Chromosome numerical or structural abnormalities cause serious chromosomal diseases such as Down syndrome. It is estimated approximately 1 percent incidence of chromosomal diseases among newborn infants. Recent progress in iPSCs research suggests patient-derived induced pluripotent stem cells (iPSCs) are highly beneficial for developing chromosomal disease models with multiple cell and tissue types for studying abnormal chromosomal diseases and developing therapeutics for these diseases.
Chromosomal diseases are caused by changes in the number or structure of chromosomes. Some chromosome changes can spontaneous abortions and stillbirths. Other changes cause some diseases after birth with serious symptoms such as intellectual disability, short stature, heart problems, seizures, or a cleft palate.
Chromosome numerical abnormalities are caused by the loss or gain of whole chromosomes. A normal person has 46 chromosomes arranged in 23 pairs. Chromosomal diseases occur when a person loses a chromosome from a pair or has more than two chromosomes of a pair. Common diseases caused by changes in the number of chromosomes include trisomy 21 (Down syndrome), trisomy 13, trisomy 18, and Turner syndrome.
Table.1 Common diseases caused by changes in chromosome number.
| Syndrome | Abnormality |
| Down's | Trisomy 21 |
| Edwards' | Trisomy 18 |
| Patau's | Trisomy 13 |
| Turner | Monosomy X |
| Klinefelter's | XXY |
| XXX | XXX |
| XYY | XYY |
Chromosome structural abnormalities have four major types including deletions, duplications, insertions, and translocation. Diseases caused by chromosome structural abnormalities include Wolf-Hirschhorn syndrome (partial deletion of the short arm of chromosome 4), Jacobsen syndrome (terminal 11q deletion), and Charcot-Marie-Tooth disease type 1A (duplication of the gene encoding peripheral myelin protein 22 on chromosome 17).
Human iPSCs provide unprecedented opportunities for chromosomal disease modeling due to several advantages, such as easy access to starting materials and easy to operate symptoms of chromosomal diseases in vitro. Utilizing patient-derived iPSCs carrying chromosomal abnormality, the in vitro models recapitulating cellular signs of in vivo chromosomal diseases can be constructed, which are useful tools for studying pathological mechanisms, regenerative therapy, and drug discovery.
Fig.2 Potential Applications of Patient-Specific iPSCs. (Sayed, 2016)
Down syndrome (DS) is the most frequent chromosome disease, occurring in about 1 in 1,000. It is caused by a third copy of chromosome 21. iPSCs derived from DS patients have been employed for DS modeling to elucidate the underlying pathology of DS and discover the treatments for DS. Transcriptional profiling of DS-iPSCs showed the misexpression of neural genes such as MAP2, GRIN3A, GABRA2, and STMN2, suggesting the chromosome 21 trisomy in iPSCs might disturb the maintenance of pluripotency. A study found the structure and density of neurons, astroglia, and oligodendrocytes were abnormal together and the expression of neuron genes is misexpressed when DS-iPSCs were differentiated into neural lineages in vitro. Furthermore, DS-neurons have been found to increase the expression of the APP (Amyloid precursor protein) gene and increase secretion and accumulation of amyloid-β (Aβ) granules made of Abeta42 pathological isoform, which may be the cause of an increased risk of DS-associated Alzheimer's disease.
Turner syndrome (TS) is caused by X chromosome monosomy. Patients with TS are likely to exert specific dysmorphic stigmata, hypogonadism, short stature, and renal dysfunctions, skeletal defects, endocrine failure, cardiac diseases, and metabolic deficiency. TS-iPSCs have been successfully generated and were used to uncover the underlying pathology of TS. When TS-iPSCs were differentiated into various somatic cells in embryoid bodies, the lower expression of placental genes, ASMTL, PPP2R3B, and CSF2RA were observed in the genomic pseudoautosomal region.
Klinefelter syndrome (KS) is caused by two or more X chromosomes in males (XXY), occurring in about 1 in 1,000. Patients with KS exerted a variety of clinical symptoms such as tall stature, reduced muscle tone, and hypogonadism. KS-iPSCs provide useful tools for studying the KS pathophysiology. KS-iPSCs have been successfully generated. Through the transcriptome profile of KS-iPSCs, abnormal expression of genes associated with KS symptoms was identified.
Equipped with state-of-the-art technologies and rich experience in stem cell therapy development, Creative Biolabs provides a full range of iPSC services including iPSC reprogramming, differentiation, characterization as well as iPSC-based stem cell therapy services. Our services will facilitate the research of pathological mechanisms of chromosomal diseases and developing new therapies for these diseases.
Reference
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