Direct reprogramming of adult fibroblasts to a pluripotent state has opened new possibilities for the generation of patient- and disease-specific stem cells. However the ability of induced pluripotent stem (iPS) cells to generate tissue that mediates functional repair has been demonstrated in very few animal models of disease to date. Here we present the proof of principle that iPS cells may be used effectively for the treatment of muscle disorders. We combine the generation of iPS cells with conditional expression of Pax7, a robust approach to derive myogenic progenitors. Transplantation of Pax7-induced iPS-derived myogenic progenitors into dystrophic mice results in extensive engraftment, which is accompanied by improved contractility of treated muscles. These findings demonstrate the myogenic regenerative potential of iPS cells and provide rationale for their future therapeutic application for muscular dystrophies.

SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is an enigmatic disease associated with epigenetic alterations in the subtelomeric heterochromatin of the D4Z4 macrosatellite repeat. Each repeat unit encodes DUX4, a gene that is normally silent in most tissues. Besides muscular loss, most patients suffer retinal vascular telangiectasias. To generate an animal model, we introduced a doxycycline-inducible transgene encoding DUX4and 3′genomic DNA into a euchromatic region of the mouse X chromosome. Without induction, DUX4 RNA was expressed at low levels in many tissues and animals displayed a variety of unexpected dominant leaky phenotypes, including male-specific lethality. Remarkably, rare live-born males expressed DUX4 RNA in the retina and presented a retinal vascular telangiectasia. By using doxycycline to induce DUX4 expression in satellite cells, we observed impaired myogenesis in vitro and in vivo. This mouse model, which shows pathologies due to FSHD-related D4Z4 sequences, is likely to be useful for testing anti-DUX4 therapies in FSHD.

Much remains unknown about the signals that induce early mesoderm to initiate hematopoietic differentiation. Here, we show that endoglin (Eng), a receptor for the TGF␤ superfamily, identifies all cells with hematopoietic fate in the early embryo. These arise in an Eng ؉ Flk1 ؉ mesodermal precursor population at embryonic day 7.5 (E7.5), a cell fraction also endowed with endothelial potential. In Eng-knockout embryos, hematopoietic colony activity and numbers of CD71 ؉ Ter119 ؉ erythroid progenitors were severely reduced. This coincided with severely reduced expression of embryonic globin and key bone morphogenic protein (BMP) target genes, including the hematopoietic regulators Scl, Gata1, Gata2, and Msx-1. To interrogate molecular pathways active in the earliest hematopoietic progenitors, we applied transcriptional profiling to sorted cells from E7. IntroductionDuring mouse development, hematopoiesis occurs at temporally and spatially distinct anatomic sites with the first appearance of hematopoietic cells observed in the blood island (BI) of the extraembryonic yolk sac (YS) at embryonic day 7 (E7.0). 1 This first wave of primitive hematopoiesis produces primitive erythrocytes, megakaryocytes, 2 and macrophages, and is followed by the generation of definitive hematopoietic precursors in the YS at approximately E8.25 days post coitum (dpc). 1 The emergence of hematopoietic stem cells (HSCs) capable of repopulating adult mice is first observed at E10.5 in the aorta-gonad-mesonephros (AGM) region, and later on in other hematopoietic sites, such as YS, placenta, and fetal liver. [3][4][5] HSCs have been proposed to originate from a common precursor for the hematopoietic and endothelial lineages, the hemangioblast, which was initially described using the in vitro embryonic stem cell (ESC) differentiation system, 6 and was later confirmed in the mouse 7 and zebrafish 8 systems. In the murine embryo, this precursor has been identified to be enriched in the primitive streak (PS), and expresses fetal liver kinase 1 (Flk-1 or VEGFR2) in addition to brachyury. Subsequently, these cells migrate to the extraembryonic region, where they give rise to hematopoietic and endothelial cells of the BIs. 7 Endothelial versus hematopoietic fate is thought to be specified en route to the extraembryonic destination because individual BIs are often polyclonal. 9 To date, little is known regarding the molecular and cellular mechanisms involved in the origin and early development of the hematopoietic lineage. It has been reported that signals from extraembryonic ectoderm and visceral endoderm, including fibroblast growth factor 8 (FGF8), WNT3, and hedgehog, are crucial for proper mesoderm patterning, and the latter two are also involved in the specification of the hematopoietic program. 10,11 Members of the TGF␤ superfamily have been shown to play an essential role during vascular development and hematopoiesis. Ligands for the TGF␤ family act through a receptor complex present in the cell surface, which upon phosphorylation causes the ac...