The broad goal of our research program is to dissect the molecular mechanisms governing the fate decisions of human pluripotent stem cells and use the knowledge to facilitate the study of early development, cell-based therapy and drug discovery. Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can grow as undifferentiated cells and can differentiate into nearly all types of cells in the body. These human pluripotent stem cells have been hailed as a possible means for treating degenerative, malignant, or genetic diseases, as well as injuries due to inflammation, infection and trauma. Meanwhile, they are an invaluable research tool for modeling early human development (both normal and abnormal), and serve as a platform to develop and test new drugs. However, to fully realize their potential, a better understanding of the factors and molecular mechanisms for pluripotency and directed differentiation must be achieved. The objective of this research plan is to define the function of a newly identified protein kinase in regulating the bone morphogenetic protein (BMP) signaling pathway and specifically, neural differentiation during early embryonic development. Our research efforts in the past four years enabled us to identify several key regulatory molecules and pathways that control pluripotency and early differentiation, establish a simple and cost- effective method for highly-efficient large-scale production of neural stem cells from hESCs and hiPSCs, explore the roles of mechanical factors in regulating cellular behaviors and fate determination, and develop new gene-delivery techniques for hESCs. More recently, we have used high-throughput screening (HTS), genomics and proteomics approaches to further advance our understanding of the mechanisms governing stem cell fate. By screening a library of small-hairpin (sh)RNAs that target the human kinome (~3,500 shRNAs targeting ~700 kinases), we identified a protein kinase of previously unknown function as a key regulator of BMP signaling - one of the most critical regulatory pathways that control the fate of human pluripotent stem cells and early embryonic development. Our preliminary results suggest that the kinase promotes the degradation of BMP type I receptors (BMPR-Is) via the proteasome pathway, thereby negatively regulating the BMP pathway, and is necessary for neural development of hESCs and Xenopus laevis. In this research plan, we aim to explore how this kinase controls proteasomal degradation of BMPR-Is in hESCs (Aim 1). In addition, we will assess how the kinase regulates early neural differentiation in hESCs (Aim 2) and neurogenesis in Xenopus laevis (Aim 3). The results from the proposed study will lead to new mechanistic insights into the regulation of BMP signaling, fate determination of human pluripotent stem cells and early embryonic development, enable us to design new strategies for directed differentiation, and facilitate the utilization of hESCs and hiPSCs for cell-based therapy and regenerative medicine.
In this proposed research, we aim to gain new mechanistic insights into the bone morphogenetic protein (BMP) signaling pathway and specifically, neural differentiation during early embryonic development. We propose to use human pluripotent stem cells and the Xenopus animal model to dissect how a newly identified protein kinase of previously unknown function promotes degradation of BMP receptors and controls neural development. The results from the proposed study will lead to new mechanistic insights into the regulation of BMP signaling, fate determination of human pluripotent stem cells and early embryonic development, enable us to design new strategies for directed differentiation and facilitate the utilization of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) for cell- based therapy and regenerative medicine.
|Geng, Yijie; Feng, Bradley (2015) Mesendogen, a novel inhibitor of TRPM6, promotes mesoderm and definitive endoderm differentiation of human embryonic stem cells through alteration of magnesium homeostasis. Heliyon 1:e00046|
|Geng, Yijie; Zhao, Yongfeng; Schuster, Lisa Corinna et al. (2015) A Chemical Biology Study of Human Pluripotent Stem Cells Unveils HSPA8 as a Key Regulator of Pluripotency. Stem Cell Reports 5:1143-54|
|Byrne, Matthew B; Kimura, Yuki; Kapoor, Ashish et al. (2014) Oscillatory behavior of neutrophils under opposing chemoattractant gradients supports a winner-take-all mechanism. PLoS One 9:e85726|
|Qu, Qiuhao; Li, Dong; Louis, Kathleen R et al. (2014) High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1. Nat Commun 5:3449|
|He, Yuan; Li, Dong; Cook, Sara L et al. (2013) Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell 24:3369-80|
|Ouyang, Mingxing; Lu, Shaoying; Kim, Taejin et al. (2013) N-cadherin regulates spatially polarized signals through distinct p120ctn and Î²-catenin-dependent signalling pathways. Nat Commun 4:1589|
|Zhou, Yan; Gormley, Matthew J; Hunkapiller, Nathan M et al. (2013) Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia. J Clin Invest 123:2862-72|
|Gabrielson, Nathan P; Lu, Hua; Yin, Lichen et al. (2012) Reactive and bioactive cationic Ã½Ã½-helical polypeptide template for nonviral gene delivery. Angew Chem Int Ed Engl 51:1143-7|
|Li, Dong; Yang, Hong; Nan, Hong et al. (2012) Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model. Blood 120:4712-9|
|Zhou, Jiaxi; Li, Dong; Wang, Fei (2012) Assessing the function of mTOR in human embryonic stem cells. Methods Mol Biol 821:361-72|
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