Our results show that Exo has a tissue specific role

Our results show that Exo1 has a tissue-specific role in the maintenance of adult stem cell homeostasis: mice exhibited a significant defect in NSCs but not in HSCs. Exo1 deficiency resulted in a decrease in NSC proliferation, which was associated with increased expression of p21, whereas no significant changes in HSC proliferation or p21 expression were observed in mice. Further analysis revealed that Exo1 deficiency led to microsatellite instability in NSCs but not in HSCs. These results suggest that different tissue stem purchase TAK-875 utilize distinct mechanisms for maintaining their genomic stability and function.
Materials and methods
Results
Discussion
Author contributions
Acknowledgments This work was supported by the National Basic Research Program of China (2011CB964800, 2012CB911203), the National Natural Science Foundation of China (81130074), and by the SENS research foundation to Z. J., and the Development Foundation of the Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College (SF1309) to J. Z.
Introduction Bone loss induced by hypoxia is associated with various pathophysiological conditions such as ischemia (Vogt et al., 1997). The long-term culturing of human bone marrow stromal cells (BMSCs) under hypoxia conditions promotes a genetic program that maintains their undifferentiated and multi-potent status (Basciano et al., 2011). Hypoxia induces BMSC proliferation and enhances long-term BMSC expansion, but results in a population with impaired osteogenic differentiation potential (Fehrer et al., 2007; Pattappa et al., 2013). Hypoxia inhibits osteogenic differentiation in BMSCs by regulating Runx2 via the basic helix–loop–helix (bHLH) transcription factor TWIST (Yang et al., 2011). Hyperbaric oxygen (HBO) therapy is a safe noninvasive modality that increases the oxygen tension of tissues and microvasculature (Korhonen et al., 1999). HBO increases the expression of placental growth factor in BMSCs (Shyu et al., 2008), fibroblast growth factor (FGF)-2 in osteoblasts (Hsieh et al., 2010), and the Wnt-3 protein in neural stem cells (Wang et al., 2007). The BMSC population contains a subset comprised of skeletal stem cells, which contribute to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipocyte in vivo, and cartilage in pellet cultures in vitro (Pittenger et al., 1999). Previous studies have suggested that Wnt signaling could be used to stimulate bone healing (Minear et al., 2010) and fracture repair (Komatsu et al., 2010). We first reported the beneficial effects of HBO on bone lengthening in a rabbit model (Ueng et al., 1998). However, little is known about the effects of HBO on the Wnt signaling pathway in BMSCs. Autocrine and paracrine Wnt signaling operates in stem cell populations and regulates mesenchymal lineage specification. The target cells for the Wnt proteins expressed by BMSCs may be either BMSCs themselves or other cell types in the bone marrow (Etheridge et al., 2004). Wnt proteins are secreted lipid-modified signaling molecules that influence multiple processes during animal development (Nusse, 2003). The Wnt family of signaling proteins mediates cell–cell communication (Lorenowicz and Korswagen, 2009; Port and Basler, 2010). In the absence of the Wnt protein, β-catenin is phosphorylated by glycogen synthase kinase-3β (GSK-3β) and subsequently degraded by proteasomes (Zeng et al., 2005). On target cells, secreted Wnt proteins interact with the receptors Frizzled and low-density lipoprotein receptor-related (LRP) 5/6 to activate the β-catenin pathway (Logan and Nusse, 2004). Activation of the Frizzled receptor complex results in the inhibition of a phosphorylation cascade that stabilizes intracellular β-catenin levels. β-Catenin is subsequently translocated into the nucleus to form a transcriptionally active β-catenin T-cell factor (TCF)/lymphoid enhancer factor (LEF) DNA-binding complex that regulates the Wnt target gene. Among Wnt family members, Wnt3a is involved in the proliferation and differentiation of BMSCs (De Boer et al., 2004). Once BMSCs are committed to the osteogenic lineage, canonical Wnt signaling stimulates their differentiation (Ling et al., 2009; Eijken et al., 2008). Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression (Gaur et al., 2005). Runx2 activates osteocalcin, which is an osteoblast-specific gene expressed by differentiated osteoblasts (Ducy, 2000).