Pluripotency factor drives cardiogenesis: Research indicates that the adult mammalian heart does not contain cardiac stem cells and the vast majority of cardiomyocytes do not divide. Heart regeneration is thus limited after injury. The postmitotic nature of cardiomyocytes blocks cardiac tumor formation but at the same time minimizes cardiomyocyte renewal. Chen et al . report that cell type–specific expression of pluripotency factors dedifferentiates adult cardiomyocytes to a state that resembles fetal cardiomyocytes, enabling adult cardiomyocytes to reenter mitosis (see the Perspective by Wang and Blau). Cardiomyocytes can be reprogrammed to a pluripotent state when expression of pluripotency factors is sustained over an extended period. If cardiomyocytes are only partially reprogrammed, the heart regenerates without tumor formation. —BAP

Tetraploid embryo complementation assay has shown that mouse ES cells alone are capable of supporting embryonic development and adult life of mice. Newly established F ₁ hybrid ES cells allow the production of ES cell-derived animals at a high enough efficiency to directly make ES cell-based genetics feasible. Here we report the establishment and characterization of 12 new F ₁ hybrid ES cell lines and the use of one of the best (G4) in a gain- and loss-of-function genetic study, where the in vivo phenotypes were assessed directly from ES cell-derived embryos. We found the generation of G4 ES cell-derived animals to be very efficient. Furthermore, even after two consecutive rounds of genetic modifications, the majority of transgenic lines retained the original potential of the parental lines; with 10–40% of chimeras producing ES cell-derived animals/embryos. Using these genetically altered ES cells, this success rate, in most cases, permitted the derivation of a sufficient number of mutants for initial phenotypic analyses only a few weeks after the establishment of the cell lines. Although the experimental design has to take into account a moderate level of uncontrolled damage on ES cell lines, our proof-of-principle experiment provides useful data to assist future designs harnessing the power of this technology to accelerate our understanding of gene function.

The glomerular filtration barrier separates the blood from the urinary space and consists of two major cell types: podocytes and fenestrated endothelial cells. Mesangial cells sit between the capillary loops and provide structural support. Proliferation and loss of mesangial cells both are central findings in a number of renal diseases, including diabetic nephropathy and mesangiolysis, respectively. Using cell-specific gene targeting, it was shown previously that vascular endothelial growth factor A (VEGF-A) production by podocytes is required for glomerular endothelial cell migration, differentiation, and survival. For further investigation of the effect of gene dose and VEGF-A knockdown within the glomerulus, mice that carry one hypomorphic VEGF-A allele and one podocyte-specific null VEGF-A allele (VEGF^hypo/loxP,Neph-Cre^+/−) were generated; in these mice, the “allelic dose” of VEGF-A is intermediate between glomerular-specific heterozygous and null states. VEGF^hypo/loxP,Neph-Cre^+/− mice die at 3 wk of age from renal failure. Although endothelial cell defects are observed, striking loss of mesangial cells occurs postnatally. In addition, differentiated mesangial cells cannot be found in glomeruli of podocyte-specific null VEGF-A mice (VEGF^loxP/loxP,Cre^+/−). Together, these results demonstrate a key role for VEGF-A production in the podocyte for mesangial cell survival and differentiation.