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Rapid and Cost-Effective Gene Targeting in Rat Embryonic stem cells by TALENs

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Journal of Genetics and Genomics 2012年第6期39卷 275-280页

作者： Charles Ashton eli and edythe broad center for regenerative medicine and stem cell research at USC Department of Cell and NeurobiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA

The rat is the preferred animal model in many areas of biomedical research and drug development. Genetic manipulation in rats has lagged behind that in mice due to the lack of efficient gene targeting tools. Previously, we generated a knockout rat via conventional homologous recombination in rat embryonic stern （ES） cells. Here, we show that efficient gene targeting in rat ES cells can be achieved quickly through transcription activator-like effector nuclease （TALEN）-mediated DNA double-strand breaks. Using the Golden Gate cloning technique, we constructed a pair of TALEN targeting vectors for the gene of interest in 5 days. After gene transfection, the targeted rat ES cell colonies were isolated, screened, and confirmed by PCR without the need of drug selection. Our results suggest that TALEN-mediated gene targeting is a superior means of establishing genetically modified rat ES cell lines with high efficiency and short turnaround time.

关键词： TAL effector BMPR2 Rat ES cells Gene-targeting

Metabolism of pluripotent stem cells

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Frontiers in Biology 2016年第5期11卷 355-365页

作者： Liang Hu Edward Trope Qi-Long Ying eli and edythe broad center for regenerative medicine and stem cell research at USC Department of Stem Cell Biology and Regenerative Medicine Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

BACKGROUND： Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal ofpluripotent stem cells （PSCs）, in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome. OBJECTIVE： To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation. METHODS： A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used：＂metabolism＂ combined with either ＂embryonic stem cell＂ or ＂epiblast stem cell.＂ RESULTS： Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized. CONCLUSION： Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.

关键词： metabolism pluripotent stem cells pluripotency epigenetics

Mending a broken heart with novel cardiogenic small molecules

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cell Regeneration 2022年第1期11卷 188-191页

作者： Nevan Powers Guo N.Huang Cardiovascular research Institute&Department of Physiology University of CaliforniaSan FranciscoSan FranciscoCA 94158USA eli and edythe broad center for Regeneration medicine and stem cell research University of CaliforniaSan FranciscoSan FranciscoCA 94158USA

Adult mammalian cardiomyocytes are unable to proliferate to regenerate lost tissue after heart *** et al.,reporting in cell stem cell,employ a FUCCI-and MADM-based system to screen for small molecules combinations that produced a collaborative effect on cardiomyocyte cycling and *** authors generate a cocktail of five small molecules that increase cardiomyocyte proliferation and regeneration in vitro and in vivo with high efficiency,and explore its potential in cardiac regenerative repair after myocardial infarction through a new potential pathway for cardiomyocyte cell-cycle re-entry.

关键词： cardio cardiac

Long-term, in vivo therapeutic effects of a single dose of miR-145 micelles for atherosclerosis

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Bioactive Materials 2023年第9期27卷 327-336页

作者： Deborah D.Chin Neil Patel Woori Lee Sonali Kanaya Jackson Cook Eun Ji Chung Department of Biomedical Engineering University of Southern CaliforniaLos AngelesCA90089United States Division of Vascular Surgery and Endovascular Therapy Department of SurgeryKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Mork Family Department of Chemical Engineering and Materials Science University of Southern CaliforniaLos AngelesCA90089United States eli and edythe broad center for regenerative medicine and stem cell research Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Division of Nephrology and Hypertension Department of MedicineKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Norris Comprehensive Cancer center Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90089United States

Atherosclerosis is a chronic inflammatory disease that is characterized by the build-up of lipid-rich plaques in the arterial walls. The standard treatment for patients with atherosclerosis is statin therapy aimed to lower serum lipid levels. Despite its widespread use, many patients taking statins continue to experience acute events. Thus, to develop improved and alternative therapies, we previously reported on microRNA-145 (miR-145 micelles) and its ability to inhibit atherosclerosis by targeting vascular smooth muscle cells (VSMCs). Importantly, one dose of miR-145 micelles significantly abrogated disease progression when evaluated two weeks post-administration. Thus, in this study, to evaluate how long the sustained effects of miR-145 micelles can be maintained and towards identifying a dosing regimen that is practical for patients with chronic disease, the therapeutic effects of a single dose of miR-145 micelles were evaluated for up to two months in vivo. After one and two months post-treatment, miR-145 micelles were found to reduce plaque size and overall lesion area compared to all other controls including statins without causing adverse effects. Furthermore, a single dose of miR-145 micelle treatment inhibited VSMC transdifferentiation into pathogenic macrophage-like and osteogenic cells in plaques. Together, our data shows the long-term efficacy and sustained effects of miR-145 micelles that is amenable using a dosing frequency relevant to chronic disease patients.

关键词： MicroRNA-145 Atherosclerosis Vascular smooth muscle cell Nanoparticle Gene therapy

The molecular basis for ethnic variation and histological subtype differences in prostate cancer

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Science China(Life Sciences) 2013年第9期56卷 780-787页

作者： ZONG Yang GOLDSTEIN Andrew S. HUANG JiaoTi Howard Hughes Medical Institute University of California Departments of Molecular and Medical Pharmacology University of California Urology University of California Jonsson Comprehensive Cancer center David Geffen School of Medicine University of California eli and edythe broad center of regenerative medicine and stem cell research University of California Pathology and Laboratory medicine University of California

Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.

关键词：前列腺癌种族差异组织学分子基础亚型神经内分泌西方国家基因组学

Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

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Asian Journal of Andrology 2014年第4期16卷 541-544页

作者： Julia Lipianskaya Alexa Cohen Clark J Chen Elaine Hsia Jill Squires Zhen Li Yaqun Zhang Wei Li Xufeng Chen Hua Xu Jiaoti Huang Departments of Pathology and Urology Jonsson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research David Geffen School of Medicine at UCLA Los Angeles CA USA.

Most prostate cancers （PCas） are classified as acinar type （conventional） adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor （AR） and prostate-specific antigen （PSA）. There are also scattered neuroendocrine （NE） cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma （SCNC） after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

关键词： neuroendocrine prostate cancer small cell carcinoma therapy

Induced Neural stem cells Generated from Rat Fibroblasts

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Genomics, Proteomics & Bioinformatics 2013年第5期11卷 312-319页

作者： Guangjun Xi Pingfang Hu Cunye Qu Shenfeng Qiu Chang Tong Qi-Long Ying eli and edythe broad center for regenerative medicine and stem cell research at USC Department of Cell and NeurobiologyUniversity of Southern California Department of Neurology Wuxi People’s Hospital Affliated to Nanjing Medical University Department of Gastroenterology Changzheng HospitalSecond Military Medical University Zilkha Neurogenetic Institute University of Southern California

The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem （ES） cell cultures. Using a cocktail of cytokines and small molecules, we dem- onstrate that primitive neural stem （NS） cells derived from mouse ES cells and rat embryos can be maintained. Furthermore, using the same set of cytokines and small molecules, we show that induced NS （iNS） cells can be generated from rat fibroblasts by forced expression of the transcrip- tional factors Oct4, Sox2 and c-Myc. The generation and long-term maintenance of iNS cells could have wide and momentous implications.

关键词： Induced neural stem cells stem cell self-renewal Fibroblasts Rat Induced pluripotent stemcells

Neuroendocrine differentiation of prostate cancer

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Asian Journal of Andrology 2013年第3期15卷 328-332页

作者： Zhen Li Clark J Chen Jason K Wang Elaine Hsia Wei Li Jill Squires Yin Sun Jiaoti Huang Departments of Pathology and Urology Jonsson Comprehensive Cancer Center and Broad Center for Regenerative Medicine and Stem Cell Research David Geffen School of Medicine at UCLA Los Angeles CA 90095-1732. USA

Benign prostate and prostatic adeno- carcinoma contain rare quiescentneuroendocrine cells while small cell neu- roendocrine carcinoma （SCNC）, a variant form of prostate cancer, contains highly proliferative neuroendocrine tumor cells. We provide evidence that IL-8-CXCR2- P53 pathway keeps the NE cells in a quiescent state normally. P53 mutation inactivates this pathway, resulting in hyper-proliferation and aggressive beha- vior of the NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are different from those of adenocarci- noma, which explains SCNC＇s distinct bio- logy and the clinical observation that it does not respond to hormonal therapy.

关键词： SMALL-cell CARCINOMA ANDROGEN-INDEPENDENT GROWTH MOLECULAR CHARACTERIZATION CXCR2 RECEPTOR MOUSE MODEL TRANSDIFFERENTIATION ADENOCARCINOMA INTERLEUKIN-8 PHENOTYPE LNCAP

Vertebrate cardiac regeneration:evolutionary and developmental perspectives

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cell Regeneration 2021年第1期10卷 54-63页

作者： Stephen Cutie Guo N.Huang Cardiovascular research Institute and Department of Physiology University of CaliforniaSan FranciscoSan FranciscoCA 94158USA eli and edythe broad center for Regeneration medicine and stem cell research University of CaliforniaSan FranciscoSan FranciscoCA 94158USA

Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures,and as members of certain species developmentally progress towards their adult *** higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults,neonates of these same species can fully regenerate heart structure and function after injury–as can adult lower vertebrates like many teleost fish and urodele *** research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally:an oxygen-rich environment,vertebrate thermogenesis,a complex adaptive immune system,and cancer risk *** this review,we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.

关键词： Heart Regeneration Development Evolution Cardiomyocyte proliferation cell cycle arrest Polyploidization Endothermy Inflammation