In the context of the above
In the context of the above studies and several others PCs are not in all instances dispensable and here the data support an important role of PC in the integrity of the ISC niche. Specifically here the observations indicate a direct dependence of PC on CSF-1R signaling via locally presented CSF-1. Indeed defects in PC numeracy and morphology may serve as a sentinel for potential disruption of the ISC niche which may take time to manifest the ultimate consequences due to the long lived nature of PC. In line with this the onset of SI adenoma formation by Apc deletion in ISCs is characterized by an expansion of ISC-like and PC-like cells, which may represent expansion of a cancer stem cell niche (Schepers et al., 2012). Thus defects in the CSF-1R regulation of PC are likely to contribute to GI disease (Bevins and Salzman, 2011) that may reflect the important role PC play in innate immunity.
The following are the supplementary data related to this article.
Acknowledgments We thank Dr Silvia Fre for the helpful discussions. Expert microscopy assistance was provided by Dr Sarah Ellis and Mr Stephen Asquith (PMCC). Funding sources: ERS receives support from NIH #CA32551 and Einstein Cancer Center grant #5P30-CA13330. RGR and JM receive support from a NHMRC Program #487922 and Cancer Council of Victoria project grant #400217, Australia. MG is supported by a fellowship from the Swiss National Science Foundation #PBBEPS-139392.
Introduction Induced pluripotent stem (iPS) angiotensin receptor blockers are a type of pluripotent stem cells by forced expression of reprogramming transcription factors (Takahashi and Yamanaka, 2006; Yu et al., 2007). Similar to human embryonic stem (ES) cells, human iPS (hiPS) cells can be differentiated into derivatives of the three primary germ layers, such as cardiomyocytes of mesoderm (Wei et al., 2012), pancreatic cells of endoderm (Zhang et al., 2009) and neurons of ectoderm (Bardy et al., 2012; Petit et al., 2011). This breakthrough holds great promise for its applications in cell transplantation, human disease modeling and drug discovery (Laustriat et al., 2010). Despite many attempts to use hiPS cells to model human neurodegenerative diseases for the last five years since they have been available (Brennand et al., 2010; Dimos et al., 2008; Ebert et al., 2009; Israel et al., 2012; Lee et al., 2009; Shi et al., 2012; Song et al., 2011), there are still many challenges. For some neurodegenerative diseases with long latency periods such as Alzheimer\'s disease (AD) and Parkinson disease (PD), it is unclear whether the late-onset disease phenotypes could be recapitulated in iPS cellular models. AD is one of the most common neurodegenerative disorders in aged individuals. It is characterized by neuropathological hallmarks including amyloid plaques, neurofibrillary tangles (NFTs) and eventually neuronal loss in the cerebral cortex and hippocampus. β-amyloid (Aβ) is a peptide of 36–43 amino acids which is processed by successive action of the β and γ secretases from the amyloid precursor protein (APP) and it is most commonly known to be associated with AD (Vassar, 2005). Since β-amyloid 1–42 (Aβ1–42) is one of the main components of the amyloid plaques, it is thought that the accumulation of Aβ1–42 in the brain correlates with AD severity significantly (Cummings and Cotman, 1995). However, the recent failure of clinical studies with γ-secretase inhibitor (semagacestat) (Schor, 2011) has raised questions about whether the clearance of Aβ plaques would treat AD effectively. Therefore, in our study we focused on the investigation of key intracellular mediators of Aβ toxicity through screens of chemical inhibitors against Aβ1–42 toxic effects on hiPS cell-derived neurons. Among the many cellular pathways contributing to cell death, cell cycle dysregulation is thought to be particularly relevant to neurons. Attempts to re-enter cell cycle induced by insults would conflict with their terminally differentiated, non-dividing state (Copani et al., 2001; Greene et al., 2007; Yang et al., 2003). In proliferating cells, cell cycle is precisely regulated by the interactions between Cyclin-dependent kinases (Cdks) and their obligate Cyclin partners. The Cdks are activated via binding with their corresponding Cyclins, and then these activated complexes phosphorylate downstream substrates to initiate a series of cellular events such as DNA replication, chromosome separation and cell division. Tumor suppressor retinoblastoma protein (Rb) is one substrate of the Cdk4/6 and Cdk2. Unphosphorylated Rb plays a role in sequestering transcription factors required for S phase entry. Once the Rb is phosphorylated by the Cdks, the phosphorylated Rb (phos-Rb) reduces its affinity for the transcription factor E2F1. E2F1 is then released from the inhibitory complex E2F-DP and directs the transcription of the S phase specific genes (Nevins, 1992). In post-mitotic cells such as neurons, the cells are held in G0 phase and they withdraw from the cell cycle by lack of active Cdk–Cyclin complexes for cell cycle progression.