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Article ; Online: Screening-Based Chemical Approaches to Unravel Stem Cell Biology

Shuibing Chen

Stem Cell Reports, Vol 11, Iss 6, Pp 1312-

2018 Volume 1323

Abstract: Cell-permeable compounds provide a convenient and efficient approach to manipulate biological processes. A number of compounds controlling stem cell self-renewal, survival, differentiation, and reprogramming have been identified through high-throughput/ ... ...

Abstract	Cell-permeable compounds provide a convenient and efficient approach to manipulate biological processes. A number of compounds controlling stem cell self-renewal, survival, differentiation, and reprogramming have been identified through high-throughput/content screens. Using these powerful chemical tools, strategies have been developed to direct human pluripotent stem cell (hPSC) differentiation to functional cells. Recently, hPSC-derived cells and organoids are used to model human diseases, which can be adapted to a high-throughput/content platform for chemical screens. The identified compounds provide novel tools for decoding the signaling pathways regulating disease progression and candidates for facilitating future drug discovery. Moreover, humanized mouse models carrying hPSC-derived cells enable an innovative system to evaluate the long-term in vivo efficacy of drug candidates on human cells. In summary, screening-based chemical approaches not only expedite strategy development of controlling stem cell fates, but also provide powerful tools for dissecting the molecular mechanisms regulating disease progression. : In this article, Chen et al. summarized the recent efforts to apply screen approach to identify small molecules controlling stem cell fates, and to establish hPSC-derived cells and organoids-based platforms for disease modeling and drug screening. Keywords: high-throughput screen, high-content screen, human pluripotent stem cells, directed differentiation, self-renewal, survival, reprogramming, organoids, disease modeling, drug discovery
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human pluripotent stem cell-based organoids and cell platforms for modelling SARS-CoV-2 infection and drug discovery

Alice Maria Giani / Shuibing Chen

Stem Cell Research, Vol 53, Iss , Pp 102207- (2021)

2021

Abstract: The coronavirus disease 2019 (COVID-19) global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 200 countries and territories worldwide and resulted in more than 2.5 million deaths. In a pressing ...

Abstract	The coronavirus disease 2019 (COVID-19) global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 200 countries and territories worldwide and resulted in more than 2.5 million deaths. In a pressing search for treatments and vaccines, research models based on human stem cells are emerging as crucial tools to investigate SARS-CoV-2 infection mechanisms and cellular responses across different tissues. Here, we provide an overview of the variety of human pluripotent stem cell-based platforms adopted in SARS-CoV-2 research, comprising monolayer cultures and organoids, which model the multitude of affected tissues in vitro. We highlight the strengths of these platforms, including their application to assess both the susceptible cell types and the pathogenesis of SARS-CoV-2. We describe their use to identify drug candidates for further investigation in addition to discussing their limitations in fully recapitulating COVID-19 pathophysiology. Overall, stem cell models are facilitating the understanding of SARS-CoV-2 and prove to be versatile platforms for studying infections.
Keywords	(6 MAX) ; SARS-CoV-2 ; COVID-19 ; Organoid ; Stem cells ; Personalized medicine ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic Alterations of NF-κB and Its Regulators

Faranak Alipourgivi / Aishat Motolani / Alice Y. Qiu / Wenan Qiang / Guang-Yu Yang / Shuibing Chen / Tao Lu

International Journal of Molecular Sciences, Vol 25, Iss 1, p

A Rich Platform to Advance Colorectal Cancer Diagnosis and Treatment

2023 Volume 154

Abstract: Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States, with an estimated 52,000 deaths in 2023. Though significant progress has been made in both diagnosis and treatment of CRC in recent years, genetic heterogeneity ... ...

Abstract	Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States, with an estimated 52,000 deaths in 2023. Though significant progress has been made in both diagnosis and treatment of CRC in recent years, genetic heterogeneity of CRC—the culprit for possible CRC relapse and drug resistance, is still an insurmountable challenge. Thus, developing more effective therapeutics to overcome this challenge in new CRC treatment strategies is imperative. Genetic and epigenetic changes are well recognized to be responsible for the stepwise development of CRC malignancy. In this review, we focus on detailed genetic alteration information about the nuclear factor (NF)-κB signaling, including both NF-κB family members, and their regulators, such as protein arginine methyltransferase 5 (PRMT5), and outer dynein arm docking complex subunit 2 (ODAD2, also named armadillo repeat-containing 4, ARMC4), etc., in CRC patients. Moreover, we provide deep insight into different CRC research models, with a particular focus on patient-derived xenografts (PDX) and organoid models, and their potential applications in CRC research. Genetic alterations on NF-κB signaling components are estimated to be more than 50% of the overall genetic changes identified in CRC patients collected by cBioportal for Cancer Genomics; thus, emphasizing its paramount importance in CRC progression. Consequently, various genetic alterations on NF-κB signaling may hold great promise for novel therapeutic development in CRC. Future endeavors may focus on utilizing CRC models (e.g., PDX or organoids, or isogenic human embryonic stem cell (hESC)-derived colonic cells, or human pluripotent stem cells (hPSC)-derived colonic organoids, etc.) to further uncover the underpinning mechanism of these genetic alterations in NF-κB signaling in CRC progression. Moreover, establishing platforms for drug discovery in dishes, and developing Biobanks, etc., may further pave the way for the development of innovative personalized medicine to treat CRC in the ...
Keywords	CRC ; genetic alteration ; NF-κB ; ODAD2 ; organoid ; PDX ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

Meili Zhang / J. Jeya Vandana / Lauretta Lacko / Shuibing Chen

Stem Cell Research, Vol 49, Iss , Pp 102063- (2020)

2020

Abstract: Conventional cancer cell lines and animal models have been mainstays of cancer research. More recently, human pluripotent stem cells (hPSCs) and hPSC-derived organoid technologies, together with genome engineering approaches, have provided a ... ...

Abstract	Conventional cancer cell lines and animal models have been mainstays of cancer research. More recently, human pluripotent stem cells (hPSCs) and hPSC-derived organoid technologies, together with genome engineering approaches, have provided a complementary platform to model cancer progression. Here, we review the application of these technologies in cancer modeling with respect to the cell-of-origin, cancer propagation, and metastasis. We further discuss the benefits and challenges accompanying the use of hPSC models for cancer research and discuss their broad applicability in drug discovery, biomarker identification, decoding molecular mechanisms, and the deconstruction of clonal and intra-tumoral heterogeneity. In summary, hPSC-derived organoids provide powerful models to recapitulate the pathogenic states in cancer and to perform drug discovery.
Keywords	Human pluripotent stem cells ; Organoids ; Cell-of-origin ; Cancer propagation ; Metastasis ; Drug discovery ; Biology (General) ; QH301-705.5
Subject code	004
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Isogenic human trophectoderm cells demonstrate the role of NDUFA4 and associated variants in ZIKV infection

iScience, Vol 26, Iss 7, Pp 107001- (2023)

2023

Abstract: Summary: Population-based genome-wide association studies (GWAS) normally require a large sample size, which can be labor intensive and costly. Recently, we reported a human induced pluripotent stem cell (hiPSC) array-based GWAS method, identifying ... ...

Abstract	Summary: Population-based genome-wide association studies (GWAS) normally require a large sample size, which can be labor intensive and costly. Recently, we reported a human induced pluripotent stem cell (hiPSC) array-based GWAS method, identifying NDUFA4 as a host factor for Zika virus (ZIKV) infection. In this study, we extended our analysis to trophectoderm cells, which constitute one of the major routes of mother-to-fetus transmission of ZIKV during pregnancy. We differentiated hiPSCs from various donors into trophectoderm cells. We then infected cells carrying loss of function mutations in NDUFA4, harboring risk versus non-risk alleles of SNPs (rs917172 and rs12386620) or having deletions in the NDUFA4 cis-regulatory region with ZIKV. We found that loss/reduction of NDUFA4 suppressed ZIKV infection in trophectoderm cells. This study validated our published hiPSC array-based system as a useful platform for GWAS and confirmed the role of NDUFA4 as a susceptibility locus for ZIKV in disease-relevant trophectoderm cells.
Keywords	Stem cells research ; Virology ; Science ; Q
Subject code	570
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Derivation and characterization of a UCP1 reporter human ES cell line

Suranjit Mukherjee / Tuo Zhang / Lauretta A. Lacko / Lei Tan / Jenny Zhaoying Xiang / Jason M. Butler / Shuibing Chen

Stem Cell Research, Vol 30, Iss , Pp 12-

2018 Volume 21

Abstract: Interest in human brown fat as a novel therapeutic target to tackle the growing obesity and diabetes epidemic has increased dramatically in recent years. While much insight into brown fat biology has been gained from murine cell lines and models, few ... ...

Abstract	Interest in human brown fat as a novel therapeutic target to tackle the growing obesity and diabetes epidemic has increased dramatically in recent years. While much insight into brown fat biology has been gained from murine cell lines and models, few resources are available to study human brown fat in vitro, which makes the need for new ways to derive and study human brown adipocytes imperative. Human ES cell based reporter systems present an excellent tool to identify, mark, and purify cell populations of choice. In this study, we detail the derivation and characterization of a novel human ES UCP1 reporter cell line that marks UCP1 positive adipocytes in vitro. We targeted a mCherry reporter to the UCP1 stop codon via CRISPR-Cas9 based gene targeting. The brown adipocytes derived from reporter cells express UCP1, display high mitochondrial content, multi-locular lipid morphology, and exhibit functional properties such as lipolysis. The mCherry positive cells purified after cell sorting show elevated expression of brown fat marker genes and a high similarity to isolated human brown fat via RNA-seq analysis. Finally, we demonstrate the utility of this reporter to real time monitor UCP1 expression upon stimulation. This reporter cell line thus presents new opportunities to study human brown fat biology by enabling future work to understand early human brown fat development, perform disease modeling, and facilitate drug screening.
Keywords	Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficient Generation of Cardiac Purkinje Cells from ESCs by Activating cAMP Signaling

Su-Yi Tsai / Karen Maass / Jia Lu / Glenn I. Fishman / Shuibing Chen / Todd Evans

Stem Cell Reports, Vol 4, Iss 6, Pp 1089-

2015 Volume 1102

Abstract: Dysfunction of the specialized cardiac conduction system (CCS) is associated with life-threatening arrhythmias. Strategies to derive CCS cells, including rare Purkinje cells (PCs), would facilitate models for mechanistic studies and drug discovery and ... ...

Abstract	Dysfunction of the specialized cardiac conduction system (CCS) is associated with life-threatening arrhythmias. Strategies to derive CCS cells, including rare Purkinje cells (PCs), would facilitate models for mechanistic studies and drug discovery and also provide new cellular materials for regenerative therapies. A high-throughput chemical screen using CCS:lacz and Contactin2:egfp (Cntn2:egfp) reporter embryonic stem cell (ESC) lines was used to discover a small molecule, sodium nitroprusside (SN), that efficiently promotes the generation of cardiac cells that express gene profiles and generate action potentials of PC-like cells. Imaging and mechanistic studies suggest that SN promotes the generation of PCs from cardiac progenitors initially expressing cardiac myosin heavy chain and that it does so by activating cyclic AMP signaling. These findings provide a strategy to derive scalable PCs, along with insight into the ontogeny of CCS development.
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A dual SHOX2:GFP; MYH6:mCherry knockin hESC reporter line for derivation of human SAN-like cells

iScience, Vol 25, Iss 4, Pp 104153- (2022)

2022

Abstract: Summary: The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and limitations in robust in vitro derivation methods. We developed a dual SHOX2:GFP; MYH6:mCherry knockin ... ...

Abstract	Summary: The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and limitations in robust in vitro derivation methods. We developed a dual SHOX2:GFP; MYH6:mCherry knockin human embryonic stem cell (hESC) reporter line, which allows the identification and purification of SAN-like cells. Using this line, we performed several rounds of chemical screens and developed an efficient strategy to generate and purify hESC-derived SAN-like cells (hESC-SAN). The derived hESC-SAN cells display molecular and electrophysiological characteristics of bona fide nodal cells, which allowed exploration of their transcriptional profile at single-cell level. In sum, our dual reporter system facilitated an effective strategy for deriving human SAN-like cells, which can potentially be used for future disease modeling and drug discovery.
Keywords	Biological sciences ; Stem cells research ; Methodology in biological sciences ; Science ; Q
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Using hESCs to Probe the Interaction of the Diabetes-Associated Genes CDKAL1 and MT1E

Min Guo / Tuo Zhang / Xue Dong / Jenny Zhaoying Xiang / Minxiang Lei / Todd Evans / Johannes Graumann / Shuibing Chen

Cell Reports, Vol 19, Iss 8, Pp 1512-

2017 Volume 1521

Abstract: Genome-wide association studies (GWASs) have identified many disease-associated variant alleles, but understanding whether and how different genes/loci interact requires a platform for probing how the variant alleles act mechanistically. Isogenic mutant ... ...

Abstract	Genome-wide association studies (GWASs) have identified many disease-associated variant alleles, but understanding whether and how different genes/loci interact requires a platform for probing how the variant alleles act mechanistically. Isogenic mutant human embryonic stem cells (hESCs) provide an unlimited resource to derive and study human disease-relevant cells. Here, we focused on CDKAL1, linked by GWASs to diabetes. Through transcript profiling, we find that expression of the metallothionein (MT) gene family, also linked by GWASs to diabetes, is significantly downregulated in CDKAL1−/− cells that have been differentiated to insulin-expressing pancreatic beta-like cells. Forced MT1E expression rescues both hypersensitivity of CDKAL1 mutant cells to glycolipotoxicity and pancreatic beta-cell dysfunction in vitro and in vivo. MT1E functions at least in part through relief of ER stress. This study establishes an isogenic hESC-based platform to study the interaction of GWAS-identified diabetes gene variants and illuminate the molecular network impacting disease progression.
Keywords	metallothionein ; CDKAL1 ; human pancreatic beta-like cells ; directed differentiation ; humanized mouse ; chemical chaperones ; endoplasmic reticulum stress ; ER ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CLIC4 regulates late endosomal trafficking and matrix degradation activity of MMP14 at focal adhesions in RPE cells

Kuo-Shun Hsu / Wataru Otsu / Yao Li / Heuy-Ching Wang / Shuibing Chen / Stephen H. Tsang / Jen-Zen Chuang / Ching-Hwa Sung

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 17

Abstract: Abstract Dysregulation in the extracellular matrix (ECM) microenvironment surrounding the retinal pigment epithelium (RPE) has been implicated in the etiology of proliferative vitreoretinopathy and age-related macular degeneration. The regulation of ECM ... ...

Abstract	Abstract Dysregulation in the extracellular matrix (ECM) microenvironment surrounding the retinal pigment epithelium (RPE) has been implicated in the etiology of proliferative vitreoretinopathy and age-related macular degeneration. The regulation of ECM remodeling by RPE cells is not well understood. We show that membrane-type matrix metalloproteinase 14 (MMP14) is central to ECM degradation at the focal adhesions in human ARPE19 cells. The matrix degradative activity, but not the assembly, of the focal adhesion is regulated by chloride intracellular channel 4 (CLIC4). CLIC4 is co-localized with MMP14 in the late endosome. CLIC4 regulates the proper sorting of MMP14 into the lumen of the late endosome and its proteolytic activation in lipid rafts. CLIC4 has the newly-identified “late domain” motif that binds to MMP14 and to Tsg101, a component of the endosomal sorting complex required for transport (ESCRT) complex. Unlike the late domain mutant CLIC4, wild-type CLIC4 can rescue the late endosomal sorting defect of MMP14. Finally, CLIC4 knockdown inhibits the apical secretion of MMP2 in polarized human RPE monolayers. These results, taken together, demonstrate that CLIC4 is a novel matrix microenvironment modulator and a novel regulator for late endosomal cargo sorting. Moreover, the late endosomal sorting of MMP14 actively regulates its surface activation in RPE cells.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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