Apoptosis is essential for embryogenesis, organ metamorphosis, and tissue homeostasis. In embryonic stem cells, self-renewal is balanced with proliferative potential, inhibition of differentiation, and prevention of senescence and apoptosis. Growing evidence supports the role of apoptosis in self-renewal, differentiation of pluripotent stem cells, and dedifferentiation (reprogramming) of somatic cells. In this paper we discuss the multiple roles of apoptosis in embryonic stem cells (ESCs) and reprogramming of differentiated cells to pluripotency. The role of caspases and p53 as key effectors in controlling the generation of iPSC is emphasized. Remarkably, the complication of apoptosis arising during reprogramming may provide insights into technical improvements for derivation of iPSC from senescent cells as a tool for modeling aging-related diseases. 1. Introduction Apoptosis is a type of programmed cell death first described by Kerr et al. in the 1970s. It is morphologically characterized by cell shrinkage, membrane blebbing and nuclear condensation, and formation of apoptotic bodies [1]. The apoptotic process is initiated by “death” signals, which trigger a complex series of events with multiple positive and negative feedback loops [2]. A central step in the execution of the apoptotic process is the activation of caspases, a group of enzymes belonging to the cysteine protease family. Activation of caspases cleaves many vital cellular proteins, breaking down the nuclear scaffold and cytoskeleton, and subsequently leads to nuclear DNA degradation [3]. Based on the original source of “death” signals, caspase-dependent apoptosis is classified into two pathways: intrinsic pathway, which is activated by modulators within the cell itself, and extrinsic pathway, which responds mainly to extracellular stimuli [4]. In the extrinsic pathway (also known as receptor-mediated death pathway), death ligands such as TRAIL and FasL induce apoptosis by activating the death receptors (DR4/TRAILR1/Apo2 and Fas/Apo1, etc.) at the cell surface. The activated death receptors oligomerize, which leads to recruitment of the adaptor proteins such as FADD (Fas-associated protein with death domain) and further chain activation of caspase-8 and -3 [2, 4, 5]. The intrinsic pathway, which is also known as mitochondria-mediated death pathway, is initiated by damage to mitochondria which results in the release of a series of proteins into cytoplasm, including cytochrome c. When released into the cytoplasm, cytochrome c complexes with Apaf-1, and this complex further activates caspase-9
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