The results of the transcriptome and

The results of the transcriptome and behavioral analyses of the present study also indicate that the spinal cord may not suffer from cellular senescence, and indeed may retain most of its functions, at least to the age of 18 months in normal mice. In contrast, the spinal cord appears to manifest a senescent phenotype upon injury. Interestingly, recent studies have suggested that senescent TAK-875 undergo changes in protein production and secretion that ultimately lead to a state called the senescent-associated secretory phenotype (SASP) (Coppe et al., 2010; Tchkonia et al., 2013). Senescent cells that have acquired this phenotype produce various secreted proteins and generate a microenvironment that promotes the survival and proliferation of tumor cells. By analogy, it is tempting to speculate that a SASP-like phenotype emerges in the spinal cord upon injury and that this condition renders the injury\'s microenvironment in aged mice more suitable for the grafted cells. It is important to note, however, that the production of cytokines (a feature of the SASP-like phenotype) in the injured spinal cord is transient, subsiding within a few weeks (Kumamaru et al., 2012), and therefore does not result in the chronic inflammation associated with SASP. Nevertheless, it is important to understand the mechanisms that underlie the distinct gene expression patterns of aged mice after SCI, because this information might contribute to improvements in the survival and growth of grafted cells in both old and young subjects.
Experimental Procedures
Author Contributions
Acknowledgments This work was supported by grants from the Japan Science and Technology–California Institute for Regenerative Medicine collaborative program, a medical research grant on traffic accidents from the General Insurance Association of Japan, and a grant for the Research Center Network for Realization of Regenerative Medicine from the A-MED to H.O. We thank J. Kohyama, F. Renault-Mihara, Y. Takahashi, T. Konomi, Y. Kobayashi, S. Nishimura, H. Iwai, G. Itakura, and R. Yamaguchi for advice on the experimental approach. We thank Dr. D. Sipp for proofreading the manuscript. We thank T. Harada and S. Miyao for animal care and technical support. H.O. is a scientific consultant and a founder scientist for SanBio and K-Pharma. M.N. is a scientific consultant and a founder scientist for K-Pharma. H.E. is employed by Dainippon Sumitomo Pharma, where he works as a collaborative research fellow. The remaining authors report no conflicts.
Introduction Chromosomal trisomy disorders have long been associated with abnormal developmental outcomes (Oster-Granite, 1986). While early studies detected large chromosomal abnormalities via karyotype analysis or fluorescence in situ hybridization (FISH), more recently, genomic approaches have facilitated unbiased identification of microdeletions and microduplications (reviewed in Watson et al., 2014), identifying many that are significantly associated with schizophrenia and bipolar disorder (CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium and Psychosis Endophenotypes International Consortium, 2016; Malhotra et al., 2011). Human induced pluripotent stem cell (hiPSC)-based models are an emerging strategy by which to evaluate the functional effects of such chromosomal aberrations in human neurons. Growing evidence suggests that hiPSCs are fundamentally similar regardless of reprogramming methods (Choi et al., 2015; Schlaeger et al., 2015) or donor cell types (Kyttala et al., 2016) and that reprogramming increases the number of genes with a detectable donor effect in disease models (Thomas et al., 2015). Mitochondrial heteroplasmy (Perales-Clemente et al., 2016), genetic (Gore et al., 2011; Hussein et al., 2011; Liu et al., 2014), and epigenetic (Mekhoubad et al., 2012; Nazor et al., 2012) differences all contribute to intra-individual variability between hiPSCs. While genetic errors likely reflect both pre-existing mutations in the source somatic cells (Abyzov et al., 2012; Young et al., 2012) and the stresses associated with cellular replication (Laurent et al., 2011; Lu et al., 2014), epigenetic aberrations occur in hiPSCs regardless of the somatic cell type of origin and likely arise during the reprogramming process (Ma et al., 2014). Genetic and epigenetic errors can distinguish hiPSC lines from the same individual. Since such mutations are assumed to arise at equal frequency in hiPSCs reprogrammed from cases and controls, they are not typically considered serious impediments to disease-modeling studies if multiple hiPSC lines are used in comparisons. Although hiPSC-based models are generally assumed to capture the genetic variants contributing to a disease state, notable exceptions have been reported. First, not only can trisomy correction be facilitated by selecting against a transgene (TKNEO) targeted to one copy of chromosome 21 (chr 21) (Li et al., 2012), but spontaneous derivation of isogenic controls can also occur in Down syndrome trisomy 21 hiPSCs (Weick et al., 2013). Second, in hiPSCs derived from a patient with Miller-Dieker syndrome (MDS; MIM #247200), patient fibroblasts lost an abnormal ring chr 17 during hiPSC derivation and duplicated the wild-type homolog, apparently via a compensatory uniparental disomy mechanism (Bershteyn et al., 2014).