In our model DNA damage forces cells into
In our model, DNA damage forces cells into cellular senescence, whereas ATM-dependent and p53-antagonized cytokine secretion activates BMP2/JAK-STAT signaling and stimulates the differentiation process in a progressive feed-forward manner. This senescent state is very different from the GFAP-associated quiescence described elsewhere (Mira et al., 2010; Sun et al., 2011), because quiescent NSCs are characterized by retention of their self-renewal profile. Moreover, this NSC-specific cellular senescence takes place in the absence of persistent DDR signaling, which is commonly required for senescence maintenance in non-stem cell types (d’Adda di Fagagna, 2008; Jackson and Bartek, 2009). Hence, these cellular senescence and ablation of self-renewal are likely to involve epigenetic mechanisms that persist after initial DNA-damage-induced cues.
Telomere-attrition-induced DNA damage in hematopoietic stem cells activates STAT3 and, in turn, BATF in a G-CSF-dependent manner, leading to their differentiation (Wang et al., 2012). Although our microarray data do not indicate this particular signaling activity in irr NSCs, STAT3 seems an important differentiation pathway as suggested by this and other studies (Fukuda et al., 2007; Lee et al., 2010). BMP2 and BMP4, which bind to the same receptor BMPR1, were shown to induce differentiation of glioblastoma-initiating cells (Piccirillo et al., 2006). In the nervous system, BMP2/4 is thought to act in concert with LIF (or another relevant IL-6 family member like CNTF), signaling through SMAD1 and JAK2-STAT3, respectively, to induce GFAP (Fukuda et al., 2007; Nakashima et al., 1999). Others have suggested that BMP2/4 may directly activate STAT3 signaling (Jeanpierre et al., 2008), and BMP4 alone was reported to induce GFAP (Obayashi et al., 2009). Our study provides evidence that BMP2 can activate JAK-STAT signaling and induce GFAP independently of LIF, whereas still requiring binding to its receptor and stimulating its kinase activity.
Previous studies have indicated that NSCs in irradiated rodent EDC.HCl activate cell-cycle checkpoints and lose their neurogenic capacity (Acharya et al., 2010; Monje et al., 2002). Other reports extended the concept of DNA-damage-induced differentiation to other types of somatic stem cells in vivo, such as hair bulge melanocyte stem cells (Inomata et al., 2009) and hematopoietic stem cells (Wang et al., 2012). Together with our findings, these convergent lines of evidence suggest that DNA-damage-induced differentiation may have been selected during evolution to disarm the oncogenic potential of damaged stem cells without the side effects associated with their physical elimination.
Introduction Multipotent mesenchymal stromal cells (MSCs) are a population of multilineage progenitor cells that were first isolated from the bone marrow (Friedenstein, 1976; Pittenger et al., 1999). These somatic progenitor cells harbor the capacity to differentiate into adipocytes, osteoblasts, and chondrocytes, as well as a number of extramesodermal lineages (Prockop, 1997). Recent studies have demonstrated that MSCs exert strong immunomodulatory effects on multiple populations of leukocytes via various mechanisms, including suppression of CD4 and CD8 lymphocyte proliferation and responses, induction of T regulatory lymphocytes (Tregs; a population of immunomodulatory T cells), and secretion of immunosuppressive molecules such as transforming growth factor-β (TGF-β) and indoleamine-2,3-dioxygenase (IDO) (Uccelli et al., 2008). MSCs also strongly suppress natural killer lymphocyte cytotoxicity and affect dendritic cell (DC) maturation, e.g., by inhibiting the differentiation of monocytes to immature myeloid DCs and decreasing the effector functions of plasmacytoid DCs (Le Blanc and Mougiakakos, 2012; Uccelli et al., 2008). Many of these components are similar to the immunomodulatory armamentarium of the immune system, which is important for preventing autoimmunity and establishing tolerance (Guleria and Sayegh, 2007; Wing and Sakaguchi, 2010), with mechanisms ranging from anti-inflammatory molecules such as TGF-β, IDO, and interleukin-10 (IL-10) to leukocyte subpopulations such as Tregs and tolerogenic DCs (Mellor and Munn, 2004; Sakaguchi et al., 2006; Swiecki and Colonna, 2010).