Tissue homeostasis depends largely on the ability to replenish impaired or aged cells. Thus, tissue-resident stem cells need to provide functional progeny throughout the lifetime of an organism. Significant work in the past years has characterized how stem cells integrate signals from their environment to shape regulatory transcriptional networks and chromatin-regulating factors that control stem cell differentiation or maintenance. There is increasing interest in how post-translational modifications, and specifically ubiquitylation, control these crucial decisions. Ubiquitylation modulates the stability and function of important factors that regulate key processes in stem cell behavior. In this review, we analyze the role of ubiquitylation in embryonic stem cells and different adult multipotent stem cell systems and discuss the underlying mechanisms that control the balance between quiescence, self-renewal, and differentiation. We also discuss deregulated processes of ubiquitin-mediated protein degradation that lead to the development of tumor-initiating cells.
Stem cells: concepts and definitionsEmbryonic stem cells and adult tissue-resident stem cells are of great interest in biology and medicine due to their unique characteristics [1]. They have the ability to self-renew, which is defined as the capacity to proliferate while being able to differentiate to downstream cellular types upon proper stimuli from their environment. This unparalleled cellular plasticity of stem cells identifies them as key determinants of tissue equilibrium.Although progenitor cells also have the ability to self-renew, this is usually a short-term characteristic [2]. The long-term self-renewal capacity of stem cells is essential to supply tissues with differentiated progeny throughout the life of the organism. Adult stem cells reside in specialized microenvironments called niches and manifest different degrees of quiescence, depending on the specific organ characteristics. For example, hematopoietic stem cells (HSCs) are dormant [3], whereas mammary stem cells (MaSCs) appear to be cycling [4] and intestinal stem cells (ISCs) proliferate rapidly [5].Stem cells can divide symmetrically or asymmetrically [6; Sidebar A]. Symmetric cell divisions ensure that all elements are distributed equally between the two identical daughter stem cells, and differentiation-usually of only one of the daughter cells-occurs at a later stage. Asymmetric cell divisions, on the other hand, lead to the unequal division of stem cell components in a process that involves proper positioning of the mitotic spindle [7]. As a result, one cell remains a stem cell, whereas the other adopts a different cell fate. Asymmetric divisions also physically displace one daughter cell from its relative position to the niche, leading to its differentiation.Signals from the niche microenvironment are critical in regulating intrinsic stem cell transcriptional programs. Various signaling pathways such as Wnt, Hedgehog, Notch, TGF-b/BMP, and JAK/STAT act in concert to sha...