- Email: [email protected]
Common Ground: Stem Cell Approaches Find Shared Pathways Underlying ALS
Cell Stem Cell
Previews cell-cell communication to increase our fundamental understanding of how premalignant cells utilize the microenvironment to promote their malignant agenda. These insights will ultimately result in novel therapeutic strategies, targeting niche cells to attenuate leukemic progression.
REFERENCES Frenette, P.S., Pinho, S., Lucas, D., and Scheiermann, C. (2013). Annu. Rev. Immunol. 31, 285–316.
Hanahan, D., and Weinberg, R.A. (2011). Cell 144, 646–674. Kode, A., Manavalan, J.S., Mosialou, I., Bhagat, G., Rathinam, C.V., Luo, N., Khiabanian, H., Lee, A., Murty, V.V., Friedman, R., et al. (2014). Nature 506, 240–244. Medyouf, H., Mossner, M., Jann, J.-C., Nolte, F., Raffel, S., Herrmann, C., Lier, A., Eisen, C., Nowak, V., Zens, B., et al. (2014). Cell Stem Cell 14, this issue, 824–837. Morrison, S.J., and Scadden, D.T. (2014). Nature 505, 327–334. Oskarsson, T., Batlle, E., and Massague´, J. (2014). Cell Stem Cell 14, 306–321.
Raaijmakers, M.H., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J.A., Ebert, B.L., Al-Shahrour, F., Hasserjian, R.P., Scadden, E.O., et al. (2010). Nature 464, 852–857. Scadden, D.T. (2012). Cell Stem Cell 10, 648–649. Schepers, K., Pietras, E.M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A.J., Hsiao, E.C., and Passegue, E. (2013). Cell Stem Cell 13, 285–299. Walkley, C.R., Olsen, G.H., Dworkin, S., Fabb, S.A., Swann, J., McArthur, G.A., Westmoreland, S.V., Chambon, P., Scadden, D.T., and Purton, L.E. (2007). Cell 129, 1097–1110.
Common Ground: Stem Cell Approaches Find Shared Pathways Underlying ALS Soledad Matus,1,2,* Danilo B. Medinas,1,3 and Claudio Hetz1,2,3,* 1Biomedical
Neuroscience Institute, Faculty of Medicine, University of Chile, Independencia 1027, Chile Biomedical Foundation, Santiago, Chile 3Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Independencia 1027, Santiago, Chile *Correspondence: [email protected] (S.M.), [email protected] (C.H.) http://dx.doi.org/10.1016/j.stem.2014.05.001 2Neurounion
The development of curative therapies for genetically complex diseases such as ALS has been delayed by the lack of relevant disease models. Recent advances using induced-pluripotent-stem-cell-derived motoneurons from patients harboring distinct ALS mutations have recapitulated essential disease features and have identified some common pathways driving disease pathogenesis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the loss of motoneurons in the spinal cord and motor cortex, leading to paralysis and premature death. Whereas most ALS cases are sporadic (sALS), around 10% are considered familial and mainly inherited in a dominant manner (fALS), involving mutations in more than two dozen genes, including superoxide dismutase 1 (SOD1), Tar DNA-binding protein-43 (TDP-43), fused-in-sarcoma (FUS), and C9orf72. The biology of ALS is very complex; however, it is known that the pathology is specific to motor neurons. Multiple pathogenic mechanisms have been proposed to contribute to the selective motoneuron degeneration, including alterations in RNA metabolism, mitochondrial dysfunction, abnormal protein aggregation, endoplasmic reticulum (ER) stress,
excitotoxicity, axonal transport defects, and gliosis, among other events. Most cellular and animal models of ALS involve the expression of supraphysiological levels of human transgenes, mostly involving mutant SOD1 and TDP-43, which contrasts with the single allele alteration observed in fALS cases. Although these ALS models have been fundamental to investigate disease pathogenesis, drugs identified to abrogate or delay experimental ALS using these models have failed in clinical trials. These shortcomings underscore the need for novel model systems to assess unique events that may underlie the selective neuronal vulnerability observed in human cells. Induced pluripotent stem cells (iPSCs) generated from ALS patients and differentiated into motoneurons represent a promising new tool for studying ALS
disease pathology. Using stem cell approaches, three recent studies reported in Cell Stem Cell (Kiskinis et al., 2014; Chen et al., 2014) and Cell Reports (Wainger et al., 2014) revealed the occurrence of inherited abnormal cellular phenotypes in ALS patient-derived motoneurons involving distinct genetic mutations. Remarkably, common pathways of degeneration have emerged through these studies (Figure 1), opening the possibility of new and effective drug screening. Kiskinis et al. (2014) and Chen et al. (2014) both established new in vitro models of ALS by generating iPSCderived motoneurons from patients carrying SOD1 mutations. Both studies developed a well-controlled cellular system by combining genetic correction of the SOD1 mutation and whole-genome
Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc. 697
Cell Stem Cell
Previews
Figure 1. Discovery of Common Molecular Mechanisms of ALS Pathogenesis using iPSC-Derived Human Motoneurons Recent studies using human motoneuron cultures from ALS patients with distinct genetic mutations have identified transversal pathological mechanisms, facilitating the development of experimental strategies to revert distinct disease features, including abnormal protein and RNA aggregation, hyperexcitability, morphological alterations, and cell death.
sequencing to ensure the isogenic backgrounds of their samples. The authors generated highly enriched and electrophysiologically active motoneuron cultures and recapitulated the spontaneous and progressive decrease in cell viability observed in humans, verifying that the phenotype was dependent on the expression of mutant SOD1 (Kiskinis et al., 2014, Chen et al., 2014). ALS-related morphological changes were recapitulated in vitro, including the reduction in soma size and altered dendrites, which was linked to the deregulation and aggregation of neurofilaments, an event that preceded the occurrence of neuronal apoptosis (Chen et al., 2014). Although mutant SOD1 aggregation is thought to be a key molecular event driving neurotoxicity, in these two studies the levels of mutant SOD1 aggregation were extremely low and only detected after inhibiting the proteasome or by extremely sensitive methods (e.g., immunogold staining followed by electron microscopy analysis), consistent with the idea that soluble oligomeric forms of mutant SOD1 are the pathogenic species. Membrane hyperexcitability is a characteristic and predictive feature of ALS. Wainger et al. (2014) demonstrated that iPSC-derived motoneurons from patients carrying SOD1, C9orf72, or FUS mutations all reproduce the spontaneous hyperexcitability observed in disease in culture, making them a useful tool for
future in vitro drug screenings. Importantly, pharmacological testing revealed that the clinically approved anticonvulsant drug retigabine reversed the pathogenic phenotype and improved the survival of human motoneurons expressing mutant SOD1. In an effort to define global perturbations in cell homeostasis, Kiskinis et al. (2014) measured the changes in gene expression triggered in mutant SOD1-expressing motoneurons. Several gene clusters were misregulated in fALS neurons, involving proteins related to cytoskeleton, mitochondrial, and proteostasis control. The latter observation, and a vast body of functional studies in ALS (Hetz and Mollereau, 2014), led the authors to explore the contribution of ER stress and the unfolded protein response (UPR) to mutant SOD1 pathogenesis, demonstrating a positive impact on neuronal survival and morphogenesis (Kiskinis et al., 2014). Using pharmacological approaches to modulate ion channels, a functional link between the electrical activity of motoneurons and the occurrence of basal ER stress was provided. In addition, targeting the UPR altered the conductivity of motoneurons, suggesting feedforward mechanisms. Finally, the authors confirmed that a subset of these transcriptional responses is conserved in motoneurons expressing a C9orf72 mutation, the most common genetic alteration in ALS, thus increasing
698 Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc.
the overall implications of these findings for a variety of ALS genetic subtypes. Recent studies have attempted to develop a model of sALS using iPSCs. Remarkably, iPSCs derived from sALS patients presented de novo TDP-43 intranuclear inclusions on a subgroup of clones (Burkhardt et al., 2013), which represents the most common histopathological hallmark of ALS. The authors used this abnormal parameter to screen a library of FDA-approved compounds. Similarly, a drug screening was performed to identify small molecules that improve survival of motoneurons expressing mutant SOD1 (Yang et al., 2013). Other studies obtained conflicting results when motoneurons were generated with iPSCs from ALS patients carrying TDP-43 mutations. In one report, ALS motoneurons underwent cell death, correlating with the accumulation of TDP-43 aggregates (Bilican et al., 2012), whereas another group did not detect any spontaneous apoptosis, but observed dendrite alterations and enhanced vulnerability to oxidative stress (Egawa et al., 2012). Similarly, two recent studies showed the presence of abnormal RNA foci and the accumulation of non-ATG-dependent translation peptides in iPSC-derived motoneurons from patients carrying C9orf72 mutations (Donnelly et al., 2013; Sareen et al., 2013). These cells were more susceptible to glutamate toxicity and presented global alterations in RNA
Cell Stem Cell
Previews metabolism, which was reverted by antisense oligonucleotides to target C9orf72 mRNA. Taken together, these studies reveal that iPSC-derived motoneurons from ALS patients develop common pathological features resembling early stages of the disease that could be used to test novel therapeutic strategies, and they support the occurrence of an intrinsic vulnerability to stress. They also caution that the appearance of morphological changes does not always culminate in motoneuron loss. These reports additionally suggest a substantial prevalence of gain-of-toxic and cell-autonomous mechanisms of neurodegeneration in ALS. The current studies illustrate that the use of combinatorial approaches to study iPSC-derived motoneurons offers a well-controlled cell culture model of ALS. The identification of robust and inherited morphological, biochemical, and electrophysiological phenotypes in iPSC-derived neurons supports and sometimes contrasts with the well-established animal models of the disease and will open the possibility of developing
novel drug screenings with therapeutic potential and the identification of novel biomarkers of ALS. These advances will also facilitate the future generation of personalized medicine through the testing of drugs to alleviate selective pathological events that may be unique to the specific genetic landscape of each patient, opening important avenues for the treatment of this fatal disease.
Chen, H., Qian, K., Du, Z., Cao, J., Petersen, A., Liu, H., Blackbourn, L.W.t., Huang, C.L., Errigo, A., Yin, Y., et al. (2014). Cell Stem Cell 14, this issue, 796–809. Donnelly, C.J., Zhang, P.W., Pham, J.T., Heusler, A.R., Mistry, N.A., Vidensky, S., Daley, E.L., Poth, E.M., Hoover, B., Fines, D.M., et al. (2013). Neuron 80, 415–428. Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., Adachi, F., Kondo, T., Okita, K., Asaka, I., et al. (2012). Sci Transl Med 4, 145ra104. Hetz, C., and Mollereau, B. (2014). Nat. Rev. Neurosci. 15, 233–249.
ACKNOWLEDGMENTS The authors are supported by P09-015-F, FONDECYT 1100176, ALS Therapy Alliance, Muscular Dystrophy Association, FONDEF D11I1007, and ACT1109 grants (C.H.), FONDECYT 11121524 (S.M.), and 3130351 (D.M.).
REFERENCES
Kiskinis, E., Sandoe, J., Williams, L.A., Boulting, G.L., Moccia, R., Wainger, B.J., Han, S., Peng, T., Thams, S., Mikkilineni, S., et al. (2014). Cell Stem Cell 14, this issue, 781–795. Sareen, D., O’Rourke, J.G., Meera, P., Muhammad, A.K., Grant, S., Simpkinson, M., Bell, S., Carmona, S., Ornelas, L., Sahabian, A., et al. (2013). Sci Transl Med 5, 208ra149.
Bilican, B., Serio, A., Barmada, S.J., Nishimura, A.L., Sullivan, G.J., Carrasco, M., Phatnani, H.P., Puddifoot, C.A., Story, D., Fletcher, J., et al. (2012). Proc. Natl. Acad. Sci. USA 109, 5803–5808.
Wainger, B.J., Kiskinis, E., Mellin, C., Wiskow, O., Han, S.S., Sandoe, J., Perez, N.P., Williams, L.A., Lee, S., Boulting, G., et al. (2014). Cell Rep. 7, 1–11.
Burkhardt, M.F., Martinez, F.J., Wright, S., Ramos, C., Volfson, D., Mason, M., Garnes, J., Dang, V., Lievers, J., Shoukat-Mumtaz, U., et al. (2013). Mol. Cell. Neurosci. 56, 355–364.
Yang, Y.M., Gupta, S.K., Kim, K.J., Powers, B.E., Cerqueira, A., Wainger, B.J., Ngo, H.D., Rosowski, K.A., Schein, P.A., Ackeifi, C.A., et al. (2013). Cell Stem Cell 12, 713–726.
Human Somatic Cell Nuclear Transfer Is Alive and Well Jose B. Cibelli1,2,* 1Departments
of Physiology and Animal Science, Michigan State University, East Lansing, MI, 48834, USA BIONAND, 29590 Campanillas, Ma´laga, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2014.05.013 2LARCel,
In this issue, Chung et al. (2014) generate human embryonic stem cells by fusing an adult somatic cell to a previously enucleated human oocyte, in agreement with recent reports by the Mitalipov and Egli groups. We can now safely say that human somatic cell nuclear transfer is alive and well. Last year, the group led by Shoukhrat Mitalipov published, for the first time, their success in generating hESCs using cloned human embryos (Tachibana et al., 2013). The field of SCNT, launched by Dolly in 1997, has since been developed by the successful cloning of more than twenty different mammalian species. Using hSCNT to generate hESCs, however, turned out to be more challenging (Cibelli et al., 2001; Fan et al., 2011; French et al., 2008; Noggle et al., 2011; Stojkovic
et al., 2005). Mitalipov’s group spent a significant amount of time refining SCNT, first with monkeys and then with humans. As a result, we now know how to overcome some fundamental roadblocks. The study by Chung et al. (2014), published in this issue along with a recently published paper by Yamada et al. (2014), brings to light fundamental aspects of hSCNT, reasserting this technique as a powerful research and therapeutic tool (Chung et al., 2014; Yamada et al., 2014).
Prior to the publication of this work and based on studies comparing donor nuclei from ESCs with those of somatic cells, there was a general notion that less differentiated cells would serve as better sources of donor nuclei. Chung et al.(2104) successfully dedifferentiated somatic cells from a 75-year-old donor, which is a landmark achievement that refutes the hypothesis that cells from an older individual are harder to dedifferentiate. Borrowing from half a century’s
Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc. 699
Previews cell-cell communication to increase our fundamental understanding of how premalignant cells utilize the microenvironment to promote their malignant agenda. These insights will ultimately result in novel therapeutic strategies, targeting niche cells to attenuate leukemic progression.
REFERENCES Frenette, P.S., Pinho, S., Lucas, D., and Scheiermann, C. (2013). Annu. Rev. Immunol. 31, 285–316.
Hanahan, D., and Weinberg, R.A. (2011). Cell 144, 646–674. Kode, A., Manavalan, J.S., Mosialou, I., Bhagat, G., Rathinam, C.V., Luo, N., Khiabanian, H., Lee, A., Murty, V.V., Friedman, R., et al. (2014). Nature 506, 240–244. Medyouf, H., Mossner, M., Jann, J.-C., Nolte, F., Raffel, S., Herrmann, C., Lier, A., Eisen, C., Nowak, V., Zens, B., et al. (2014). Cell Stem Cell 14, this issue, 824–837. Morrison, S.J., and Scadden, D.T. (2014). Nature 505, 327–334. Oskarsson, T., Batlle, E., and Massague´, J. (2014). Cell Stem Cell 14, 306–321.
Raaijmakers, M.H., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J.A., Ebert, B.L., Al-Shahrour, F., Hasserjian, R.P., Scadden, E.O., et al. (2010). Nature 464, 852–857. Scadden, D.T. (2012). Cell Stem Cell 10, 648–649. Schepers, K., Pietras, E.M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A.J., Hsiao, E.C., and Passegue, E. (2013). Cell Stem Cell 13, 285–299. Walkley, C.R., Olsen, G.H., Dworkin, S., Fabb, S.A., Swann, J., McArthur, G.A., Westmoreland, S.V., Chambon, P., Scadden, D.T., and Purton, L.E. (2007). Cell 129, 1097–1110.
Common Ground: Stem Cell Approaches Find Shared Pathways Underlying ALS Soledad Matus,1,2,* Danilo B. Medinas,1,3 and Claudio Hetz1,2,3,* 1Biomedical
Neuroscience Institute, Faculty of Medicine, University of Chile, Independencia 1027, Chile Biomedical Foundation, Santiago, Chile 3Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Independencia 1027, Santiago, Chile *Correspondence: [email protected] (S.M.), [email protected] (C.H.) http://dx.doi.org/10.1016/j.stem.2014.05.001 2Neurounion
The development of curative therapies for genetically complex diseases such as ALS has been delayed by the lack of relevant disease models. Recent advances using induced-pluripotent-stem-cell-derived motoneurons from patients harboring distinct ALS mutations have recapitulated essential disease features and have identified some common pathways driving disease pathogenesis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the loss of motoneurons in the spinal cord and motor cortex, leading to paralysis and premature death. Whereas most ALS cases are sporadic (sALS), around 10% are considered familial and mainly inherited in a dominant manner (fALS), involving mutations in more than two dozen genes, including superoxide dismutase 1 (SOD1), Tar DNA-binding protein-43 (TDP-43), fused-in-sarcoma (FUS), and C9orf72. The biology of ALS is very complex; however, it is known that the pathology is specific to motor neurons. Multiple pathogenic mechanisms have been proposed to contribute to the selective motoneuron degeneration, including alterations in RNA metabolism, mitochondrial dysfunction, abnormal protein aggregation, endoplasmic reticulum (ER) stress,
excitotoxicity, axonal transport defects, and gliosis, among other events. Most cellular and animal models of ALS involve the expression of supraphysiological levels of human transgenes, mostly involving mutant SOD1 and TDP-43, which contrasts with the single allele alteration observed in fALS cases. Although these ALS models have been fundamental to investigate disease pathogenesis, drugs identified to abrogate or delay experimental ALS using these models have failed in clinical trials. These shortcomings underscore the need for novel model systems to assess unique events that may underlie the selective neuronal vulnerability observed in human cells. Induced pluripotent stem cells (iPSCs) generated from ALS patients and differentiated into motoneurons represent a promising new tool for studying ALS
disease pathology. Using stem cell approaches, three recent studies reported in Cell Stem Cell (Kiskinis et al., 2014; Chen et al., 2014) and Cell Reports (Wainger et al., 2014) revealed the occurrence of inherited abnormal cellular phenotypes in ALS patient-derived motoneurons involving distinct genetic mutations. Remarkably, common pathways of degeneration have emerged through these studies (Figure 1), opening the possibility of new and effective drug screening. Kiskinis et al. (2014) and Chen et al. (2014) both established new in vitro models of ALS by generating iPSCderived motoneurons from patients carrying SOD1 mutations. Both studies developed a well-controlled cellular system by combining genetic correction of the SOD1 mutation and whole-genome
Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc. 697
Cell Stem Cell
Previews
Figure 1. Discovery of Common Molecular Mechanisms of ALS Pathogenesis using iPSC-Derived Human Motoneurons Recent studies using human motoneuron cultures from ALS patients with distinct genetic mutations have identified transversal pathological mechanisms, facilitating the development of experimental strategies to revert distinct disease features, including abnormal protein and RNA aggregation, hyperexcitability, morphological alterations, and cell death.
sequencing to ensure the isogenic backgrounds of their samples. The authors generated highly enriched and electrophysiologically active motoneuron cultures and recapitulated the spontaneous and progressive decrease in cell viability observed in humans, verifying that the phenotype was dependent on the expression of mutant SOD1 (Kiskinis et al., 2014, Chen et al., 2014). ALS-related morphological changes were recapitulated in vitro, including the reduction in soma size and altered dendrites, which was linked to the deregulation and aggregation of neurofilaments, an event that preceded the occurrence of neuronal apoptosis (Chen et al., 2014). Although mutant SOD1 aggregation is thought to be a key molecular event driving neurotoxicity, in these two studies the levels of mutant SOD1 aggregation were extremely low and only detected after inhibiting the proteasome or by extremely sensitive methods (e.g., immunogold staining followed by electron microscopy analysis), consistent with the idea that soluble oligomeric forms of mutant SOD1 are the pathogenic species. Membrane hyperexcitability is a characteristic and predictive feature of ALS. Wainger et al. (2014) demonstrated that iPSC-derived motoneurons from patients carrying SOD1, C9orf72, or FUS mutations all reproduce the spontaneous hyperexcitability observed in disease in culture, making them a useful tool for
future in vitro drug screenings. Importantly, pharmacological testing revealed that the clinically approved anticonvulsant drug retigabine reversed the pathogenic phenotype and improved the survival of human motoneurons expressing mutant SOD1. In an effort to define global perturbations in cell homeostasis, Kiskinis et al. (2014) measured the changes in gene expression triggered in mutant SOD1-expressing motoneurons. Several gene clusters were misregulated in fALS neurons, involving proteins related to cytoskeleton, mitochondrial, and proteostasis control. The latter observation, and a vast body of functional studies in ALS (Hetz and Mollereau, 2014), led the authors to explore the contribution of ER stress and the unfolded protein response (UPR) to mutant SOD1 pathogenesis, demonstrating a positive impact on neuronal survival and morphogenesis (Kiskinis et al., 2014). Using pharmacological approaches to modulate ion channels, a functional link between the electrical activity of motoneurons and the occurrence of basal ER stress was provided. In addition, targeting the UPR altered the conductivity of motoneurons, suggesting feedforward mechanisms. Finally, the authors confirmed that a subset of these transcriptional responses is conserved in motoneurons expressing a C9orf72 mutation, the most common genetic alteration in ALS, thus increasing
698 Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc.
the overall implications of these findings for a variety of ALS genetic subtypes. Recent studies have attempted to develop a model of sALS using iPSCs. Remarkably, iPSCs derived from sALS patients presented de novo TDP-43 intranuclear inclusions on a subgroup of clones (Burkhardt et al., 2013), which represents the most common histopathological hallmark of ALS. The authors used this abnormal parameter to screen a library of FDA-approved compounds. Similarly, a drug screening was performed to identify small molecules that improve survival of motoneurons expressing mutant SOD1 (Yang et al., 2013). Other studies obtained conflicting results when motoneurons were generated with iPSCs from ALS patients carrying TDP-43 mutations. In one report, ALS motoneurons underwent cell death, correlating with the accumulation of TDP-43 aggregates (Bilican et al., 2012), whereas another group did not detect any spontaneous apoptosis, but observed dendrite alterations and enhanced vulnerability to oxidative stress (Egawa et al., 2012). Similarly, two recent studies showed the presence of abnormal RNA foci and the accumulation of non-ATG-dependent translation peptides in iPSC-derived motoneurons from patients carrying C9orf72 mutations (Donnelly et al., 2013; Sareen et al., 2013). These cells were more susceptible to glutamate toxicity and presented global alterations in RNA
Cell Stem Cell
Previews metabolism, which was reverted by antisense oligonucleotides to target C9orf72 mRNA. Taken together, these studies reveal that iPSC-derived motoneurons from ALS patients develop common pathological features resembling early stages of the disease that could be used to test novel therapeutic strategies, and they support the occurrence of an intrinsic vulnerability to stress. They also caution that the appearance of morphological changes does not always culminate in motoneuron loss. These reports additionally suggest a substantial prevalence of gain-of-toxic and cell-autonomous mechanisms of neurodegeneration in ALS. The current studies illustrate that the use of combinatorial approaches to study iPSC-derived motoneurons offers a well-controlled cell culture model of ALS. The identification of robust and inherited morphological, biochemical, and electrophysiological phenotypes in iPSC-derived neurons supports and sometimes contrasts with the well-established animal models of the disease and will open the possibility of developing
novel drug screenings with therapeutic potential and the identification of novel biomarkers of ALS. These advances will also facilitate the future generation of personalized medicine through the testing of drugs to alleviate selective pathological events that may be unique to the specific genetic landscape of each patient, opening important avenues for the treatment of this fatal disease.
Chen, H., Qian, K., Du, Z., Cao, J., Petersen, A., Liu, H., Blackbourn, L.W.t., Huang, C.L., Errigo, A., Yin, Y., et al. (2014). Cell Stem Cell 14, this issue, 796–809. Donnelly, C.J., Zhang, P.W., Pham, J.T., Heusler, A.R., Mistry, N.A., Vidensky, S., Daley, E.L., Poth, E.M., Hoover, B., Fines, D.M., et al. (2013). Neuron 80, 415–428. Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., Adachi, F., Kondo, T., Okita, K., Asaka, I., et al. (2012). Sci Transl Med 4, 145ra104. Hetz, C., and Mollereau, B. (2014). Nat. Rev. Neurosci. 15, 233–249.
ACKNOWLEDGMENTS The authors are supported by P09-015-F, FONDECYT 1100176, ALS Therapy Alliance, Muscular Dystrophy Association, FONDEF D11I1007, and ACT1109 grants (C.H.), FONDECYT 11121524 (S.M.), and 3130351 (D.M.).
REFERENCES
Kiskinis, E., Sandoe, J., Williams, L.A., Boulting, G.L., Moccia, R., Wainger, B.J., Han, S., Peng, T., Thams, S., Mikkilineni, S., et al. (2014). Cell Stem Cell 14, this issue, 781–795. Sareen, D., O’Rourke, J.G., Meera, P., Muhammad, A.K., Grant, S., Simpkinson, M., Bell, S., Carmona, S., Ornelas, L., Sahabian, A., et al. (2013). Sci Transl Med 5, 208ra149.
Bilican, B., Serio, A., Barmada, S.J., Nishimura, A.L., Sullivan, G.J., Carrasco, M., Phatnani, H.P., Puddifoot, C.A., Story, D., Fletcher, J., et al. (2012). Proc. Natl. Acad. Sci. USA 109, 5803–5808.
Wainger, B.J., Kiskinis, E., Mellin, C., Wiskow, O., Han, S.S., Sandoe, J., Perez, N.P., Williams, L.A., Lee, S., Boulting, G., et al. (2014). Cell Rep. 7, 1–11.
Burkhardt, M.F., Martinez, F.J., Wright, S., Ramos, C., Volfson, D., Mason, M., Garnes, J., Dang, V., Lievers, J., Shoukat-Mumtaz, U., et al. (2013). Mol. Cell. Neurosci. 56, 355–364.
Yang, Y.M., Gupta, S.K., Kim, K.J., Powers, B.E., Cerqueira, A., Wainger, B.J., Ngo, H.D., Rosowski, K.A., Schein, P.A., Ackeifi, C.A., et al. (2013). Cell Stem Cell 12, 713–726.
Human Somatic Cell Nuclear Transfer Is Alive and Well Jose B. Cibelli1,2,* 1Departments
of Physiology and Animal Science, Michigan State University, East Lansing, MI, 48834, USA BIONAND, 29590 Campanillas, Ma´laga, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2014.05.013 2LARCel,
In this issue, Chung et al. (2014) generate human embryonic stem cells by fusing an adult somatic cell to a previously enucleated human oocyte, in agreement with recent reports by the Mitalipov and Egli groups. We can now safely say that human somatic cell nuclear transfer is alive and well. Last year, the group led by Shoukhrat Mitalipov published, for the first time, their success in generating hESCs using cloned human embryos (Tachibana et al., 2013). The field of SCNT, launched by Dolly in 1997, has since been developed by the successful cloning of more than twenty different mammalian species. Using hSCNT to generate hESCs, however, turned out to be more challenging (Cibelli et al., 2001; Fan et al., 2011; French et al., 2008; Noggle et al., 2011; Stojkovic
et al., 2005). Mitalipov’s group spent a significant amount of time refining SCNT, first with monkeys and then with humans. As a result, we now know how to overcome some fundamental roadblocks. The study by Chung et al. (2014), published in this issue along with a recently published paper by Yamada et al. (2014), brings to light fundamental aspects of hSCNT, reasserting this technique as a powerful research and therapeutic tool (Chung et al., 2014; Yamada et al., 2014).
Prior to the publication of this work and based on studies comparing donor nuclei from ESCs with those of somatic cells, there was a general notion that less differentiated cells would serve as better sources of donor nuclei. Chung et al.(2104) successfully dedifferentiated somatic cells from a 75-year-old donor, which is a landmark achievement that refutes the hypothesis that cells from an older individual are harder to dedifferentiate. Borrowing from half a century’s
Cell Stem Cell 14, June 5, 2014 ª2014 Elsevier Inc. 699