DS is caused by the trisomy of part or all of human chromosome 21, but its phenotypic features differ from person to person. Understanding and investigating the DS mechanisms are challenges because of the genetic complexity and individual variability of DS phenotypes. Mouse models are useful for DS research, but DS modeling in mice is particularly complex because of the size of the region involved as well as the number of candidate genes and incomplete synteny between animal and human chromosomes. The hESCs , which have the potential to provide an unlimited supply of different cell types for tissue replacement, drug screening, and functional genomics applications, were first derived by Thomson et al. . Although some hESCs with trisomy 21 have been established, the production of different types for DS studies is also limited because of ethical challenges. In addition, the transplantation of hESC-differentiated cells can trigger immune-rejection by the host. In the present study, reprogramming iPSC-DS could provide a source for DS modeling, optimal patient care, drug screening, and eventually autologous cell-replacement therapies. Compared with a previous study by Park et al. , we generated iPSCs from DS patients with various karyotypes (trisomy 21 and translocation). We did not find significant differences between iPSC-DS/trisomy 21 and iPSC-DS/translocation cell lines in the abilities of self-renewal and pluripotency. Although our results were consistent with the previous report, the current study confirmed that iPSCs can be generated from patients with various karyotypes.
iPSCs were first derived by Yamnaka et al.  from mouse fibroblasts with retroviral vectors. In our study, we used lentiviral vectors encoding the four transcription factors (OCT4, SOX2, KLF4, and c-MYC) co-expressed with discernable fluorescent proteins to generate the iPSC-DS. An obvious difference between retroviral and lentiviral vectors is the degree of silencing to which they are subject in pluripotent cells . We have determined the silencing of exogenous genes by monitoring expression of each fluorescent protein. It is know that integration of retroviral and lentiviral vectors into the genome may affect the behaviors of the iPSCs, for sustained expression or reaction of reprogramming factors to prevent proper differentiation of iPSCs. Even for future clinical applications, it would be necessary to reprogram patient cells by using nonintegrating vectors [31, 36]. A number of studies have described successful derivation of iPSCs by using adenoviral vectors, episomal vectors, or the introduction of reprogramming proteins, synthetic modified mRNA [37–40], but a vector-free protocol is usually limited by the low efficiency of iPSCs derivation. Given the rapid pace of the field, further optimization of a highly efficient and vector-free method of generation of iPSCs will facilitate the clinical translation of this technology.
The iPSC technology allows the generation of disease- and patient-specific iPSCs and offers a new cell model for human disease-mechanism studies without ethical controversies, as well as transplantation medicines without immune rejection. With the technology, one group created a human Marfan syndrome "model" to prove the hypothesis that fibrillin-1 mutations result in the disease phenotypes . The hypothesis that the DS gene is dosage dependent predicts that a region critical for specific phenotypes contains a dosage-sensitive gene or genes , of which a dosage imbalance results in the formation of different phenotypes. The establishment of different types of iPSC-DSs can be used to test this hypothesis.
DS is the major cause of congenital heart disease and the most frequent genetic cause of mental retardation. It is also associated with increased risks of leukemia and immune system defects. In a future study, the iPSC-DS "model" can be used to differentiate cardiomyocytes, neuron cells, and lymphocytes for transplantation to improve the phenotypes of patients. For example, ventricular septal defect is a common congenital heart disorder. In future clinical applications, it may be possible to use functional cardiac tissue directly differentiated from autologous iPSC in three-dimensional scaffold to repair the defect . In addition, the study of the differences of cell behavior between the iPSCs-DS, iPSCs derived from normal patients, and iPSCs-DS from different karyotypes would be helpful to understand the disease mechanism and the development of personalized therapy.