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Author(s): Yuji Nakada [1]; Diana C. Canseco [1]; SuWannee Thet [1]; Salim Abdisalaam [2]; Aroumougame Asaithamby [2]; Celio X. Santos [3]; Ajay M. Shah [3]; Hua Zhang [4]; James E. [...]

Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts (1,2), mediated primarily by proliferation of pre-existing cardiomyocytes (3-5). However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers (6). In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function (7-10). Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific a myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals., It was recently reported that new cardiomyocytes in the adult heart are derived from pre-existing cardiomyocytes (3-5), although the identity of cycling cardiomyoctes, and the mechanism of their proliferative competency [...]

How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo (1-10). ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified (3,11,12). Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development., We used multiple approaches, including expression cloning, to identify the receptor(s) for ANGPTLs. Human LILRB2, when ectopically expressed on Baf3 cells, enabled the cells to specifically bind glutathione S-transferase (GST)-ANGPTL5 [...]

Nature 485, 656-660 (2012); doi:10.1038/nature11095 The surname of author HoangDinh Huynh was inadvertently misspelled as Hyunh. This has been corrected online in the PDF and HTML of the original paper. [...]