitation of the original iPS cell generation techniques. Thus, reprogramming strategies with nonintegrating systems seems to be solutions to make iPS-based therapy feasible. In 2008, Stadtfeld et al.23 established mouse iPS cells from fibroblasts and liver cells by nonintegrating adenoviruses carrying four defined factors, suggesting that insertional mutagenesis is not required for in vitro reprogramming. At the same time, Okita et al.24 successfully generated iPS cells by transient transfection of two plasmids containing cDNAs encoding four factors, eliminating transgenic integration by the use of retroviruses. More recently, Somers et al.25 and Carey et al.26 individually described a “stem cell cassette” or a polycistronic virus, a single lentiviral vector composed of all four factors, was able to yield iPS with reduced insertional mutagenesis and viral reactivation. Another novel reprogramming technique using piggyBac transposon was published.9,10,27 A polycistronic plasmid harboring four factors and piggyBac transposon was constructed and integrated into the genome in the presence of piggyBac transposase. As the reprogramming process achieved, the inserted fragment was easily removed by reexpressing transposase. The transposon-based method eliminates the use of virus, displays equivalent efficiencies to retroviral transduction, excises integrated sequences without genome alteration, and therefore represents a landmark progress toward therapeutically relevant virus-free iPS cells. To avoid introducing exogenous genetic materials, two amazing advances were reported. Zhou et al.28 demonstrated that mouse fibroblasts could be fully reprogrammed by direct delivery of recombinant reprogramming proteins. In 2010, an impressive work conducted by Warren et al.29 showed a strategy for reprogramming by administration of synthetic mRNAs that code for key factors and created RNA-iPS cells. Both techniques are safer, simpler, and faster approaches than the currently established genetic method.

4. Reactive oxygen species and stem cells differentiation

High efficiency of iPS cells reprogramming/differentiation is required in clinical application. Many studies have reported that reactive oxygen species (ROS) play a critical role in mediating iPS cells or stem cells reprogramming/differentiation.30,31 Intracellular ROS serves as a second messenger in signaling transduction pathways. They are produced in vascular cells by a number of oxidases, such as the NADPH oxidases and xanthine oxidase, lipoxygenases, cytochrome p450, and uncoupling of the mitochondrial respiratory chain.32 iPS cells have similar function in stress defense mechanisms and mitochondrial regulation with human ES cells.33 Francisco et al.34 had revealed that high glucose promoted stem cell differentiation into cardiomyocyte by activating NADPH oxidase as well as increasing intracellular ROS level. Ji et al.35 had reported ROS-enhanced stem cell differentiation via mediating extracellular signal-regulated kinase/c-Jun N-terminal kinase, P38 mitogen-activated protein kinase, and protein kinase B. Furthermore, Varum et al.36 had shown that attenuating the mitochondrial respiratory chain can increase pluripotency in human ES cells by facilitating intracellular ROS generation. Moreover, generation of ROS and the activities of antioxidant enzymes must be mainly manipulated to preserve the homeostasis of the intracellular redox status. Intracellular antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, play an important role to mitigate oxidative stress, such as SODs protect against superoxide-mediated cytotoxicity by catalyzing O2 to form H2O2. SOD is inactivated by H2O2 formed by repressing of the superoxide anion.37 Not only ROS level is activated but also intracellular antioxidant enzymes are mediated during differentiation. Chen et al.38 had validated that intracellular antioxidant enzymes, mitochondrial mass, as well as oxygen consumption rate were increased during differentiation in human mesenchymal stem cells.

5. Clinical application of iPS cells

5.1. iPS cells in the diseases of central nervous system

The development of stem cell studies makes cell transplantation a promising therapy for the diseases of central nervous system, including stroke, traumatic brain injury, hypoxic encephalopathy, and degenerative disorders.39 Parkinson’s disease (PD) is the best candidate for the cell replacement therapy because only one group of cells are affected, which are dopaminergic neurons. The main pathology of PD is cellular loss of the substantia nigra pars compacta dopaminergic neurons that project to the striatum.40 Clinical signs of PD, which include rest tremor, rigidity, and bradykinesia, are evident when about 80% of striatal and 50% of nigral neurons are lost.41 The first attempt of cell replacement therapy was to use fetal mesencephalic tissue, and the results were successful in the earliest reports.39,42,43 However, adverse effects and limitations were revealed in the following studies, which included off-medication dyskinesia,44,45,46 graft-induced inflammatory responses,47 and limited tissue availability.39

Graft-induced dyskinesia may be caused by unfavorable composition of the fetal mesencephalic grafts. The fetal mesencephalic tissue includes not only dopaminergic but also nondopaminergic neurons.39 The exclusion of serotonin and γ-aminobutyric acid neurons and enrichment of substantia nigra dopaminergic neurons will decrease the occurrence of dyskinesia.47 Stem cells are ideal cell sources to achieve this goal. Recent evidence has shown that dopaminergic neurons derived from ES cells and bone marrow-derived neural progenitors are functional when grafted into parkinsonian rats.48,49 Several methods are able to improve the effectiveness of midbrain dopaminergic neuron generation from stem cells, including manipulating transcription factor (e.g., Nurr1, Pitx3, or Lmx1a), coculture with astrocytes, and using fluorescence-activated cell sorting.47 The ability of deriving large quantities of correctly differentiated dopamine neurons makes stem cells a good cell sources for transplantation in PD.

Cell replacement therapy is more complicated for stroke, brain injury, and other degenerative diseases, such as Alzheimer’s disease. The difficulties are because of variable cell types involved, which include neurons, astrocytes, oligodendrocytes, and endothelial cells of blood vessels.50 ES cells have been demonstrated to have good developmental potential and significant survival rate after transplantation into the brain.51 Transplantation of ES cells also recovered behavioral dysfunction induced by middle cerebral arterial occlusion in an animal model.52 However, the ethical consideration, the limited availability, and the possibility of immune rejection after transplantation restrict the accessibility of ES cells.

Because iPS cells are derived from the somatic cells, potential immune rejection and ethical consideration can be avoided. Recently, Wernig et al.53 demonstrated that neurons and glial cells could be derived from iPS cells in vitro, and that transplantation of iPS cell-derived neurons into brain was able to improve behavior in a rat model of PD. We also demonstrated an efficient method to differentiate iPS cells into astrocyte-like and neuron-like cells, which displayed functional electrophysiological properties. Our in vivo study showed that direct injection of iPS cells into damaged areas of rat cortex significantly decreased the infarct size, improved the motor function, attenuated inflammatory cytokines, and mediated neuroprotection after middle cerebral artery occlusion. Subdural injection of iPS cells with fibrin glue was as effective as the direct-injection method and provided a safer choice for cell replacement therapy.54

Teratoma or tumor formation is a major adverse effect of cell transplantation using ES or iPS cells.55 One of the methods to prevent teratoma/tumor formation is elimination of nonneural progenitors, which can be achieved by the elaboration of differentiation protocols that allow maximal homogeneity of the transplant56 or by cell sorting before transplantation.57 Exclusion of poorly differentiated ES or iPS cells can also reduce the rate of teratoma or tumor formation.58 Some antioxidants may prevent tumorigenesis after cell transplantation. Resveratrol, a natural polyphenol antioxidant, is demonstrated that it can inhibit teratoma formation in vivo.59 Our recent study also found that docosahexaenoic acid can inhibit teratoma formation in addition to promoting dopaminergic differentiation in iPS cells in PD-like rats.60 It has been only two years since the development of iPS cells. Enhancement of effectiveness and eliminating adverse effects of this cell transplantation therapy required more extensive studies.

5.2. iPS cells in cardiovascular diseases

In the aging population of a modern world, cardiovascular diseases are major medical problems because they usually cause morbidity and mortality.1 The treatments of cardiovascular diseases include medication, surgical intervention, rehabilitation, exercise programs, and transplantation.61 There are several side effects, complications, and limitations of transplantation therapy, such as immunological reaction, infection, and limited availability.62 A new hope in cardiovascular regenerative medicine has been revealed since Doetschman et al.63 successfully induced mouse ES cells differentiating into cardiomyocytes in vitro in 1985. Many studies had reported facilitated differentiation from ES cells or iPS cells into cardiomyocytes, endothelial vascular cells, and smooth muscle cells.64,65 In animal models, cardiovascular regeneration therapy markedly attenuated ventricular wall thinning as well as enhanced contractility of cardiomyocytes postligation of the left anterior descending artery,66 restored the function of heart and electric stability after myocardial infarction,67 and enriched the formation of small capillaries and venules.68

5.3. iPS cells in lung diseases

Acute lung injury (ALI) is characterized by neutrophil accumulation in the lungs, interstitial edema, disruption of epithelial integrity, and leakage of proteins into the alveolar space.69,70,71,72 Infection, associated with endotoxemia and blood loss are frequent predisposing factors to the development of ALI69; and in experimental settings, endotoxemia produces ALI. Neutrophils play a central role in this acute pulmonary inflammatory process as their elimination can prevent the development of ALI.73 The neutrophils present in the lungs during ALI produce inflammatory mediators, including cytokines, such as interleukin-6 and macrophage inflammatory peptide-2, and demonstrate increased activation of transcriptional regulatory factors, including nuclear factor-κB (NF-κB).73,74,75,76

Binding elements for NF-κB are present in the enhancer/promoter regions of cytokine genes, such as interleukin-1β, macrophage inflammatory peptide-2, and tumor necrosis factor-α, as well as other important immunoregulatory molecules, such as intercellular adhesion molecule-1 and complement C4 protein.77 Inhibition of NF-κB activation prevents endotoxin-induced increases in proinflammatory cytokine expression in the lungs.76

iPS cell administration improved the impairment of pulmonary function in endotoxin-induced ALI, including airway resistance (enhanced pause), lung tidal volumes, and arterial partial oxygen pressure levels. Hypoxemia is the major symptom and sign of ALI, no matter whether in the mice model or in human cases. The effect of iPS cell treatment was to rescue the hypoxemia, similar to another study using a therapeutic agent in an animal model of lung injury.78 A recent study found that transplantation of human ES cells abrogated bleomycin-induced lung injury in mice and restored blood arterial oxygen saturation and lung tidal volume.79 Our study showed that the intravenous injection of iPS cells led to recovery of the impairment of both airway resistance and lung tidal volume induced by the instillation of endotoxin intratracheally. In a previous mice model of early ALI, most changes in bronchoalveolar lavage suggestive of acute pulmonary irritation were compatible with the changes in pulmonary function, such as airway resistance (enhanced pause) and tidal volume.80 Thus, iPS cell therapy not only abolished endotoxin-induced lung injury in mice but also improved the changes in pulmonary physiological function. This novel cellular therapy opened an era of cell-based transplantation by overcoming the immune rejection and the ethical controversy over the use of ES cells and mesenchymal stem cells.

5.4. iPS in liver diseases

Liver diseases and liver injuries are common health problems throughout the world. The loss of functional liver tissue after injury will activate a wound healing process aimed to repair and restore the integrity of the injured liver. Intense or uncontrollable insults could efface the healing response and result in end-stage liver disease, which is irreversibly associated with liver failure. Currently, orthotopic liver transplantation is the most effective therapy for acute and chronic liver failure. However, it is limited by shortage of donors, operative risk, lifelong use of immunosuppressive agents, and very high costs. The development and application of cell therapies has been attempted to treat different forms of liver diseases.81,82,83,84,85,86 Cell therapy has been considered as a potential therapeutic alternative to orthotopic liver transplantation.87,88,89 It has minimal invasive procedures and fewer surgical complications.90,91,92 These cells, particularly the stem cell population, appeared very attractive and have gained considerable attention for its potential to supportive tissue regeneration. Besides, they have the potential to generate large amounts of donor cells available for transplant or to be stored for future use.

Although previous studies using stem cells in the treatment of liver diseases have shown beneficial effects, the underlying mechanisms accounting for their therapeutic effects have not been completely revealed. One of the possible explanations is that the transplanted stem cells generate cells that function as normal hepatocytes. However, it has been noticed that the percentage of liver repopulation remains very low despite efforts to improve cell engraftment. Another explanation is the indirect paracrine effects that initiated in the damaged liver after stem cell transplant.93 Some soluble factors could have been secreted to facilitate the process of repair and regeneration. It is still unclear how these soluble factors regulate the recovery process in the injured liver after stem cell transplantation.

Currently, the therapeutic roles of iPS cell or iPS-derived hepatocytes (IDHs)-like cells for liver injury have gained increasing attention.94,95 Si-Tayeb et al.94 reported that human iPS cells from foreskin fibroblasts could be used to efficiently generate human hepatocyte-like cells. The IDHs-like cells displayed several hepatic functions, including albumin expression, accumulation of glycogen, metabolism of indocyanine green, accumulation of lipid, active uptake of low-density lipoprotein, synthesis of urea, and expressed the same hepatocyte mRNA fingerprint. However, the levels of expression of these enzymes were lower in most cases when compared with adult liver samples, suggesting that although hepatocyte-like cells derived from human iPS cells have differentiated to a state that supports many hepatic activities, they do not entirely recapitulate mature liver function. Similarly, it is not clear that whether iPS cells and IDHs have the homing characteristic of locating the area of acute hepatic failure and further can rescue the liver function.

6. Summary

In the past, scientists tried to ameliorate the injury through transplantation of target cells- or stem cells-derived precursors. However, it is hard to prepare enough amounts of target cells in vitro or to efficiently isolate differentiated cells from stem cell populations. The generation of iPS cells stands a better chance than other reprogramming procedures (somatic cell nuclear transfer, cell fusion, and so forth) of overcoming these issues, whereas a large number of iPS cells can be prepared in vitro. To date, iPS-derived strategies have been applied to four disease models, sickle cell anemia, PD, hemophilia A, and acute myocardial infarction. However, there still exist several questions to be answered, such as what are the detailed molecular mechanisms of reprogramming? Can iPS cells be generated solely by chemical compounds like epigenetic modifier without DNA transduction? How to improve the yield of iPS? In addition, to provide replacement cells for therapy, a new cell by lineage switching or direct conversion from a normal somatic cell should also be considered.96 In conclusion, the iPS techniques open a new era for stem cell research and offer promising opportunities for patient-specific pluripotent cell-based regenerative medicine.

References

  1. Sun, Y. Myocardial repair/remodelling following infarction: roles of local factors. Cardiovasc Res. 2009; 81: 482–490
  2. Evans, M.J. and Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981; 292: 154–156
  3. Martin, G.R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981; 78: 7634–7638
  4. Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282: 1145–1147
  5. Takahashi, K. and Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126: 663–676
  6. Hanna, J., Carey, B.W., and Jaenisch, R. Reprogramming of somatic cell identity. Cold Spring Harb Symp Quant Biol. 2008; 73: 147–155
  7. Maherali, N. and Hochedlinger, K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell. 2008; 3: 595–605
  8. Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G.W., Cook, E.G. et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009; 136: 964–977
  9. Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., Hamalainen, R. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009; 458: 766–770
  10. Yusa, K., Rad, R., Takeda, J., and Bradley, A. Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods. 2009; 6: 363–369
  11. Li, W., Wei, W., Zhu, S., Zhu, J., Shi, Y., Lin, T. et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell. 2009; 4: 16–19
  12. Liao, J., Cui, C., Chen, S., Ren, J., Chen, J., Gao, Y. et al. Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell. 2009; 4: 11–15
  13. Liu, H., Zhu, F., Yong, J., Zhang, P., Hou, P., Li, H. et al. Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell. 2008; 3: 587–590
  14. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131: 861–872
  15. Sun, N., Longaker, M.T., and Wu, J.C. Human iPS cell-based therapy: considerations before clinical applications. Cell Cycle. 2010; 9: 880–885
  16. Feng, B., Ng, J.H., Heng, J.C., and Ng, H.H. Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell. 2009; 4: 301–312
  17. Colman, A. and Dreesen, O. Induced pluripotent stem cells and the stability of the differentiated state. EMBO Rep. 2009; 10: 714–721
  18. Moretti, A., Bellin, M., Welling, A., Jung, C.B., Lam, J.T., Bott-Flugel, L. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010; 363: 1397–1409
  19. Okita, K., Ichisaka, T., and Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448: 313–317
  20. Wernig, M., Meissner, A., Cassady, J.P., and Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008; 2: 10–12
  21. Meissner, A., Wernig, M., and Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol. 2007; 25: 1177–1181
  22. Nakagawa, Masato, Koyanagi, Michiyo, Tanabe, Koji, Takahashi, Kazutoshi, Ichisaka, Tomoko, Aoi, Takashi et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology. 2008; 26: 101–106
  23. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science. 2008; 322: 945–949
  24. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., and Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008; 322: 949–953
  25. Somers, A., Jean, J.C., Sommer, C.A., Omari, A., Ford, C.C., Mills, J.A. et al. Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells. 2010; 28: 1728–1740
  26. Carey, B.W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M. et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci USA. 2009; 106: 157–162
  27. Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 2009; 458: 771–775
  28. Zhou, H., Wu, S., Joo, J.Y., Zhu, S., Han, D.W., Lin, T. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2009; 4: 381–384
  29. Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010; 7: 618–630
  30. Sauer, H., Rahimi, G., Hescheler, J., and Wartenberg, M. Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett. 2000; 476: 218–223
  31. Schmelter, M., Ateghang, B., Helmig, S., Wartenberg, M., and Sauer, H. Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J. 2006; 20: 1182–1184
  32. Papaharalambus, C.A. and Griendling, K.K. Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. Trends Cardiovasc Med. 2007; 17: 48–54
  33. Armstrong, L., Tilgner, K., Saretzki, G., Atkinson, S.P., Stojkovic, M., Moreno, R. et al. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells. 2010; 28: 661–673
  34. Crespo, F.L., Sobrado, V.R., Gomez, L., Cervera, A.M., and McCreath, K.J. Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose. Stem Cells. 2010; 28: 1132–1142
  35. Ji, A.R., Ku, S.Y., Cho, M.S., Kim, Y.Y., Kim, Y.J., Oh, S.K. et al. Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med. 2010; 42: 175–186
  36. Varum, S., Momcilovic, O., Castro, C., Ben-Yehudah, A., Ramalho-Santos, J., and Navara, C.S. Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain. Stem Cell Res. 2009; 3: 142–156
  37. Jewett, S.L., Rocklin, A.M., Ghanevati, M., Abel, J.M., and Marach, J.A. A new look at a time-worn system: oxidation of CuZn-SOD by H2O2. Free Radic Biol Med. 1999; 26: 905–918
  38. Chen, C.T., Shih, Y.R., Kuo, T.K., Lee, O.K., and Wei, Y.H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells. 2008; 26: 960–968
  39. 39Lindvall, O., Kokaia, Z., and Martinez-Serrano, A. Stem cell therapy for human neurodegenerative disorders-how to make it work. Nat Med. 2004; : S42–S50
  40. Samii, A., Nutt, J.G., and Ransom, B.R. Parkinson’s disease. Lancet. 2004; 363: 1783–1793
  41. Fearnley, J.M. and Lees, A.J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991; 114: 2283–2301
  42. Lindvall, O. and Hagell, P. Clinical observations after neural transplantation in Parkinson’s disease. Prog Brain Res. 2000; 127: 299–320
  43. Kordower, J.H., Freeman, T.B., Snow, B.J., Vingerhoets, F.J., Mufson, E.J., Sanberg, P.R. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med. 1995; 332: 1118–1124
  44. Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V., Brin, M.F. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003; 54: 403–414
  45. Hagell, P., Piccini, P., Bjorklund, A., Brundin, P., Rehncrona, S., Widner, H. et al. Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci. 2002; 5: 627–628
  46. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001; 344: 710–719
  47. Hedlund, E. and Perlmann, T. Neuronal cell replacement in Parkinson’s disease. J Intern Med. 2009; 266: 358–371
  48. Yang, D., Zhang, Z.J., Oldenburg, M., Ayala, M., and Zhang, S.C. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells. 2008; 26: 55–63
  49. Glavaski-Joksimovic, A., Virag, T., Chang, Q.A., West, N.C., Mangatu, T.A., McGrogan, M.P. et al. Reversal of dopaminergic degeneration in a parkinsonian rat following micrografting of human bone marrow-derived neural progenitors. Cell Transplant. 2009; 18: 801–814
  50. Zhang, Z.G. and Chopp, M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009; 8: 491–500
  51. Takahashi, K., Yasuhara, T., Shingo, T., Muraoka, K., Kameda, M., Takeuchi, A. et al. Embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells. Brain Res. 2008; 1234: 172–182
  52. Yanagisawa, D., Qi, M., Kim, D.H., Kitamura, Y., Inden, M., Tsuchiya, D. et al. Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embryonic stem cells. Neurosci Lett. 2006; 407: 74–79
  53. Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F. et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA. 2008; 105: 5856–5861
  54. Chen, S.J., Chang, C.M., Tsai, S.K., Chang, Y.L., Chou, S.J., Huang, S.S. et al. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev. 2010; 19: 1757–1767
  55. Erdo, F., Buhrle, C., Blunk, J., Hoehn, M., Xia, Y., Fleischmann, B. et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab. 2003; 23: 780–785
  56. Brederlau, A., Correia, A.S., Anisimov, S.V., Elmi, M., Paul, G., Roybon, L. et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells. 2006; 24: 1433–1440
  57. Chung, S., Shin, B.S., Hedlund, E., Pruszak, J., Ferree, A., Kang, U.J. et al. Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation. J Neurochem. 2006; 97: 1467–1480
  58. Tabar, V., Panagiotakos, G., Greenberg, E.D., Chan, B.K., Sadelain, M., Gutin, P.H. et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol. 2005; 23: 601–606
  59. Kao, C.L., Tai, L.K., Chiou, S.H., Chen, Y.J., Lee, K.H., Chou, S.J. et al. Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev. 2010; 19: 247–258
  60. Hung, C.W., Liou, Y.J., Lu, S.W., Tseng, L.M., Kao, C.L., Chen, S.J. et al. Stem cell-based neuroprotective and neurorestorative strategies. Int J Mol Sci. 2010; 11: 2039–2055
  61. Christie, J.D., Edwards, L.B., Aurora, P., Dobbels, F., Kirk, R., Rahmel, A.O. et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult lung and heart/lung transplantation report–2008. J Heart Lung Transplant. 2008; 27: 957–969
  62. Augoustides, J.G. and Riha, H. Recent progress in heart failure treatment and heart transplantation. J Cardiothorac Vasc Anesth. 2009; 23: 738–748
  63. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W., and Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985; 87: 27–45
  64. Iacobas, I., Vats, A., and Hirschi, K.K. Vascular potential of human pluripotent stem cells. Arterioscler Thromb Vasc Biol. 2010; 30: 1110–1117
  65. Xie, C.Q., Huang, H., Wei, S., Song, L.S., Zhang, J., Ritchie, R.P. et al. A comparison of murine smooth muscle cells generated from embryonic versus induced pluripotent stem cells. Stem Cells Dev. 2009; 18: 741–748
  66. Kofidis, T., de Bruin, J.L., Hoyt, G., Ho, Y., Tanaka, M., Yamane, T. et al. Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant. 2005; 24: 737–744
  67. Laflamme, M.A., Chen, K.Y., Naumova, A.V., Muskheli, V., Fugate, J.A., Dupras, S.K. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007; 25: 1015–1024
  68. Li, Z., Wu, J.C., Sheikh, A.Y., Kraft, D., Cao, F., Xie, X. et al. Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation. 2007; 116: I46–54
  69. Ware, L.B. and Matthay, M.A. The acute respiratory distress syndrome. N Engl J Med. 2000; 342: 1334–1349
  70. Chollet-Martin, S., Jourdain, B., Gibert, C., Elbim, C., Chastre, J., and Gougerot-Pocidalo, M.A. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. Am J Respir Crit Care Med. 1996; 154: 594–601
  71. Goodman, R.B., Strieter, R.M., Martin, D.P., Steinberg, K.P., Milberg, J.A., Maunder, R.J. et al. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996; 154: 602–611
  72. Suter, P.M., Suter, S., Girardin, E., Roux-Lombard, P., Grau, G.E., and Dayer, J.M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis. 1992; 145: 1016–1022
  73. Abraham, E., Carmody, A., Shenkar, R., and Arcaroli, J. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2000; 279: L1137–1145
  74. Parsey, M.V., Tuder, R.M., and Abraham, E. Neutrophils are major contributors to intraparenchymal lung IL-1 beta expression after hemorrhage and endotoxemia. J Immunol. 1998; 160: 1007–1013
  75. Shenkar, R. and Abraham, E. Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein. J Immunol. 1999; 163: 954–962
  76. Xing, Z., Jordana, M., Kirpalani, H., Driscoll, K.E., Schall, T.J., and Gauldie, J. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol. 1994; 10: 148–153
  77. Foo, S.Y. and Nolan, G.P. NF-kappaB to the rescue: RELs, apoptosis and cellular transformation. Trends Genet. 1999; 15: 229–235
  78. Treml, B., Neu, N., Kleinsasser, A., Gritsch, C., Finsterwalder, T., Geiger, R. et al. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med. 2010; 38: 596–601
  79. Wang, D., Morales, J.E., Calame, D.G., Alcorn, J.L., and Wetsel, R.A. Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther. 2010; 18: 625–634
  80. Pauluhn, J. Comparative assessment of early acute lung injury in mice and rats exposed to 1,6-hexamethylene diisocyanate-polyisocyanate aerosols. Toxicology. 2008; 247: 33–45
  81. Kawashita, Y., Guha, C., Yamanouchi, K., Ito, Y., Kamohara, Y., and Kanematsu, T. Liver repopulation: a new concept of hepatocyte transplantation. Surg Today. 2005; 35: 705–710
  82. Horslen, S.P. and Fox, I.J. Hepatocyte transplantation. Transplantation. 2004; 77: 1481–1486
  83. Fox, I.J. and Roy-Chowdhury, J. Hepatocyte transplantation. J Hepatol. 2004; 40: 878–886
  84. Ito, M., Nagata, H., Miyakawa, S., and Fox, I.J. Review of hepatocyte transplantation. J Hepatobiliary Pancreat Surg. 2009; 16: 97–100
  85. Weber, A., Groyer-Picard, M.T., Franco, D., and Dagher, I. Hepatocyte transplantation in animal models. Liver Transpl. 2009; 15: 7–14
  86. Puppi, J. and Dhawan, A. Human hepatocyte transplantation overview. Methods Mol Biol. 2009; 481: 1–16
  87. Keeffe, E.B. Liver transplantation: current status and novel approaches to liver replacement. Gastroenterology. 2001; 120: 749–762
  88. Lee, L.A. Advances in hepatocyte transplantation: a myth becomes reality. J Clin Invest. 2001; 108: 367–369
  89. Ott, M., Schmidt, H.H., Cichon, G., and Manns, M.P. Emerging therapies in hepatology: liver-directed gene transfer and hepatocyte transplantation. Cells Tissues Organs. 2000; 167: 81–87
  90. Kakinuma, S., Nakauchi, H., and Watanabe, M. Hepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease. J Gastroenterol. 2009; 44: 167–172
  91. Yoshimi, A., Nannya, Y., Ueda, K., Asano, D., Yamamoto, G., Kumano, K. et al. Successful hematopoietic stem cell transplantation from an HLA-identical sibling in a patient with aplastic anemia after HLA-haploidentical living-related liver transplantation for fulminant hepatitis. Biol Blood Marrow Transplant. 2009; 15: 389–390
  92. Navarro-Alvarez, N., Soto-Gutierrez, A., and Kobayashi, N. Stem cell research and therapy for liver disease. Curr Stem Cell Res Ther. 2009; 4: 141–146
  93. Kuo, T.K., Hung, S.P., Chuang, C.H., Chen, C.T., Shih, Y.R., Fang, S.C. et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008; 134: 2111–2121 (2121 e1–e3)
  94. Si-Tayeb, K., Noto, F.K., Nagaoka, M., Li, J., Battle, M.A., Duris, C. et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology. 2010; 51: 297–305
  95. Espejel, S., Roll, G.R., McLaughlin, K.J., Lee, A.Y., Zhang, J.Y., Laird, D.J. et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest. 2010; 120: 3120–3126
  96. Gurdon, J.B. and Melton, D.A. Nuclear reprogramming in cells. Science. 2008; 322: 1811–1815

References

  1. Sun, Y. Myocardial repair/remodelling following infarction: roles of local factors. Cardiovasc Res200981482–490

  2. Evans, M.J. and Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature1981292154–156


  3. Martin, G.R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA1981787634–7638


  4. Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. et al. Embryonic stem cell lines derived from human blastocysts. Science19982821145–1147


  5. Takahashi, K. and Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell2006126663–676


  6. Hanna, J., Carey, B.W., and Jaenisch, R. Reprogramming of somatic cell identity. Cold Spring Harb Symp Quant Biol200873147–155


  7. Maherali, N. and Hochedlinger, K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell20083595–605


  8. Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G.W., Cook, E.G. et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell2009136964–977


  9. Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., Hamalainen, R. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature2009458766–770


  10. Yusa, K., Rad, R., Takeda, J., and Bradley, A. Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods20096363–369


  11. Li, W., Wei, W., Zhu, S., Zhu, J., Shi, Y., Lin, T. et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell2009416–19


  12. Liao, J., Cui, C., Chen, S., Ren, J., Chen, J., Gao, Y. et al. Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell2009411–15


  13. Liu, H., Zhu, F., Yong, J., Zhang, P., Hou, P., Li, H. et al. Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell20083587–590


  14. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell2007131861–872


  15. Sun, N., Longaker, M.T., and Wu, J.C. Human iPS cell-based therapy: considerations before clinical applications. Cell Cycle20109880–885


  16. Feng, B., Ng, J.H., Heng, J.C., and Ng, H.H. Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell20094301–312


  17. Colman, A. and Dreesen, O. Induced pluripotent stem cells and the stability of the differentiated state. EMBO Rep200910714–721


  18. Moretti, A., Bellin, M., Welling, A., Jung, C.B., Lam, J.T., Bott-Flugel, L. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med20103631397–1409


  19. Okita, K., Ichisaka, T., and Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature2007448313–317


  20. Wernig, M., Meissner, A., Cassady, J.P., and Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell2008210–12


  21. Meissner, A., Wernig, M., and Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol2007251177–1181


  22. Nakagawa, Masato, Koyanagi, Michiyo, Tanabe, Koji, Takahashi, Kazutoshi, Ichisaka, Tomoko, Aoi, Takashi et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology200826101–106


  23. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science2008322945–949


  24. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., and Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science2008322949–953


  25. Somers, A., Jean, J.C., Sommer, C.A., Omari, A., Ford, C.C., Mills, J.A. et al. Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells2010281728–1740


  26. Carey, B.W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M. et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci USA2009106157–162


  27. Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature2009458771–775


  28. Zhou, H., Wu, S., Joo, J.Y., Zhu, S., Han, D.W., Lin, T. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell20094381–384


  29. Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell20107618–630


  30. Sauer, H., Rahimi, G., Hescheler, J., and Wartenberg, M. Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett2000476218–223


  31. Schmelter, M., Ateghang, B., Helmig, S., Wartenberg, M., and Sauer, H. Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J2006201182–1184


  32. Papaharalambus, C.A. and Griendling, K.K. Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. Trends Cardiovasc Med20071748–54


  33. Armstrong, L., Tilgner, K., Saretzki, G., Atkinson, S.P., Stojkovic, M., Moreno, R. et al. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells201028661–673


  34. Crespo, F.L., Sobrado, V.R., Gomez, L., Cervera, A.M., and McCreath, K.J. Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose. Stem Cells2010281132–1142


  35. Ji, A.R., Ku, S.Y., Cho, M.S., Kim, Y.Y., Kim, Y.J., Oh, S.K. et al. Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med201042175–186


  36. Varum, S., Momcilovic, O., Castro, C., Ben-Yehudah, A., Ramalho-Santos, J., and Navara, C.S. Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain. Stem Cell Res20093142–156


  37. Jewett, S.L., Rocklin, A.M., Ghanevati, M., Abel, J.M., and Marach, J.A. A new look at a time-worn system: oxidation of CuZn-SOD by H2O2. Free Radic Biol Med199926905–918


  38. Chen, C.T., Shih, Y.R., Kuo, T.K., Lee, O.K., and Wei, Y.H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells200826960–968


  39. Lindvall, O., Kokaia, Z., and Martinez-Serrano, A. Stem cell therapy for human neurodegenerative disorders-how to make it work. Nat Med2004; : S42–S50


  40. Samii, A., Nutt, J.G., and Ransom, B.R. Parkinson’s disease. Lancet20043631783–1793


  41. Fearnley, J.M. and Lees, A.J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain19911142283–2301


  42. Lindvall, O. and Hagell, P. Clinical observations after neural transplantation in Parkinson’s disease. Prog Brain Res2000127299–320


  43. Kordower, J.H., Freeman, T.B., Snow, B.J., Vingerhoets, F.J., Mufson, E.J., Sanberg, P.R. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med19953321118–1124


  44. Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V., Brin, M.F. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol200354403–414


  45. Hagell, P., Piccini, P., Bjorklund, A., Brundin, P., Rehncrona, S., Widner, H. et al. Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci20025627–628


  46. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med2001344710–719


  47. Hedlund, E. and Perlmann, T. Neuronal cell replacement in Parkinson’s disease. J Intern Med2009266358–371


  48. Yang, D., Zhang, Z.J., Oldenburg, M., Ayala, M., and Zhang, S.C. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells20082655–63


  49. Glavaski-Joksimovic, A., Virag, T., Chang, Q.A., West, N.C., Mangatu, T.A., McGrogan, M.P. et al. Reversal of dopaminergic degeneration in a parkinsonian rat following micrografting of human bone marrow-derived neural progenitors. Cell Transplant200918801–814


  50. Zhang, Z.G. and Chopp, M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol20098491–500


  51. Takahashi, K., Yasuhara, T., Shingo, T., Muraoka, K., Kameda, M., Takeuchi, A. et al. Embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells. Brain Res20081234172–182


  52. Yanagisawa, D., Qi, M., Kim, D.H., Kitamura, Y., Inden, M., Tsuchiya, D. et al. Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embryonic stem cells. Neurosci Lett200640774–79


  53. Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F. et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA20081055856–5861


  54. Chen, S.J., Chang, C.M., Tsai, S.K., Chang, Y.L., Chou, S.J., Huang, S.S. et al. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev2010191757–1767


  55. Erdo, F., Buhrle, C., Blunk, J., Hoehn, M., Xia, Y., Fleischmann, B. et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab200323780–785


  56. Brederlau, A., Correia, A.S., Anisimov, S.V., Elmi, M., Paul, G., Roybon, L. et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells2006241433–1440


  57. Chung, S., Shin, B.S., Hedlund, E., Pruszak, J., Ferree, A., Kang, U.J. et al. Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation. J Neurochem2006971467–1480


  58. Tabar, V., Panagiotakos, G., Greenberg, E.D., Chan, B.K., Sadelain, M., Gutin, P.H. et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol200523601–606


  59. Kao, C.L., Tai, L.K., Chiou, S.H., Chen, Y.J., Lee, K.H., Chou, S.J. et al. Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev201019247–258


  60. Hung, C.W., Liou, Y.J., Lu, S.W., Tseng, L.M., Kao, C.L., Chen, S.J. et al. Stem cell-based neuroprotective and neurorestorative strategies. Int J Mol Sci2010112039–2055


  61. Christie, J.D., Edwards, L.B., Aurora, P., Dobbels, F., Kirk, R., Rahmel, A.O. et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult lung and heart/lung transplantation report–2008. J Heart Lung Transplant200827957–969


  62. Augoustides, J.G. and Riha, H. Recent progress in heart failure treatment and heart transplantation. J Cardiothorac Vasc Anesth200923738–748


  63. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W., and Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol19858727–45


  64. Iacobas, I., Vats, A., and Hirschi, K.K. Vascular potential of human pluripotent stem cells. Arterioscler Thromb Vasc Biol2010301110–1117


  65. Xie, C.Q., Huang, H., Wei, S., Song, L.S., Zhang, J., Ritchie, R.P. et al. A comparison of murine smooth muscle cells generated from embryonic versus induced pluripotent stem cells. Stem Cells Dev200918741–748


  66. Kofidis, T., de Bruin, J.L., Hoyt, G., Ho, Y., Tanaka, M., Yamane, T. et al. Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant200524737–744


  67. Laflamme, M.A., Chen, K.Y., Naumova, A.V., Muskheli, V., Fugate, J.A., Dupras, S.K. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol2007251015–1024


  68. Li, Z., Wu, J.C., Sheikh, A.Y., Kraft, D., Cao, F., Xie, X. et al. Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation2007116I46–54


  69. Ware, L.B. and Matthay, M.A. The acute respiratory distress syndrome. N Engl J Med20003421334–1349


  70. Chollet-Martin, S., Jourdain, B., Gibert, C., Elbim, C., Chastre, J., and Gougerot-Pocidalo, M.A. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. Am J Respir Crit Care Med1996154594–601


  71. Goodman, R.B., Strieter, R.M., Martin, D.P., Steinberg, K.P., Milberg, J.A., Maunder, R.J. et al. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med1996154602–611


  72. Suter, P.M., Suter, S., Girardin, E., Roux-Lombard, P., Grau, G.E., and Dayer, J.M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis19921451016–1022


  73. Abraham, E., Carmody, A., Shenkar, R., and Arcaroli, J. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol2000279L1137–1145


  74. Parsey, M.V., Tuder, R.M., and Abraham, E. Neutrophils are major contributors to intraparenchymal lung IL-1 beta expression after hemorrhage and endotoxemia. J Immunol19981601007–1013


  75. Shenkar, R. and Abraham, E. Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein. J Immunol1999163954–962


  76. Xing, Z., Jordana, M., Kirpalani, H., Driscoll, K.E., Schall, T.J., and Gauldie, J. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol199410148–153


  77. Foo, S.Y. and Nolan, G.P. NF-kappaB to the rescue: RELs, apoptosis and cellular transformation. Trends Genet199915229–235


  78. Treml, B., Neu, N., Kleinsasser, A., Gritsch, C., Finsterwalder, T., Geiger, R. et al. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med201038596–601


  79. Wang, D., Morales, J.E., Calame, D.G., Alcorn, J.L., and Wetsel, R.A. Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther201018625–634


  80. Pauluhn, J. Comparative assessment of early acute lung injury in mice and rats exposed to 1,6-hexamethylene diisocyanate-polyisocyanate aerosols. Toxicology200824733–45


  81. Kawashita, Y., Guha, C., Yamanouchi, K., Ito, Y., Kamohara, Y., and Kanematsu, T. Liver repopulation: a new concept of hepatocyte transplantation. Surg Today200535705–710


  82. Horslen, S.P. and Fox, I.J. Hepatocyte transplantation. Transplantation2004771481–1486


  83. Fox, I.J. and Roy-Chowdhury, J. Hepatocyte transplantation. J Hepatol200440878–886


  84. Ito, M., Nagata, H., Miyakawa, S., and Fox, I.J. Review of hepatocyte transplantation. J Hepatobiliary Pancreat Surg20091697–100


  85. Weber, A., Groyer-Picard, M.T., Franco, D., and Dagher, I. Hepatocyte transplantation in animal models. Liver Transpl2009157–14


  86. Puppi, J. and Dhawan, A. Human hepatocyte transplantation overview. Methods Mol Biol20094811–16


  87. Keeffe, E.B. Liver transplantation: current status and novel approaches to liver replacement. Gastroenterology2001120749–762


  88. Lee, L.A. Advances in hepatocyte transplantation: a myth becomes reality. J Clin Invest2001108367–369


  89. Ott, M., Schmidt, H.H., Cichon, G., and Manns, M.P. Emerging therapies in hepatology: liver-directed gene transfer and hepatocyte transplantation. Cells Tissues Organs200016781–87


  90. Kakinuma, S., Nakauchi, H., and Watanabe, M. Hepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease. J Gastroenterol200944167–172


  91. Yoshimi, A., Nannya, Y., Ueda, K., Asano, D., Yamamoto, G., Kumano, K. et al. Successful hematopoietic stem cell transplantation from an HLA-identical sibling in a patient with aplastic anemia after HLA-haploidentical living-related liver transplantation for fulminant hepatitis. Biol Blood Marrow Transplant200915389–390


  92. Navarro-Alvarez, N., Soto-Gutierrez, A., and Kobayashi, N. Stem cell research and therapy for liver disease. Curr Stem Cell Res Ther20094141–146


  93. Kuo, T.K., Hung, S.P., Chuang, C.H., Chen, C.T., Shih, Y.R., Fang, S.C. et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology20081342111–2121 (2121 e1–e3)


  94. Si-Tayeb, K., Noto, F.K., Nagaoka, M., Li, J., Battle, M.A., Duris, C. et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology201051297–305


  95. Espejel, S., Roll, G.R., McLaughlin, K.J., Lee, A.Y., Zhang, J.Y., Laird, D.J. et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest20101203120–3126


  96. Gurdon, J.B. and Melton, D.A. Nuclear reprogramming in cells. Science20083221811–1815