43.4: Somatic to iPS Cell Reprogramming
Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012 for this discovery.
The expression of OSKM factors brings about several cellular changes in different phases. The initiation phase downregulates genes specific to the somatic cell, upregulates genes involved in proliferation, and reactivates telomerase. Cells such as fibroblasts undergo a mesenchymal to epithelial transition, where they acquire an apical-basal polarity and express epithelial cell markers, such as cadherin, vimentins, and tight junctions. The intermediate phase involves the activation of genes required for pluripotency. Cells undergoing reprogramming use glycolysis preferentially over oxidative phosphorylation for ATP generation. This change occurs because reprogramming factors transform the elongated mitochondria into spherical ones, with very few cristae. The maturation phase induces epigenetic changes and cytoskeletal remodeling.
The entire reprogramming process alters the expression of around 1500 genes. After reprogramming, less than 1% of the cells become pluripotent. This percentage can be increased by altering the chromatin structure, repressing the expression of proteins, such as p53, that promote cell senescence, and suppressing signaling pathways or enzymes that are barriers to reprogramming.