T he earliest event in cardiogenesis is commitment of mesodermal cells to a cardiogenic fate and their migration into the anterolateral region of the embryo during gastrulation. 1 It is therefore important to understand how mesodermal cells are instructed to assume a cardiac fate to elucidate the molecular mechanisms later in heart development. In mammals, these instructive events are largely unknown. Their identification could provide insights into pathways governing cell lineage specification and differentiation, including transcription factor network and extracellular cues that activate them. 2 In addition, understanding early cardiogenesis is of particular interest because cardiomyocyte loss from damage in mammals is largely irreversible and frequently underlies impaired cardiac function in individuals with heart disease. Although there are still multiple barriers to successful regenerative therapies for cardiac disease using embryonic or adult stem cells, cell-based therapeutic approaches remain a valuable goal, particularly when using strategies that do not cross species barriers. 3,4 In this light, embryonic stem cells (ESCs), which faithfully recapitulate early stages of cardiac cell commitment and differentiation, provide a powerful model for investigating how best to control the earliest events in mammalian cardiomyogenesis and ultimately enhance differentiation efficiency.Proteins essential for heart induction have been studied extensively in ESCs, which includes Wnt/-catenin, transforming growth factor- family, bone morphogenetic proteins and Cripto. [5][6][7] Cripto is a glycosylphosphatidylinositolanchored multifunctional protein that is involved in the activation of a complex network of signaling pathways both in development and tumorigenesis. 8,9 Cripto stimulates signaling by the transforming growth factor -family member Nodal or related ligands growth/differentiation factor (GDF)1 and -3, 10,11 through activin type IB (activin receptor-like kinase [ALK]-4) and activin type IIB serine/threonine kinase receptors. 10,12,13 Besides its well-documented stimulatory effect on the canonical Nodal-GDF1-3/ALK-4/Smad2 pathway, Nodal/ALK-4 -independent Cripto activities have also been described. 9,14 Notably, recent data highlight a novel role of Cripto as Activin/transforming growth factor- antagonist. 15,16 Original received September 16, 2008; resubmission received May 21, 2009; revised resubmission received June 22, 2009; accepted June 23, 2009. From the Stem Cell Fate Laboratory (C.D., E.L., S.I., O.G., G.M.), Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Naples, Italy; Institute of Genetics and Biophysics "A. Buzzati-Traverso" (C.D., E.L., S.I., O.G., A.M.L., G.L.L., G.M.), Consiglio Nazionale delle Ricerche, Naples, Italy; Vesalius Research Center (M.A., P.C.), VIB, Leuven, Belgium; and Vesalius Research Center (P.C.), Katholieke Universiteit Leuven, Belgium.Correspondence to Gabriella Minchiotti, Institute of Genetics and Biophysics "A. We have ...
Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. However, our understanding of the molecular mechanisms underlying satellite cell activation is still largely undefined. Here, we show that Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. Conditional inactivation of cripto in adult satellite cells compromises skeletal muscle regeneration, whereas gain of function of Cripto accelerates regeneration, leading to muscle hypertrophy. Moreover, we provide evidence that Cripto modulates myogenic cell determination and promotes proliferation by antagonizing the TGF-β ligand myostatin. Our data provide unique insights into the molecular and cellular basis of Cripto activity in skeletal muscle regeneration and raise previously undescribed implications for stem cell biology and regenerative medicine. myogenic commitment | skeletal muscle stem cells | teratocarcinoma derived growth factor-1 (TDGF-1) | growth differentiation factor-8 (GDF-8)
We propose a model in which Apj controls a regulatory Cerberus-Baf60c pathway in pluripotent stem cell cardiomyogenesis, and speculate that this regulatory circuit may regulate cardiac progenitor cell behaviour.
Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. Despite extensive studies, knowledge of the molecular mechanisms underlying the early events associated with satellite cell activation and myogenic commitment in muscle regeneration remains still incomplete. Cripto is a novel regulator of postnatal skeletal muscle regeneration and a promising target for future therapy. Indeed, Cripto is expressed both in myogenic and inflammatory cells in skeletal muscle after acute injury and it is required in the satellite cell compartment to achieve effective muscle regeneration. A critical requirement to further explore the in vivo cellular contribution of Cripto in regulating skeletal muscle regeneration is the possibility to overexpress Cripto in its endogenous configuration and in a cell and time-specific manner. Here we report the generation and the functional characterization of a novel mouse model for conditional expression of Cripto, i.e., the Tg:DsRedloxP/loxPCripto-eGFP mice. Moreover, by using a satellite cell specific Cre-driver line we investigated the biological effect of Cripto overexpression in vivo, and provided evidence that overexpression of Cripto in the adult satellite cell compartment promotes myogenic commitment and differentiation, and enhances early regeneration in a mouse model of acute injury.
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