Induced pluripotent stem cells and senescence: learning the biology to improve the technology

Abstract

The discovery that adult somatic cells can be reprogrammed into pluripotent cells by expressing a combination of factors associated with pluripotency holds immense promise for a wide range of biotechnological and therapeutic applications. However, some hurdles-such as improving the low reprogramming efficiencies and ensuring the pluripotent potential, genomic integrity and safety of the resulting cells-must be overcome before induced pluripotent stem cells (iPSCs) can be used for clinical purposes. Several groups have recently shown that key tumour suppressors-such as members of the p53 and p16(INK4a)/retinoblastoma networks-control the efficiency of iPSC generation by activating cell-intrinsic programmes such as senescence. Here, we discuss the implications of these discoveries for improving the safety and efficiency of iPSC generation, and for increasing our understanding of different aspects of basic biology-such as the control of pluripotency or the mechanisms involved in the generation of cancer stem cells.

Figure 1

Generation of secondary iPSCs. Reprogramming factors are expressed from doxycycline-inducible vectors in primary somatic cells. Induction of reprogramming into primary iPSCs is achieved by treatment with doxycycline, colony selection and treatment withdrawal. The resulting iPSCs are then differentiated in vitro to somatic cells that carry the DOX-inducible factors; alternatively, chimeric animals can be produced from which to obtain somatic cells—such as B cells or fibroblasts. Secondary somatic cells—which all contain integrated reprogramming factors—can undergo reprogramming by DOX induction to produce secondary iPSCs with greater efficiency. DOX, doxycycline; iPSCs, induced pluripotent stem cells; KLF4, Kruppel-like factor 4; OCT4, octamer 4; SOX2, SRY-box 2.

Figure 2

Alternative cell fates limit reprogramming efficiency. During successful reprogramming, the expression of reprogramming factors in somatic cells results in the generation of iPSCs. In some cases, the reprogramming process is not complete and partially reprogrammed iPSCs that have undergone incomplete chromatin remodelling are obtained. Alternatively, the expression of the reprogramming factors can cause senescence (RIS), apoptosis, or contribute to the oncogenic transformation of the resulting cells. ESC, embryonic stem cell; iPSCs, induced pluripotent stem cells; KLF4, Kruppel-like factor 4; OCT4, octamer 4; RIS, reprogramming-induced senescence; SOX2, SRY-box 2.

Figure 3

Similarities between reprogramming to pluripotency and oncogenic transformation. (A) Aberrant oncogene expression triggers senescence (OIS) in primary cells, which limits oncogenic transformation. The expression of the reprogramming factors also triggers senescence (RIS), limiting the efficiency of reprogramming. (B) As a consequence, when senescence is disabled, cells are more susceptible to either oncogenic transformation or reprogramming. OIS, oncogene-induced senescence; RIS, reprogramming-induced senescence.