Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

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The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein-binding protein (CBP) over p300 by the Wnt/Bcatenin pathway is known to suppress differentiation and increase proliferation. We show that the B-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the B-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage.

The receptor tyrosine kinase EphB4 and its ligand EphrinB2 play a crucial role in vascular development during embryogenesis. The soluble monomeric derivative of the extracellular domain of EphB4 (sEphB4) was designed as an antagonist of EphB4/EphrinB2 signaling. sEphB4 blocks activation of EphB4 and EphrinB2; suppresses endothelial cell migration, adhesion, and tube formation in vitro; and inhibits the angiogenic effects of various growth factors (VEGF and bFGF) in vivo. sEphB4 also inhibits tumor growth in murine tumor xenograft models. sEphB4 IntroductionDifferentiation of mesodermal cells to angioblasts occurs with simultaneous commitment to either arterial or venous lineage. Angioblasts spontaneously aggregate, proliferate, and differentiate to form endothelial tubes of each lineage. Independently developing arterial and venous vascular networks eventually join to form the original cardiovascular loop in the process of vasculogenesis. [1][2][3] Sprouting of new vessels from this primary complex, or angiogenesis, is mediated by growth factors that induce endothelial cell (EC) proliferation, migration, and assembly, followed closely by the recruitment of perivascular cells, including smooth muscle cells, and remodeling of the extracellular matrix. 4,5 A number of ECspecific receptor tyrosine kinases have been identified that play important roles in the early development of blood vessels and formation of the cardiovascular system, and include VEGF receptors and Tie-1 and Tie-2 receptors. [5][6][7][8][9][10][11] More recently, Eph receptors and their ligands have been shown to play a critical role in the development and maturation of the cardiovascular system. [11][12][13] The Ephs and Ephrins together comprise the largest of the receptor tyrosine kinase subfamilies (with 14 receptors and 8 ligands) and are subdivided into EphA and EphB categories based on sequence homologies and binding properties to Ephrin ligands. EphA receptors bind to glycosylphosphatidylinositol (GPI)-anchored Ephrin ligands (EphrinA subfamily), whereas EphB receptors bind Ephrin ligands that contain transmembrane and cytoplasmic domains (EphrinB subfamily). 14 The extracellular domain of Eph receptors consists of a ligand-binding (globular or G) and a cysteine-rich (C) domain followed by 2 fibronectin III-like repeats (F1 and F2). The intracellular domain contains an autoinhibitory tyrosine in the juxtamembrane region, followed by a kinase domain, sterile ␣ and PDZ-binding motifs. 15,16 Eph receptor tyrosine kinases and their Ephrin ligands regulate a diverse array of cellular functions such as cell migration, repulsion, and adhesion, but lack effects on cell proliferation. 9,[17][18][19][20][21] These functions are dependent on bidirectional signals between cells expressing receptors and cells expressing ligands, which, for uniformity of communication, are termed "forward" and "reverse" signaling, respectively. 6,9,11,[21][22][23][24][25] EphrinB2 is specifically expressed in arterial angioblasts and endothelial and perivascular mesench...