Human Pluripotent Stem cells (hPSCs), including embryonic stem cells (ESCs) and especially, induced pluripotent stem cells (iPSCs) established from patient's tissues, offer a new research tool for understanding disease pathogenesis, a versatile template for drug discovery, and a promising source of cell therapy. A key step in realizing these potentials of human PSCs is genetic modification / gene targeting, as in the creation of transgenic animals that has revolutionized biomedical research and discovery. Unlike their mouse counterparts, transgenesis of hPSCs is inefficient and the transgene expression is often not stable, especially upon neural differentiation, let alone functional regulation. Technical difficulties in genetically modifying hPSCs and unavailability of commonly needed hPSC lines, as opposed to readily available transgenic animals, have become a significant barrier to neuroscience research. The present proposal aims to overcome these hurdles by building and distributing transgenic hPSCs and related reagents. Building upon our decade's experience in hPSC research, we will first establish hESC lines with a (GFP) reporter in neural genes that are most frequently sought by investigators in neuroscience using the TALEN- or CRISPR/CAS-mediated homologous recombination technology (Aim 1). We will also build hPSC lines with a functional regulator in an envy site under the control of a neural promoter (Aim 2), which will allow interrogation of the function of human neural cells in vitro and in vivo. These cell lines will be distributed through the WiCell Institute or an NIH designated distribution center (e.g., Rutgers University Cell and DNA Repository [RUCDR]). To promote neuroscience research in a broad spectrum as well as that involving specialized model systems (e.g., disease iPSCs), we will further deposit the transgenic reagents that are proven effective through Addegene for dissemination (Aim 3). Availability of such hPSC lines and tools will substantially speed up the next wave of neuroscience discovery in a cost effective manner and enable translation to clinical neuroscience.
The unique transgenic human PSC lines and reagents to be established and distributed will impact on a broad community of neuroscience researchers by speeding up the next wave of neuroscience discovery and enabling translation to human health.
|Qian, Kun; Huang, Hailong; Peterson, Andrew et al. (2017) Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo. Stem Cell Reports 8:843-855|
|Jones, Jeffrey R; Zhang, Su-Chun (2016) Engineering human cells and tissues through pluripotent stem cells. Curr Opin Biotechnol 40:133-138|
|Lu, Jianfeng; Zhong, Xuefei; Liu, Huisheng et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89-94|
|Chen, Yuejun; Xiong, Man; Dong, Yi et al. (2016) Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease. Cell Stem Cell 18:817-26|
|Tao, Yunlong; Zhang, Su-Chun (2016) Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell 19:573-586|
|Zhong, Xuefei; Hao, Ling; Lu, Jianfeng et al. (2016) Quantitative analysis of serotonin secreted by human embryonic stem cells-derived serotonergic neurons via pH-mediated online stacking-CE-ESI-MRM. Electrophoresis 37:1027-30|
|Liu, Huisheng; Lu, Jianfeng; Chen, Hong et al. (2015) Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability. Sci Rep 5:12189|
|Chen, Yuejun; Cao, Jingyuan; Xiong, Man et al. (2015) Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9. Cell Stem Cell 17:233-44|
|Du, Zhong-Wei; Chen, Hong; Liu, Huisheng et al. (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6:6626|
|Chen, Yuejun; Xiong, Man; Zhang, Su-Chun (2015) Illuminating Parkinson's therapy with optogenetics. Nat Biotechnol 33:149-50|
Showing the most recent 10 out of 12 publications