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De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells.
The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, and its size needs to be carefully controlled. Downsizing the ER by autophagy is now shown to involve Sec62, a protein that also helps to build up the organelle. This link suggests a molecular switch for ER size control.
Two studies now show that Ewing's tumour-associated antigen 1 (ETAA1) is recruited to sites of DNA replication stress through its interaction with replication protein A, where it stimulates the ATR kinase to promote efficient genome duplication. These findings provide exciting insight into the already very complex regulatory mechanism of the ATR activation cascade.
It is well established that mutant forms of the p53 tumour suppressor acquire pro-oncogenic activities. Inhibition of the mevalonate pathway is now shown to promote degradation of select oncogenic mutant p53 proteins, indicating that destabilization of mutant p53 could be a promising therapeutic strategy.
Embryonic stem cells maintain pluripotency through countless mitoses. A recent report shows that the transcription factor Esrrb remains bound to chromatin during mitosis, including at regulatory regions that support pluripotency. Mitotic chromatin occupancy by Esrrb might stabilize the defining transcriptional programmes of embryonic stem cells through cell division.
Strikoudis et al. show that Phf5a is necessary for ESC self-renewal, efficient iPSC reprogramming and contributes to muscle specification by stabilizing Paf1C and controlling RNA polymerase II elongation.
Festuccia et al. show that the pluripotency regulator Esrrb is retained on mitotic chromosomes, both in embryonic stem cells and during early embryogenesis, and epigenetically marks key regulatory regions during mitosis.
Two studies by Pasakarnis et al. and Ducuing and Vincent show that the actin cable does not drive dorsal closure, but facilitates closure of the epidermis by providing zipping integrity and homogenizing mechanical tension along the leading edge.
Two studies by Pasakarnis et al. and Ducuing and Vincent show that the actin cable does not drive dorsal closure, but facilitates closure of the epidermis by providing zipping integrity and homogenizing mechanical tension along the leading edge.
Fumagalli et al. show that Sec62 delivers ER components to the autolysosome for clearance by acting as a receptor for autophagy protein LC3-II. This identifies Sec62 as a critical factor for selective ER turnover.
Bass et al. and Haahr et al. identify ETAA1 as a critical replication stress response factor that interacts with DNA damage response proteins and activates ATR to maintain genomic stability.
Bass et al. and Haahr et al. now identify ETAA1 as a critical replication stress response factor that interacts with DNA damage response proteins and activates ATR to maintain genomic stability.
In meiosis, double-strand breaks (DSBs) are induced to initiate chromosome pairing and synapsis. Stanzione et al. identify IHO1 as a protein recruited by HORMAD1 to unsynapsed chromosome axes and required for DSB formation.
Ni et al. report that Snail1 promotes mammary tumour initiation and maintenance independently of its role in EMT. They show that Snail1 forms a complex with HDAC1 and p53 that results in p53 inactivation and degradation, permitting tumour formation.
Iwakuma and colleagues report that statins, through their action on the mevalonate pathway, lead to the ubiquitin-mediated degradation of misfolded mutant p53 by impairing its interaction with the Hsp40 family member, DNAJA1.
Muthuswamy et al. report that in macrophages SCRIB interacts with the NADPH oxidase complex to promote the production of reactive oxygen species needed to kill bacteria. Conversely, loss of SCRIB promotes M1 macrophage polarization and inflammation.
By modulating the presence of lamellipodia and filopodia, Sixt and colleagues determine that migrating dendritic cells rely on these protrusions for directed migration in complex environments, whereas locomotion per se is not driven by lamellipodia.
