Abstract: The present invention provides Jagged 1 and Frizzled 4 as cell surface markers for isolating human cardiomyogenic ventricular progenitor cells, in particular progenitor cells that preferentially differentiate into cardiac ventricular muscle cells. Thus, the invention provides human ventricular progenitor (HVP) cells. The invention provides in vitro methods of the separation of Islet 1+ Jagged 1+ ventricular progenitor cells and/or Islet 1+/Frizzled 4+ ventricular progenitor cells and/or Islet 1+/Jagged 1+/Frizzled 4+ ventricular progenitor cells, and the large scale expansion and propagation thereof. Large clonal populations of isolated Jagged 1+ and/or Frizzled 4+ventricular progenitor cells are also provided. Methods of in vivo use of Jagged 1+ and/or Frizzled 4+ ventricular progenitor cells for cardiac repair or to improve cardiac function are also provided. Methods of using the Jagged 1+ and/or Frizzled 4+ ventricular progenitor cells for cardiac toxicity screening of test compounds are also provided.

Abstract: The present invention relates to the generation of vascularized human heart tissue from human primordial Islet1-positive (ISL1+) progenitors, and more particularly the generation of vascularized human heart tissue from human primordial Islet1+ cardiovascular stem cells which are positive for markers ISL1+/NKX2.5?/KDR?. One aspect of the invention relates to isolation of human ISL1+ primordial cells from human pluripotent cells, such as human ES cells or other human pluripotent stem cell sources, wherein the human ISL1+ primordial cells can differentiate into three different lineages; cardiomyocyte lineages, endothelial lineages and smooth muscle lineages. Another aspect relates to use and implantation of the human primordial ISL1+ progenitors into an animal model to generate human vascularized heart tissue, and more particularly, the production of an in vivo humanized model of vascular disease.

Abstract: Aspects of the invention described herein relate to synthetic, modified RNAs and their use in vivo to modulate gene expression. Aspects of the invention further relate to the use of these synthetic, modified RNAs in myocytes, cardiomyoctes, and tumors.

Abstract: The present invention relates to the generation of vascularized human heart tissue from human primordial Islet1-positive (ISL1+) progenitors, and more particularly the generation of vascularized human heart tissue from human primordial Islet1+ cardiovascular stem cells which are positive for markers ISL1+/NKX2.5?/KDR?. One aspect of the invention relates to isolation of human ISL1+ primordial cells from human pluripotent cells, such as human ES cells or other human pluripotent stem cell sources, wherein the human ISL1+ primordial cells can differentiate into three different lineages; cardiomyocyte lineages, endothelial lineages and smooth muscle lineages. Another aspect relates to use and implantation of the human primordial ISL1+ progenitors into an animal model to generate human vascularized heart tissue, and more particularly, the production of an in vivo humanized model of vascular disease.

Abstract: The present invention generally relates to a population of committed ventricular progenitor (CVP) cells and their use to generate a tissue engineered myocardium, in particular two dimensional tissue engineered myocardium which is comparable to functional ventricular heart muscle. One embodiment of present invention provides a composition and methods for the production of a tissue engineered myocardium which has functional properties of cardiac muscle, such as contractibility (e.g. contraction force) and numerous properties of mature fully functional ventricular heart muscle tissue. In particular, in one embodiment, a composition comprising the tissue engineered myocardium comprises committed ventricular progenitor (CVP) cells seeded on a free-standing biopolymer structure to form functional ventricular myocardium tissue.

Abstract: The present invention generally relates to methods and compositions to generate a secondary iPS (2iPS) cell to produce somatic cells of a rare differentiation cell type fate. In some embodiments, the method relates to an increase in efficiency of differentiation and production of high yields of somatic cells of a rare differentiation cell type fate produced from secondary iPS (2iPS) cells as compared to their differentiation from other pluripotent stem cell sources such as ES cells or primary iPS cells. In some embodiments, the present invention relates to compositions, methods and systems for reprogramming a first somatic cell into a primary iPS cell, where the primary iPS cell is then differentiated along a selected linage to produce a second somatic cell, which is then reprogrammed to a secondary iPS cell (2iPS) cell. The 2iPS cell has a high efficiency of differentiating into a cell of the same cell type as the second somatic cell, e.g.

Abstract: The present invention relates to methods for the induction and a cell to enter the Islet 1+ (Isl1+) lineage and methods for expansion of cells of islet 1+ lineage. One aspect of the present invention relates to methods to induce a cell to enter the islet 1+ lineage, and more particularly to a method to induce a cell to enter a the Isl1+ lineage to become an Isl1+ progenitor that is capable of differentiating along multiple different lineages such as a endothelial lineage, a smooth muscle lineage or a cardiac lineage. In particular, one embodiment present invention relates to methods to induce a cell to enter the Isl1+ lineage by inhibiting a wnt signalling pathway in the cell. Another aspect of the present invention relates to methods to expand a cell of the Isl1+ lineage, such as a Isl1+ progenitor by activating a wnt signalling pathway in the Isl1+ progenitor.

Abstract: The present invention relates generally to the field of cardiovascular repair, and more particularly to methods and compositions for the survival of cells in response to mechanical stress and to the proliferation of postnatal cardiomyocytes. The present invention relates to a nuclear form of Creb312(N) polypeptide which when expressed in a cell promotes cell survival in response to stress such as mechanical stretch stress. Another aspect of the invention relates to the expression of the nuclear form of Creb312(N) polypeptide in a cardiomyocyte promotes propagation or regeneration of the cardiomyocyte.

Abstract: The present invention relates to isolation of cardiovascular stem cells, and more particularly to cardiovascular stem cells positive for markers isll+/Nkx2.5+/flkl+ and cardiovascular stem cells which can differentiate along endothelial, cardiac, and smooth muscle cell lineages. The invention relates to uses of the cardiovascular stem cells, in particular for the treatment of cardiovascular disorders and as an assay comprising a plurality of cardiovascular stem cells. The invention also relates to a method for isolation and enrichment of stem cells using mesenchymal cell feeder layer and uses of mesenchymal feeder layer as a screening assay for agents which effect stem cells.

Abstract: The present invention provides in vitro methods of expansion and propagation of undifferentiated progenitor cells and more specifically undifferentiated progenitor cells containing Islet1, a marker apparently unique to proliferating cardiac stem cells. Methods are described for isolation of stem cell populations as well as for provoking expansion and propagation of undifferentiated progenitor cells without differentiation, to provide cardiac repair or improve cardiac function, for example.

Abstract: Methods for the delivery of genes to improve cardiac function including the use of viral vectors, isolation of the heart from systemic circulation, and induction of hypothermia/cardiac arrest are described. The method results in high-level, long-term expression of reporter genes and enhanced cardiac function in hamster models of heart disease.

Abstract: The invention relates to novel promoter sequences derived from a portion upstream of the coding sequence of the gene for the CARP protein (Cardiac Ankyrin Repeat Protein), and which are capable of controlling the level and the specificity of expression of a transgene in vivo in cardiac muscle cells. The invention thus describes novel compositions, constructs, vectors and their uses in vivo for the transfer and expression of a nucleic acid in vivo in cardiac muscle cells. The subject of the present invention is also the use of the promoter sequences for generating transgenic animals which constitute models for studying certain cardiac pathologies.

Abstract: Heart failure following myocardial infarction is treated by administration of an angiotensin II inhibitor for 8-12 weeks, followed by administration of a growth hormone for 1-3 weeks.

Abstract: The invention relates to novel promoter sequences derived from a portion upstream of the coding sequence of the gene for the CARP protein (Cardiac Ankyrin Repeat Protein), and which are capable of controlling the level and the specificity of expression of a transgene in vivo in cardiac muscle cells.

Abstract: The present invention relates to a human type-5 recombinant adenovirus vector for achieving cardiac restricted transcription involving utilization of the cardiomyocyte-restricted cardiac ankyrin repeat protein (CARP) promoter with inclusion of the inverted terminal repeat sequences from human adeno-associated virus (AAV). Using green fluorescent protein (GFP) as a marker gene, the recombinant adenovirus vector (Ad/CG/ITR) is shown to direct transgene expression to myocardial tissue in vivo and in vitro in mouse models.

Abstract: Heart failure following myocardial infarction is treated by administration of an angiotensin II inhibitor for 8-12 weeks, followed by administration of a growth hormone for 1-3 weeks.

Abstract: Methods for the delivery of genes to improve cardiac function including the use of viral vectors, isolation of the heart from systemic circulation, and induction of hypothermia/cardiac arrest are described. The method results in high-level, long-term expression of reporter genes and enhanced cardiac function in hamster models of heart disease.

Abstract: Heart failure following myocardial infarction is treated by administration of an angiotensin II inhibitor for 8-12 weeks, followed by administration of a growth hormone for 1-3 weeks.

Abstract: In accordance with the present invention, there are provided targeted loss of function mutant mice which express less than endogenous levels of at least one member of the steroid/thyroid superfamily of receptors in at least one specific tissue type. For example, mutations in the RXR&agr; gene in mouse germlines are lethal in the embryonic stage between E13.5 and E16.5 when bred to homozygosity. The major defect responsible for this lethal effect is hypoplastic development of the ventricular chambers of the heart, which is manifest as a grossly thinned ventricular wall with concurrent defects in ventricular septation. This phenotype is identical to a subset of the effects of embryonic vitamin A deficiency, and therefore establishes RXR&agr; as a genetic component of the vitamin A signaling pathway in cardiac morphogenesis.

Abstract: The invention features methods of identifying a compound which suppresses ventricular muscle cell hypertrophy. In one embodiment, ventricular muscle cells are contacted with a test compound, which acts through an RAR or RXR receptor, in the presence of an inducer of hypertrophy. Development of ventricular muscle cell hypertrophy is then measured to identify compounds having the desired activity.