Work in model organisms has revealed that a small number of signal transduction pathways, including the Wnt/b-catenin pathway, play key roles throughout development, as well as in tissue repair and stem cell homeostasis in adults. Interestingly, the composition of the Wnt/b-catenin pathway differs in distinct cellular contexts, depending on expression of unique modifiers of the signaling pathway, or expression of different isoforms of conserved pathway components. We and others have evidence (see Preliminary studies) that Wnt/b-catenin signaling is repressed in pluripotent human embryonic stem cells (hESCs) undergoing selfrenewal, and that signaling is active during differentiation into both early and later mesodermal cell lineages. We hypothesize that context-dependent modifiers of Wnt/b-catenin signaling play key roles in the self-renewal and differentiation of hESCs. The initial goal of this proposal is to test the hypothesis that context-dependent modulators of Wnt/b-catenin signaling play key roles in regulating self-renewal and differentiation in hESCs. We believe that pursuit of this goal will reveal detailed mechanisms by which Wnt/beta-catenin signaling regulates self-renewal and specification of cell fate in hESCs. Our second goal is to expand our investigation of the roles of signal transduction pathways in stem cells to include the Hedgehog, Notch, and TGFb pathways, using novel multiplexed fluorescent reporters to enable simultaneous monitoring of multiple pathways in live cells. We believe that the development of the technology to simultaneously visualize the state of activity of multiple signaling pathways in live cells will have numerous uses in studies of signaling pathways in normal and diseased tissues.
Human embryonic stem cells (hESCs) have the capacity to renew themselves in culture and to differentiate into different cell types, such as heart or nervous system. Wnts are secreted proteins that act as messengers between cells, and which can instruct hESCs to alter whether they self-renew or whether they differentiate. We propose experiments that will provide insights into the mechanisms by which Wnts control self renewal and differentiation of hESCs.
|Hofsteen, Peter; Robitaille, Aaron Mark; Strash, Nicholas et al. (2018) ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells. iScience 2:88-100|
|Kim, Yong Kyun; Refaeli, Ido; Brooks, Craig R et al. (2017) Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development. Stem Cells 35:2366-2378|
|Artoni, Filippo; Kreipke, Rebecca E; Palmeira, Ondina et al. (2017) Loss of foxo rescues stem cell aging in Drosophila germ line. Elife 6:|
|Palpant, Nathan J; Pabon, Lil; Friedman, Clayton E et al. (2017) Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells. Nat Protoc 12:15-31|
|Yang, Xiulan; Murry, Charles E (2017) One Stride Forward: Maturation and Scalable Production of Engineered Human Myocardium. Circulation 135:1848-1850|
|Kadota, Shin; Pabon, Lil; Reinecke, Hans et al. (2017) In Vivo Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Neonatal and Adult Rat Hearts. Stem Cell Reports 8:278-289|
|Nakamura, Paul A; Shimchuk, Andy A; Tang, Shibing et al. (2017) Small molecule Photoregulin3 prevents retinal degeneration in the RhoP23H mouse model of retinitis pigmentosa. Elife 6:|
|Moody, James D; Levy, Shiri; Mathieu, Julie et al. (2017) First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. Proc Natl Acad Sci U S A 114:10125-10130|
|Mathieu, Julie; Ruohola-Baker, Hannele (2017) Metabolic remodeling during the loss and acquisition of pluripotency. Development 144:541-551|
|Rabinowitz, Jeremy S; Robitaille, Aaron M; Wang, Yuliang et al. (2017) Transcriptomic, proteomic, and metabolomic landscape of positional memory in the caudal fin of zebrafish. Proc Natl Acad Sci U S A 114:E717-E726|
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