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Jiang S, Bao H. Exploring the mechanism of esculetin extracted from Chroogomphus rutilus in treating liver cancer based on network pharmacology, molecular docking, and in vivo experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119837. [PMID: 40254108 DOI: 10.1016/j.jep.2025.119837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chroogomphus rutilus (C. rutilus) is a traditional Chinese medicine recorded in the book Illustrations of Medicinal Fungi in China that possesses a long history of use for the treatment of various diseases, including cancer. Esculetin (ES), the primary pharmacologically active ingredient of C. rutilus, exerts significant therapeutic effects against liver cancer (LC). Nonetheless, the underlying therapeutic mechanisms of ES against LC remain poorly understood. AIM OF THE STUDY To investigate the mechanisms of ES in LC treatment. MATERIALS AND METHODS ES was isolated and identified from C. rutilus. Subsequently, related targets and mechanism of ES against LC were predicted through network pharmacology and molecular docking. The antitumor effect of ES was examined using H22 tumor-bearing mouse models. The antitumor mechanism of ES was elucidated and validated using TUNEL, enzyme-linked immunosorbent assay (ELISA), immunofluorescence analysis, Western blot (WB), and quantitative real-time polymerase chain reaction (qPCR). RESULTS The chemical structure was determined using NMR carbon and hydrogen spectra. Network pharmacology analysis indicated that ES exerted anti-LC effects via the PI3K/AKT signaling pathway and associated proteins. TUNEL and ELISA revealed that ES exhibited an obvious antitumor effect in vivo and that the levels of TNF-α, IFN-γ, IL-2, and IL-6 were significantly increased. Immunofluorescence, WB, and qPCR analyses showed that ES upregulated the protein expression of Bax, caspase-3, and caspase-9 and downregulated the protein expression of Bcl-2, VEGF, and p-AKT. CONCLUSION This study demonstrates that the mechanisms of ES in LC treatment include enhancing immunity, inhibiting angiogenesis, and promoting apoptosis of tumor cells.
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Affiliation(s)
- Shuang Jiang
- Key Laboratory of Edible Fungi Resources and Utilization, Ministry of Agriculture and Rural Affairs, Jilin Agricultural University, No. 2888 Xincheng Street, Nanguan District, Changchun, Jilin, 130118, China; College of Chinese Medicine Materials, Jilin Agricultural University, Changchun, 130118, China.
| | - Haiying Bao
- Key Laboratory of Edible Fungi Resources and Utilization, Ministry of Agriculture and Rural Affairs, Jilin Agricultural University, No. 2888 Xincheng Street, Nanguan District, Changchun, Jilin, 130118, China; College of Chinese Medicine Materials, Jilin Agricultural University, Changchun, 130118, China.
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Singh A, Kim HE, Rawson L, Miao M, Cohen DJ. Engineering Cellular Self-Adhesions Inside 3D Printed Micro-Arches to Enhance Cell:Biomaterial Attachment. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2502425. [PMID: 40411865 DOI: 10.1002/adma.202502425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 05/02/2025] [Indexed: 05/26/2025]
Abstract
A cell can bind to itself and form a self-adhesion that can be engineered and harnessed as a new way to adhere cells to engineered materials-a key challenge for biomaterials are demonstrated. Here, a 3D structure smaller is developed than a single cell, that a Self-Adhesion-Tunnel (SAT) is called, that causes cells to wrap around it and bind to themselves. This process is driven through the cadherin proteins that regulate cell-cell adhesion, and it is shown that many of the key elements of a normal cell-cell adhesion are found in self-adhesions. Size and shape of the SAT determine the efficiency of self-adhesion formation, and >90% efficient formation of self-adhesions are observed in both kidney and skin cells per SAT. Self-adhesions can persist for at least 24 hrs and act to stabilize the cell-material interface and reduce migration. Overall, this ability to co-opt the native cell-cell adhesion machinery in cells and use it as an attachment strategy can provide new approaches for soft-tissue implant integration and tissue engineering scaffolds where stable tissue-material interfaces are critical.
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Affiliation(s)
- Anamika Singh
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA
| | - Hannah E Kim
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA
| | - Lauren Rawson
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA
| | - Margaret Miao
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA
| | - Daniel J Cohen
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA
- Omenn Darling Bioengineering Institute, Princeton University, Princeton, NJ, USA
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Halmi CA, Leonard CE, McIntosh AT, Taneyhill LA. N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation. Development 2025; 152:dev204369. [PMID: 40260574 PMCID: PMC12070061 DOI: 10.1242/dev.204369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 04/01/2025] [Indexed: 04/23/2025]
Abstract
The trigeminal ganglion emerges from the condensation of two distinct precursor cell populations, cranial placodes and neural crest. While its dual cellular origin is well understood, the molecules underlying its formation remain relatively obscure. Trigeminal ganglion assembly is mediated, in part, by neural cadherin (N-cadherin), which is initially expressed by placodal neurons and is required for their proper coalescence with neural crest cells. Axon outgrowth first occurs from placodal neurons, but as gangliogenesis proceeds, neural crest cells also differentiate into N-cadherin-expressing neurons, and both extend axons toward targets. However, the role of N-cadherin in axon outgrowth and target innervation has not been explored. Our data show that N-cadherin knockdown in chick trigeminal placode cells decreases trigeminal ganglion size, nerve growth and target innervation in vivo, and reduces neurite complexity of neural crest-derived neurons in vitro. Furthermore, blocking N-cadherin-mediated adhesion prevents axon extension in most placodal neurons in vitro. Collectively, these findings reveal cell- and non-cell autonomous functions for N-cadherin, highlighting its crucial role in mediating reciprocal interactions between neural crest- and placode-derived neurons throughout trigeminal ganglion development.
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Affiliation(s)
- Caroline A. Halmi
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Carrie E. Leonard
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Alec T. McIntosh
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
| | - Lisa A. Taneyhill
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
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Oishi K, Matsumoto K, Hashimoto S, Uchida F, Hara R, Nishimuta M, Matsumoto T, Iwatake M, Tomoshige K, Doi R, Machino R, Obata T, Nagayasu T. Spheroid morphology of lung cancer cell lines correlates with oncological profiles. Discov Oncol 2025; 16:627. [PMID: 40293538 PMCID: PMC12037941 DOI: 10.1007/s12672-025-02132-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 03/12/2025] [Indexed: 04/30/2025] Open
Abstract
We assessed the correlation between Multicellular tumor spheroids (MCTS) morphology and the oncological profile of lung cancer cells. MCTS were generated in five lung cancer cell lines and classified into Type-A MCTS, which showed strong aggregation, and Type-B MCTS, which showed weak aggregation. Drug resistance was higher in Type-A MCTS, and invasive ability was higher in Type-B MCTS. The oncologic profile of lung cancer cell lines correlated with MCTS morphology. MCTS morphology could thus be used in basic oncology research and as a clinical prognostic tool.Registry and the Registration No. of the study/trial Not Applicable.
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Affiliation(s)
- Kaido Oishi
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan.
| | - Keitaro Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan.
| | - Shintaro Hashimoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Fumitake Uchida
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Ryosuke Hara
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Masato Nishimuta
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Takamune Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Mayumi Iwatake
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Koichi Tomoshige
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Ryoichiro Doi
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Ryusuke Machino
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Tomohiro Obata
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Medical-Engineering Hybrid Professional Development Program, Nagasaki University, Nagasaki, Japan
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Oyón Díaz de Cerio J, Venneri G, Orefice I, Forestiero M, Baena CR, Tassone GB, Percopo I, Sardo A, Panno ML, Giordano F, Di Dato V. Effects of Amphidinium carterae Phytocompounds on Proliferation and the Epithelial-Mesenchymal Transition Process in T98G Glioblastoma Cells. Mar Drugs 2025; 23:173. [PMID: 40278295 PMCID: PMC12029094 DOI: 10.3390/md23040173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/02/2025] [Accepted: 04/14/2025] [Indexed: 04/26/2025] Open
Abstract
Glioblastoma (GBM) is an aggressive type of brain cancer, frequently invasive, with a low survival rate and complicated treatment. Recent studies have shown the modulation of epithelial-mesenchymal transition (EMT) biomarkers in glioblastoma cells associated with tumor progression, chemoresistance, and relapse after treatment. GBM handlings are based on aggressive chemical therapies and surgical resection with poor percentage of survival, boosting the search for more specific remedies. Marine eukaryotic microalgae are rapidly advancing as a source of anticancer drugs due to their ability to produce potent secondary metabolites with biological activity. Among such microalgae, dinoflagellates, belonging to the species Amphidinium carterae, are known producers of neurotoxins and cytotoxic compounds. We tested the capability of chemical extracts from two different strains of A. carterae to modulate the EMT markers in T98G, human GBM cells. In vitro proliferation and migration studies and EMT biomarkers' abundance and modulation assays showed that the different A. carterae strains differently modulated both EMT markers and the proliferation/migration capability of GBM cells. This study sets the bases to find a marine microalgae-derived natural compound that could potentially target the epithelial-mesenchymal transition in brain-derived tumor types.
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Affiliation(s)
- Julia Oyón Díaz de Cerio
- Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn Napoli, 80133 Naples, Italy; (J.O.D.d.C.); (I.O.); (C.R.B.); (A.S.)
| | - Giulia Venneri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (G.V.); (M.F.); (G.B.T.); (M.L.P.)
| | - Ida Orefice
- Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn Napoli, 80133 Naples, Italy; (J.O.D.d.C.); (I.O.); (C.R.B.); (A.S.)
| | - Martina Forestiero
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (G.V.); (M.F.); (G.B.T.); (M.L.P.)
| | - Carlos Roman Baena
- Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn Napoli, 80133 Naples, Italy; (J.O.D.d.C.); (I.O.); (C.R.B.); (A.S.)
| | - Gianluca Bruno Tassone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (G.V.); (M.F.); (G.B.T.); (M.L.P.)
| | - Isabella Percopo
- Department of Research Infrastructures for Marine Biological Resources, Stazione Zoologica Anton Dohrn Napoli, 80122 Naples, Italy;
| | - Angela Sardo
- Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn Napoli, 80133 Naples, Italy; (J.O.D.d.C.); (I.O.); (C.R.B.); (A.S.)
| | - Maria Luisa Panno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (G.V.); (M.F.); (G.B.T.); (M.L.P.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (G.V.); (M.F.); (G.B.T.); (M.L.P.)
| | - Valeria Di Dato
- Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn Napoli, 80133 Naples, Italy; (J.O.D.d.C.); (I.O.); (C.R.B.); (A.S.)
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Santarriaga S, Vater M, Dujmic P, Gerlovin K, Lee CW, Karmacharya R. Effects of Complex I Inhibition on the Architecture of Neural Rosettes Differentiated from Human-Induced Pluripotent Stem Cells. Stem Cells Dev 2025; 34:164-176. [PMID: 40079171 PMCID: PMC12021791 DOI: 10.1089/scd.2024.0169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 02/14/2025] [Indexed: 03/14/2025] Open
Abstract
Orchestrated changes in cell arrangements and cell-to-cell contacts are susceptible to cellular stressors during central nervous system development. Effects of mitochondrial complex I inhibition on cell-to-cell contacts have been studied in vascular and intestinal structures; however, its effects on developing neuronal cells are largely unknown. We investigated the effects of the classical mitochondrial stressor and complex I inhibitor, rotenone, on the architecture of neural rosettes-radially organized neuronal progenitor cells (NPCs)-differentiated from human-induced pluripotent stem cells. We then analyzed the effects of rotenone on the distribution of cell-contact proteins within neural rosettes. Exposure to rotenone for 24 hours led to a dose-dependent irreversible disruption of the neural rosette architecture and relocalization of the cell-contact proteins ZO-1, β-catenin, and N-cadherin from the rosette center to the pericellular region. Though the levels of nestin and SOX2 remained unchanged, NPCs showed decreased levels of the NPC marker PAX6 and exhibited impaired neurogenesis following rotenone exposure. Our study suggests that complex I inhibition leads to a rearrangement of intercellular contacts with disruptive effects on neuronal development.
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Affiliation(s)
| | | | - Petra Dujmic
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Chemical Biology Program, Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA
| | - Kaia Gerlovin
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Chemical Biology Program, Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA
| | - Chun Wing Lee
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- McLean Hospital, Belmont, Massachusetts, USA
| | - Rakesh Karmacharya
- Address correspondence to: Dr. Rakesh Karmacharya, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN6, Boston, MA 02114, USA
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Zhang HA, Zhang BY, Tang HB. Effects of macrophages on the osteogenic differentiation of adipose tissue-derived stem cells in two-dimensional and three-dimensional cocultures. World J Stem Cells 2025; 17:99326. [DOI: 10.4252/wjsc.v17.i2.99326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Fracture is one of the most pervasive injuries in the musculoskeletal system, and there is a complex interaction between macrophages and adipose tissue-derived stem cells (ADSCs) in fracture healing. However, two-dimensional (2D) coculture of macrophages and ADSCs can not accurately mimic the in vivo cell microenvironment.
AIM To establish both 2D and 3D osteogenic coculture models to investigate the interaction between macrophages and ADSCs.
METHODS After obtaining ADSCs from surgery and inducing differentiation of the THP1 cell line, we established 2D and 3D osteogenic coculture models. To assess the level of osteogenic differentiation, we used alizarin red staining and measured the relative expression levels of osteogenic differentiation markers osteocalcin, Runt-related transcription factor 2, and alkaline phosphatase through polymerase chain reaction. Verification was conducted by analyzing the expression changes of N-cadherin and the activation of the Wnt/β-catenin signaling pathway using western blotting.
RESULTS In this study, it was discovered that macrophages in 3D culture inhibited osteogenic differentiation of ADSCs, contrary to the effect in 2D culture. This observation confirmed the significance of intricate intercellular connections in the 3D culture environment. Additionally, the 3D culture group exhibited significantly higher N-cadherin expression and showed reduced β-catenin and Wnt1 protein levels compared to the 2D culture group.
CONCLUSION Macrophages promoted ADSC osteogenic differentiation in 2D culture conditions but inhibited it in 3D culture. The 3D culture environment might inhibit the Wnt/β-catenin signaling pathway by upregulating N-cadherin expression, ultimately hindering the osteogenic differentiation of ADSCs. By investigating the process of osteogenesis in ADSCs, this study provides novel ideas for exploring 3D osteogenesis in ADSCs, fracture repair, and other bone trauma repair.
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Affiliation(s)
- He-Ao Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Bo-Yu Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hong-Bo Tang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Díaz-Carballo D, Safoor A, Saka S, Noa-Bolaño A, D'Souza F, Klein J, Acikelli AH, Malak S, Rahner U, Turki AT, Höppner A, Kamitz A, Song W, Chen YG, Kamada L, Tannapfel A, Brinkmann S, Ochsenfarth C, Strumberg D. The neuroepithelial origin of ovarian carcinomas explained through an epithelial-mesenchymal-ectodermal transition enhanced by cisplatin. Sci Rep 2024; 14:29286. [PMID: 39592661 PMCID: PMC11599565 DOI: 10.1038/s41598-024-76984-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
Acquired resistance to platinum-derived cytostatics poses major challenges in ovarian carcinoma therapy. In this work, we show a shift in the epithelial-mesenchymal transition (EMT) process towards an "ectodermal" conversion of ovarian carcinoma cells in response to cisplatin treatment, a progression we have termed epithelial-mesenchymal-ectodermal transition (EMET). EMET appears to occur via the classical EMT as judged by a) the downregulation of several epithelial markers and b) upregulation of Vimentin, accompanied by various embryonal transcription factors and, importantly, a plethora of neuronal markers, consistent with ectodermal differentiation. Moreover, we isolated cells from ovarian carcinoma cultures exhibiting a dual neural/stemness signature and multidrug resistance (MDR) phenotype. We also found that the epithelial cells differentiate from these neural/stem populations, indicating that the cell of origin in this tumor must in fact be a neural cell type with stemness features. Notably, some transcription factors like PAX6 and PAX9 were not localized in the nucleoplasm of these cells, hinting at altered nuclear permeability. In addition, the neuronal morphology was rapidly established when commercially available and primary ovarian carcinoma cells were cultured in the form of organoids. Importantly, we also identified a cell type in regular ovarian tissues, which possess similar neural/stemness features as observed in 2D or 3D cultures. The signature of this cell type is amplified in ovarian carcinoma tumors, suggesting a neuroepithelial origin of this tumor type. In conclusion, we propose that ovarian carcinomas harbor a small population of cells with an intrinsic neuronal/stemness/MDR phenotype, serving as the cradle from which ovarian carcinoma evolves.
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Affiliation(s)
- David Díaz-Carballo
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany.
| | - Ayesha Safoor
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Sahitya Saka
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, USA
| | - Adrien Noa-Bolaño
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Flevy D'Souza
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Jacqueline Klein
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Ali H Acikelli
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Sascha Malak
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Udo Rahner
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Amin T Turki
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Anne Höppner
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Annabelle Kamitz
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
| | - Wanlu Song
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lalitha Kamada
- Clinic of Pediatric Oncology, Hematology and Immunology, Düsseldorf University Hospital , 40225, Düsseldorf, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany
| | - Sebastian Brinkmann
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany
| | - Crista Ochsenfarth
- Department of Anesthesia, Intensive Care, Pain and Palliative Medicine, Ruhr-University Bochum Medical School, Marien Hospital Herne, 44625, Herne, Germany
| | - Dirk Strumberg
- Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany
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Brien H, Lee JC, Sharma J, Hamann CA, Spetz MR, Lippmann ES, Brunger JM. Templated Pluripotent Stem Cell Differentiation via Substratum-Guided Artificial Signaling. ACS Biomater Sci Eng 2024; 10:6465-6482. [PMID: 39352143 PMCID: PMC11480943 DOI: 10.1021/acsbiomaterials.4c00885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024]
Abstract
The emerging field of synthetic morphogenesis implements synthetic biology tools to investigate the minimal cellular processes sufficient for orchestrating key developmental events. As the field continues to grow, there is a need for new tools that enable scientists to uncover nuances in the molecular mechanisms driving cell fate patterning that emerge during morphogenesis. Here, we present a platform that combines cell engineering with biomaterial design to potentiate artificial signaling in pluripotent stem cells (PSCs). This platform, referred to as PSC-MATRIX, extends the use of programmable biomaterials to PSCs competent to activate morphogen production through orthogonal signaling, giving rise to the opportunity to probe developmental events by initiating morphogenetic programs in a spatially constrained manner through non-native signaling channels. We show that the PSC-MATRIX platform enables temporal and spatial control of transgene expression in response to bulk, soluble inputs in synthetic Notch (synNotch)-engineered human PSCs for an extended culture of up to 11 days. Furthermore, we used PSC-MATRIX to regulate multiple differentiation events via material-mediated artificial signaling in engineered PSCs using the orthogonal ligand green fluorescent protein, highlighting the potential of this platform for probing and guiding fate acquisition. Overall, this platform offers a synthetic approach to interrogate the molecular mechanisms driving PSC differentiation that could be applied to a variety of differentiation protocols.
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Affiliation(s)
- Hannah
J. Brien
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Joanne C. Lee
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Jhanvi Sharma
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Catherine A. Hamann
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Madeline R. Spetz
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Ethan S. Lippmann
- Department
of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
- Center
for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Jonathan M. Brunger
- Department
of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
- Center
for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee 37235, United States
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10
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Sterling NA, Cho SH, Kim S. Entosis implicates a new role for P53 in microcephaly pathogenesis, beyond apoptosis. Bioessays 2024; 46:e2300245. [PMID: 38778437 DOI: 10.1002/bies.202300245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Entosis, a form of cell cannibalism, is a newly discovered pathogenic mechanism leading to the development of small brains, termed microcephaly, in which P53 activation was found to play a major role. Microcephaly with entosis, found in Pals1 mutant mice, displays P53 activation that promotes entosis and apoptotic cell death. This previously unappreciated pathogenic mechanism represents a novel cellular dynamic in dividing cortical progenitors which is responsible for cell loss. To date, various recent models of microcephaly have bolstered the importance of P53 activation in cell death leading to microcephaly. P53 activation caused by mitotic delay or DNA damage manifests apoptotic cell death which can be suppressed by P53 removal in these animal models. Such genetic studies attest P53 activation as quality control meant to eliminate genomically unfit cells with minimal involvement in the actual function of microcephaly associated genes. In this review, we summarize the known role of P53 activation in a variety of microcephaly models and introduce a novel mechanism wherein entotic cell cannibalism in neural progenitors is triggered by P53 activation.
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Affiliation(s)
- Noelle A Sterling
- Shriners Hospitals Pediatric Research Center, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Biomedical Sciences Graduate Program, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Seo-Hee Cho
- Center for Translational Medicine, Department of Medicine, Sydney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Seonhee Kim
- Shriners Hospitals Pediatric Research Center, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
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11
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Zhao H, Xiong T, Chu Y, Hao W, Zhao T, Sun X, Zhuang Y, Chen B, Zhao Y, Wang J, Chen Y, Dai J. Biomimetic Dual-Network Collagen Fibers with Porous and Mechanical Cues Reconstruct Neural Stem Cell Niche via AKT/YAP Mechanotransduction after Spinal Cord Injury. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2311456. [PMID: 38497893 DOI: 10.1002/smll.202311456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/21/2024] [Indexed: 03/19/2024]
Abstract
Tissue engineering scaffolds can mediate the maneuverability of neural stem cell (NSC) niche to influence NSC behavior, such as cell self-renewal, proliferation, and differentiation direction, showing the promising application in spinal cord injury (SCI) repair. Here, dual-network porous collagen fibers (PCFS) are developed as neurogenesis scaffolds by employing biomimetic plasma ammonia oxidase catalysis and conventional amidation cross-linking. Following optimizing the mechanical parameters of PCFS, the well-matched Young's modulus and physiological dynamic adaptability of PCFS (4.0 wt%) have been identified as a neurogenetic exciter after SCI. Remarkably, porous topographies and curving wall-like protrusions are generated on the surface of PCFS by simple and non-toxic CO2 bubble-water replacement. As expected, PCFS with porous and matched mechanical properties can considerably activate the cadherin receptor of NSCs and induce a series of serine-threonine kinase/yes-associated protein mechanotransduction signal pathways, encouraging cellular orientation, neuron differentiation, and adhesion. In SCI rats, implanted PCFS with matched mechanical properties further integrated into the injured spinal cords, inhibited the inflammatory progression and decreased glial and fibrous scar formation. Wall-like protrusions of PCFS drive multiple neuron subtypes formation and even functional neural circuits, suggesting a viable therapeutic strategy for nerve regeneration and functional recovery after SCI.
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Affiliation(s)
- Haitao Zhao
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
| | - Tiandi Xiong
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Yun Chu
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Wangping Hao
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
| | - Tongtong Zhao
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Xinyue Sun
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Yan Zhuang
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Bing Chen
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, 100101, China
| | - Yannan Zhao
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, 100101, China
| | - Jun Wang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China
| | - Yanyan Chen
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Jianwu Dai
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, 100101, China
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12
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Jiang Q, Li Y, Cai S, Shi X, Yang Y, Xing Z, He Z, Wang S, Su Y, Chen M, Chen Z, Shi Z. GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer. Acta Pharm Sin B 2024; 14:698-711. [PMID: 38322340 PMCID: PMC10840430 DOI: 10.1016/j.apsb.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 09/25/2023] [Accepted: 11/06/2023] [Indexed: 02/08/2024] Open
Abstract
Glutamate-ammonia ligase (GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.
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Affiliation(s)
- Qiwei Jiang
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yong Li
- Department of Gastrointestinal Surgery & General Surgery, the Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Songwang Cai
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Xingyuan Shi
- Department of Radiation Oncology, The Fifth Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yang Yang
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Zihao Xing
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Zhenjie He
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Shengte Wang
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yubin Su
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 519000, China
| | - Zhesheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Zhi Shi
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
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13
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Barresi M, Hickmott RA, Bosakhar A, Quezada S, Quigley A, Kawasaki H, Walker D, Tolcos M. Toward a better understanding of how a gyrified brain develops. Cereb Cortex 2024; 34:bhae055. [PMID: 38425213 DOI: 10.1093/cercor/bhae055] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 01/26/2024] [Accepted: 01/28/2024] [Indexed: 03/02/2024] Open
Abstract
The size and shape of the cerebral cortex have changed dramatically across evolution. For some species, the cortex remains smooth (lissencephalic) throughout their lifetime, while for other species, including humans and other primates, the cortex increases substantially in size and becomes folded (gyrencephalic). A folded cortex boasts substantially increased surface area, cortical thickness, and neuronal density, and it is therefore associated with higher-order cognitive abilities. The mechanisms that drive gyrification in some species, while others remain lissencephalic despite many shared neurodevelopmental features, have been a topic of investigation for many decades, giving rise to multiple perspectives of how the gyrified cerebral cortex acquires its unique shape. Recently, a structurally unique germinal layer, known as the outer subventricular zone, and the specialized cell type that populates it, called basal radial glial cells, were identified, and these have been shown to be indispensable for cortical expansion and folding. Transcriptional analyses and gene manipulation models have provided an invaluable insight into many of the key cellular and genetic drivers of gyrification. However, the degree to which certain biomechanical, genetic, and cellular processes drive gyrification remains under investigation. This review considers the key aspects of cerebral expansion and folding that have been identified to date and how theories of gyrification have evolved to incorporate this new knowledge.
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Affiliation(s)
- Mikaela Barresi
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
- ACMD, St Vincent's Hospital Melbourne, Regent Street, Fitzroy, VIC 3065, Australia
| | - Ryan Alexander Hickmott
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
- ACMD, St Vincent's Hospital Melbourne, Regent Street, Fitzroy, VIC 3065, Australia
| | - Abdulhameed Bosakhar
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
| | - Sebastian Quezada
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
| | - Anita Quigley
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
- ACMD, St Vincent's Hospital Melbourne, Regent Street, Fitzroy, VIC 3065, Australia
- School of Engineering, RMIT University, La Trobe Street, Melbourne, VIC 3000, Australia
- Department of Medicine, University of Melbourne, St Vincent's Hospital, Regent Street, Fitzroy, VIC 3065, Australia
| | - Hiroshi Kawasaki
- Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa 920-8640, Japan
| | - David Walker
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
| | - Mary Tolcos
- School of Health and Biomedical Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia
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14
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Frith TJR, Briscoe J, Boezio GLM. From signalling to form: the coordination of neural tube patterning. Curr Top Dev Biol 2023; 159:168-231. [PMID: 38729676 DOI: 10.1016/bs.ctdb.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
The development of the vertebrate spinal cord involves the formation of the neural tube and the generation of multiple distinct cell types. The process starts during gastrulation, combining axial elongation with specification of neural cells and the formation of the neuroepithelium. Tissue movements produce the neural tube which is then exposed to signals that provide patterning information to neural progenitors. The intracellular response to these signals, via a gene regulatory network, governs the spatial and temporal differentiation of progenitors into specific cell types, facilitating the assembly of functional neuronal circuits. The interplay between the gene regulatory network, cell movement, and tissue mechanics generates the conserved neural tube pattern observed across species. In this review we offer an overview of the molecular and cellular processes governing the formation and patterning of the neural tube, highlighting how the remarkable complexity and precision of vertebrate nervous system arises. We argue that a multidisciplinary and multiscale understanding of the neural tube development, paired with the study of species-specific strategies, will be crucial to tackle the open questions.
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Affiliation(s)
| | - James Briscoe
- The Francis Crick Institute, London, United Kingdom.
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15
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Helmer P, Vallee RB. A two-kinesin mechanism controls neurogenesis in the developing brain. Commun Biol 2023; 6:1219. [PMID: 38040957 PMCID: PMC10692124 DOI: 10.1038/s42003-023-05604-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 11/17/2023] [Indexed: 12/03/2023] Open
Abstract
During the course of brain development, Radial Glial Progenitor (RGP) cells give rise to most of the neurons required for a functional cortex. RGPs can undergo symmetric divisions, which result in RGP duplication, or asymmetric divisions, which result in one RGP as well as one to four neurons. The control of this balance is not fully understood, but must be closely regulated to produce the cells required for a functioning cortex, and to maintain the stem cell pool. In this study, we show that the balance between symmetric and asymmetric RGP divisions is in part regulated by the actions of two kinesins, Kif1A and Kif13B, which we find have opposing roles in neurogenesis through their action on the mitotic spindle in dividing RGPs. We find that Kif1A promotes neurogenesis, whereas Kif13B promotes symmetric, non-neurogenic divisions. Interestingly, the two kinesins are closely related in structure, and members of the same kinesin-3 subfamily, thus their opposing effects on spindle orientation appear to represent a novel mechanism for the regulation of neurogenesis.
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Affiliation(s)
- Paige Helmer
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
- Department of Biological Sciences, Columbia University, New York, NY, 10032, USA.
| | - Richard B Vallee
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
- Department of Biological Sciences, Columbia University, New York, NY, 10032, USA.
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16
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Zhang Y, Jiao Z, Wang S. Bone Marrow Mesenchymal Stem Cells Release miR-378a-5p-Carried Extracellular Vesicles to Alleviate Rheumatoid Arthritis. J Innate Immun 2023; 15:893-910. [PMID: 37926093 PMCID: PMC10715757 DOI: 10.1159/000534830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
This study investigates whether bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) can affect rheumatoid arthritis (RA) by delivering microRNA (miR)-378a-5p to regulate the interferon regulatory factor 1/signal transducer and transcription 1 (IRF1/STAT1) axis. We identified RA-associated miRNAs using the GEO microarray dataset GSE121894. We found the most important miRNAs in RA synovial tissues using RT-qPCR. BMSC-derived EVs were ultracentrifuged and cocultured with human synovial microvascular endothelial cells (HSMECs) in vitro. Dual-luciferase and RNA immunoprecipitation studies examined miR-378a-5p's specific binding to IRF1. We also measured angiogenesis, migration, and proliferation using CCK-8, Transwell, and tube formation assays. Collagen-induced arthritis (CIA) mice models were created by inducing arthritis and scoring it. RA synovial tissues had low miR-378a-5p expression, whereas BMSC-derived EVs had high levels. The transfer of miR-378a-5p by BMSC-derived EVs to HSMECs boosted proliferation, migration, and angiogenesis. miR-378a-5p inhibited IRF1. MiR-378a-5p-containing BMSC-derived EVs decreased STAT1 phosphorylation and HSMEC IRF1 expression. EVs with miR-378a-5p mimic promoted HSMEC proliferation, migration, and angiogenesis, whereas dexmedetomidine inhibited STAT1 phosphorylation. In CIA mice, BMSC-derived EVs containing miR-378a-5p enhanced synovial vascular remodeling and histopathology. Thus, miR-378a-5p from BMSC-derived EVs promotes HSMEC proliferation, migration, and angiogenesis, inactivating the IRF1/STAT1 axis and preventing RA.
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Affiliation(s)
- Yaqin Zhang
- Department of Rheumatology, The Second Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Ziying Jiao
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, PR China
| | - Shanshan Wang
- Department of Endocrinology, Anhui No.2 Provincial People’s Hospital, Hefei, PR China
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17
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Tsai CY, Ko HJ, Chiou SJ, Lin XY, Chuang TH, Cheng JT, Su YF, Loh JK, Hong YR. GSKIP modulates cell aggregation through EMT/MET signaling rather than differentiation in SH-SY5Y human neuroblastoma cells. J Cell Commun Signal 2023; 17:1039-1054. [PMID: 37133713 PMCID: PMC10409706 DOI: 10.1007/s12079-023-00752-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 04/18/2023] [Indexed: 05/04/2023] Open
Abstract
GSK3β interacting protein (GSKIP) is a small A-kinase anchor protein previously reported to mediate the N-cadherin/β-catenin pool for differentiation in SH-SY5Y cells through overexpression of GSKIP to present the neuron outgrowth phenotype. To further investigate how GSKIP functions in neurons, CRISPR/Cas9 technology was utilized to knock out GSKIP (GSKIP-KO) in SH-SY5Y. Several GSKIP-KO clones resulted in an aggregation phenotype and reduced cell growth without retinoic acid (RA) treatment. However, neuron outgrowth was still observed in GSKIP-KO clones treated with RA. The GSKIP-KO clones exhibited an aggregation phenotype through suppression of GSK3β/β-catenin pathways and cell cycle progression rather than cell differentiation. Gene set enrichment analysis indicated that GSKIP-KO was related to epithelial mesenchymal transition/mesenchymal epithelial transition (EMT/MET) and Wnt/β-catenin/cadherin signaling pathways, suppressing cell migration and tumorigenesis through the inhibition of Wnt/β-catenin mediated EMT/MET. Conversely, reintroduction of GSKIP into GSKIP-KO clones restored cell migration and tumorigenesis. Notably, phosphor-β-catenin (S675) and β-catenin (S552) but not phosphor-β-catenin (S33/S37/T41) translocated into the nucleus for further gene activation. Collectively, these results suggested that GSKIP may function as an oncogene to form an aggregation phenotype for cell survival in harsh environments through EMT/MET rather than differentiation in the GSKIP-KO of SH-SY5Y cells. GSKIP Implication in Signaling Pathways with Potential Impact on SHSY-5Y Cell Aggregation.
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Affiliation(s)
- Cheng-Yu Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huey-Jiun Ko
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shean-Jaw Chiou
- Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Xin-Yi Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Tsung-Hsien Chuang
- Immunology Research Center, National Health Research Institutes, Miaoli, 350, Taiwan
| | - Jiin-Tsuey Cheng
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Yu-Feng Su
- Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Joon-Khim Loh
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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18
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Rakotomamonjy J, Rylaarsdam L, Fares-Taie L, McDermott S, Davies D, Yang G, Fagbemi F, Epstein M, Fairbanks-Santana M, Rozet JM, Guemez-Gamboa A. PCDH12 loss results in premature neuronal differentiation and impeded migration in a cortical organoid model. Cell Rep 2023; 42:112845. [PMID: 37480564 PMCID: PMC10521973 DOI: 10.1016/j.celrep.2023.112845] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 05/15/2023] [Accepted: 07/06/2023] [Indexed: 07/24/2023] Open
Abstract
Protocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Biallelic loss-of-function variants in PCDH12 are associated with several neurodevelopmental disorders (NDDs). Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease. Here, we show that PCDH12 loss severely impairs cerebral organoid development, with reduced proliferative areas and disrupted laminar organization. 2D models further show that neural progenitor cells lacking PCDH12 prematurely exit the cell cycle and differentiate earlier when compared with wild type. Furthermore, we show that PCDH12 regulates neuronal migration and suggest that this could be through a mechanism requiring ADAM10-mediated ectodomain shedding and/or membrane recruitment of cytoskeleton regulators. Our results demonstrate a critical involvement of PCDH12 in cortical organoid development, suggesting a potential cause for the pathogenic mechanisms underlying PCDH12-related NDDs.
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Affiliation(s)
- Jennifer Rakotomamonjy
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Lauren Rylaarsdam
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Lucas Fares-Taie
- Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France
| | - Sean McDermott
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Devin Davies
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - George Yang
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Fikayo Fagbemi
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Maya Epstein
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Martín Fairbanks-Santana
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jean-Michel Rozet
- Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France
| | - Alicia Guemez-Gamboa
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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Ferreira NGBP, Madeira JLO, Gergics P, Kertsz R, Marques JM, Trigueiro NSS, Benedetti AFF, Azevedo BV, Fernandes BHV, Bissegatto DD, Biscotto IP, Fang Q, Ma Q, Ozel AB, Li J, Camper SA, Jorge AAL, Mendonça BB, Arnhold IJP, Carvalho LR. Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders. Endocr Connect 2023; 12:e220473. [PMID: 37166408 PMCID: PMC10388658 DOI: 10.1530/ec-22-0473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/11/2023] [Indexed: 05/12/2023]
Abstract
Context Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition. Objectives The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant. Design Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing. Results One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected. Conclusion A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations. Significance statement A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.
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Affiliation(s)
- Nathalia G B P Ferreira
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Joao L O Madeira
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Peter Gergics
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Renata Kertsz
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Juliana M Marques
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Nicholas S S Trigueiro
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | | | - Bruna V Azevedo
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Bianca H V Fernandes
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Universidade de São Paulo, Zebrafish Facility, São Paulo, São Paulo, Brazil
| | - Debora D Bissegatto
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Isabela P Biscotto
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Qing Fang
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Qianyi Ma
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Asye B Ozel
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Jun Li
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Sally A Camper
- Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Alexander A L Jorge
- Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Berenice B Mendonça
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Ivo J P Arnhold
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Luciani R Carvalho
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
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Li X, Zou S, Tu X, Hao S, Jiang T, Chen JG. Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells, Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice. Neurosci Bull 2023; 39:1131-1145. [PMID: 36646976 PMCID: PMC10313612 DOI: 10.1007/s12264-022-01004-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/04/2022] [Indexed: 01/18/2023] Open
Abstract
Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.
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Affiliation(s)
- Xue Li
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China
| | - Shimin Zou
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China
| | - Xiaomeng Tu
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China
| | - Shishuai Hao
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China
| | - Tian Jiang
- Research Center for Translational Medicine, the Affiliated Wenling Hospital of Wenzhou Medical University, Wenling, 317500, China
| | - Jie-Guang Chen
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, and Zhejiang Provincial Key Laboratory of Optometry and Ophthalmology, Wenzhou, 325027, China.
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21
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Yang Y, Ren ZZ, Wei WJ, He ZL, Deng YL, Wang Z, Fan YC, Zhou J, Jiang LH. Study on the biological mechanism of urolithin a on nasopharyngeal carcinoma in vitro. PHARMACEUTICAL BIOLOGY 2022; 60:1566-1577. [PMID: 35952389 PMCID: PMC9377270 DOI: 10.1080/13880209.2022.2106251] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 06/08/2022] [Accepted: 07/22/2022] [Indexed: 06/15/2023]
Abstract
CONTEXT Urolithin A (UroA) can inhibit the growth of many human cancer cells, but it has not be reported if UroA inhibits nasopharyngeal carcinoma (NPC) cells. OBJECTIVE To explore the inhibitory effect of UroA on NPC and potential mechanism in vitro. MATERIALS AND METHODS RNA-sequencing-based mechanistic prediction was conducted by comparing KEGG enrichment of 40 μM UroA-treated for 24 h with untreated CNE2 cells. The untreated cells were selected as control. After NPC cells were treated with 20-60 μM UroA, proliferation, migration and invasion of were measured by colony formation, wound healing and transwell experiments. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) were measured by flow cytometry, Hoechst 33342, Rhodamine 123, JC-1 staining and ROS assay methods, respectively. Gene and protein expression were measured by RT-qPCR and Western blotting assay. RESULTS RNA-sequencing and KEGG enrichment revealed UroA mainly altered the ECM receptor interaction pathway. UroA inhibited cells proliferation, epithelial-mesenchymal-transition pathway, migration and invasion with IC50 values of 34.72 μM and 44.91 μM, induced apoptosis, MMP depolarization and increase ROS content at a concentration of 40 μM. UroA up-regulated E-cadherin, Bax/Bcl-2, c-caspase-3 and PARP proteins, while inhibiting COL4A1, MMP2, MMP9, N-cadherin, Vimentin and Snail proteins at 20-60 μM. Moreover, co-treatment of UroA (40 μM) and NAC (5 mM) could reverse the effect of UroA on apoptosis-related proteins. DISCUSSION AND CONCLUSIONS RNA-sequencing technology based on bioinformatic analyses may be applicable for studiying the mechanism of drugs for tumour treatment.
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Affiliation(s)
- Yang Yang
- School of Pharmacy, Guilin Medical University, Guilin, PR China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
| | - Zhen-Zhen Ren
- School of Pharmacy, Guilin Medical University, Guilin, PR China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
| | - Wu-Jun Wei
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
- Department of Laboratory Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, PR China
| | - Zhi-Long He
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
- College of Light Industry and Food Engineering, Guangxi University, Nanning, PR China
| | - You-Lin Deng
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
| | - Zhuan Wang
- College of Light Industry and Food Engineering, Guangxi University, Nanning, PR China
| | - Yu-Chun Fan
- Medical College, Guangxi University, Nanning, PR China
| | - Jie Zhou
- Medical College, Guangxi University, Nanning, PR China
| | - Li-He Jiang
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, PR China
- College of Light Industry and Food Engineering, Guangxi University, Nanning, PR China
- Medical College, Guangxi University, Nanning, PR China
- Key Laboratory of Tumor Immunology and Pathology (Army Medical University), Ministry of Education, Chongqing, PR China
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22
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Gerstmann K, Kindbeiter K, Telley L, Bozon M, Reynaud F, Théoulle E, Charoy C, Jabaudon D, Moret F, Castellani V. A balance of noncanonical Semaphorin signaling from the cerebrospinal fluid regulates apical cell dynamics during corticogenesis. SCIENCE ADVANCES 2022; 8:eabo4552. [PMID: 36399562 PMCID: PMC9674300 DOI: 10.1126/sciadv.abo4552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 10/03/2022] [Indexed: 06/01/2023]
Abstract
During corticogenesis, dynamic regulation of apical adhesion is fundamental to generate correct numbers and cell identities. While radial glial cells (RGCs) maintain basal and apical anchors, basal progenitors and neurons detach and settle at distal positions from the apical border. Whether diffusible signals delivered from the cerebrospinal fluid (CSF) contribute to the regulation of apical adhesion dynamics remains fully unknown. Secreted class 3 Semaphorins (Semas) trigger cell responses via Plexin-Neuropilin (Nrp) membrane receptor complexes. Here, we report that unconventional Sema3-Nrp preformed complexes are delivered by the CSF from sources including the choroid plexus to Plexin-expressing RGCs via their apical endfeet. Through analysis of mutant mouse models and various ex vivo assays mimicking ventricular delivery to RGCs, we found that two different complexes, Sema3B/Nrp2 and Sema3F/Nrp1, exert dual effects on apical endfeet dynamics, nuclei positioning, and RGC progeny. This reveals unexpected balance of CSF-delivered guidance molecules during cortical development.
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Affiliation(s)
- Katrin Gerstmann
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Karine Kindbeiter
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Ludovic Telley
- Department of Basic Neuroscience, University of Geneva, 1211 Geneva 4, Switzerland
| | - Muriel Bozon
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Florie Reynaud
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Emy Théoulle
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Camille Charoy
- UCL Institute of Ophthalmology, University College London, London, UK
| | - Denis Jabaudon
- Department of Basic Neuroscience, University of Geneva, 1211 Geneva 4, Switzerland
| | - Frédéric Moret
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
| | - Valerie Castellani
- MeLis, CNRS UMR 5284, INSERM U1314, University of Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, 8 avenue Rockefeller, 69008 Lyon, France
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23
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de Thonel A, Ahlskog JK, Daupin K, Dubreuil V, Berthelet J, Chaput C, Pires G, Leonetti C, Abane R, Barris LC, Leray I, Aalto AL, Naceri S, Cordonnier M, Benasolo C, Sanial M, Duchateau A, Vihervaara A, Puustinen MC, Miozzo F, Fergelot P, Lebigot É, Verloes A, Gressens P, Lacombe D, Gobbo J, Garrido C, Westerheide SD, David L, Petitjean M, Taboureau O, Rodrigues-Lima F, Passemard S, Sabéran-Djoneidi D, Nguyen L, Lancaster M, Sistonen L, Mezger V. CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. Nat Commun 2022; 13:7002. [PMID: 36385105 PMCID: PMC9668993 DOI: 10.1038/s41467-022-34476-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.
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Affiliation(s)
- Aurélie de Thonel
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France.
| | - Johanna K Ahlskog
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Kevin Daupin
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Véronique Dubreuil
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Jérémy Berthelet
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Carole Chaput
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
- Ksilink, Strasbourg, France
| | - Geoffrey Pires
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Camille Leonetti
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Ryma Abane
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Lluís Cordón Barris
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman, Liège, Belgium
| | - Isabelle Leray
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000, Nantes, France
| | - Anna L Aalto
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Sarah Naceri
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Marine Cordonnier
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Carène Benasolo
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Matthieu Sanial
- CNRS, UMR 7592 Institut Jacques Monod, F-75205, Paris, France
| | - Agathe Duchateau
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Anniina Vihervaara
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- KTH Royal Institute of Technology, Stockholm, Sweden
| | - Mikael C Puustinen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Federico Miozzo
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
- Neuroscience Institute-CNR (IN-CNR), Milan, Italy
| | - Patricia Fergelot
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux, Bordeaux, France
| | - Élise Lebigot
- Service de Biochimie-pharmaco-toxicologie, Hôpital Bicêtre, Hopitaux Universitaires Paris-Sud, 94270 Le Kremlin Bicêtre, Paris-Sud, France
| | - Alain Verloes
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
- Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France
| | - Pierre Gressens
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
| | - Didier Lacombe
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux, Bordeaux, France
| | - Jessica Gobbo
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Carmen Garrido
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Sandy D Westerheide
- Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, University of South Florida, Tampa, FL, USA
| | - Laurent David
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000, Nantes, France
| | - Michel Petitjean
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Olivier Taboureau
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | | | - Sandrine Passemard
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
| | | | - Laurent Nguyen
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman, Liège, Belgium
| | - Madeline Lancaster
- MRC Laboratory of Molecular Biology, Cambridge Biomedical, Campus, Cambridge, UK
| | - Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Valérie Mezger
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France.
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László ZI, Lele Z. Flying under the radar: CDH2 (N-cadherin), an important hub molecule in neurodevelopmental and neurodegenerative diseases. Front Neurosci 2022; 16:972059. [PMID: 36213737 PMCID: PMC9539934 DOI: 10.3389/fnins.2022.972059] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/31/2022] [Indexed: 12/03/2022] Open
Abstract
CDH2 belongs to the classic cadherin family of Ca2+-dependent cell adhesion molecules with a meticulously described dual role in cell adhesion and β-catenin signaling. During CNS development, CDH2 is involved in a wide range of processes including maintenance of neuroepithelial integrity, neural tube closure (neurulation), confinement of radial glia progenitor cells (RGPCs) to the ventricular zone and maintaining their proliferation-differentiation balance, postmitotic neural precursor migration, axon guidance, synaptic development and maintenance. In the past few years, direct and indirect evidence linked CDH2 to various neurological diseases, and in this review, we summarize recent developments regarding CDH2 function and its involvement in pathological alterations of the CNS.
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Affiliation(s)
- Zsófia I. László
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Zsolt Lele
- Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
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25
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Martínez Traverso IM, Steimle JD, Zhao X, Wang J, Martin JF. LATS1/2 control TGFB-directed epithelial-to-mesenchymal transition in the murine dorsal cranial neuroepithelium through YAP regulation. Development 2022; 149:dev200860. [PMID: 36125128 PMCID: PMC9587805 DOI: 10.1242/dev.200860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/12/2022] [Indexed: 11/20/2022]
Abstract
Hippo signaling, an evolutionarily conserved kinase cascade involved in organ size control, plays key roles in various tissue developmental processes, but its role in craniofacial development remains poorly understood. Using the transgenic Wnt1-Cre2 driver, we inactivated the Hippo signaling components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos and found that the double conditional knockout (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos had microcephaly with delayed and defective neural tube closure. Furthermore, neuroepithelial cell shape and architecture were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. RNA sequencing of embryonic neural tubes revealed increased TGFB signaling in Lats1/2 DCKO mutants. Moreover, markers of epithelial-to-mesenchymal transition (EMT) were upregulated in the cranial neural tube. Inactivation of Hippo signaling downstream effectors, Yap and Taz, suppressed neuroepithelial defects, aberrant EMT and TGFB upregulation in Lats1/2 DCKO embryos, indicating that LATS1/2 function via YAP and TAZ. Our findings reveal important roles for Hippo signaling in modulating TGFB signaling during neural crest EMT.
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Affiliation(s)
- Idaliz M. Martínez Traverso
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
- Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jeffrey D. Steimle
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiaolei Zhao
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - James F. Martin
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
- Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX 77030, USA
- Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX 77030 , USA
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HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch–Nyhan disease. Cell Mol Life Sci 2022; 79:341. [PMID: 35660973 PMCID: PMC9167210 DOI: 10.1007/s00018-022-04326-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/05/2022] [Accepted: 04/23/2022] [Indexed: 11/20/2022]
Abstract
In Lesch–Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH+ cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders.
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Casas Gimeno G, Paridaen JTML. The Symmetry of Neural Stem Cell and Progenitor Divisions in the Vertebrate Brain. Front Cell Dev Biol 2022; 10:885269. [PMID: 35693936 PMCID: PMC9174586 DOI: 10.3389/fcell.2022.885269] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 04/20/2022] [Indexed: 12/23/2022] Open
Abstract
Robust brain development requires the tight coordination between tissue growth, neuronal differentiation and stem cell maintenance. To achieve this, neural stem cells need to balance symmetric proliferative and terminal divisions with asymmetric divisions. In recent years, the unequal distribution of certain cellular components in mitosis has emerged as a key mechanism to regulate the symmetry of division, and the determination of equal and unequal sister cell fates. Examples of such components include polarity proteins, signaling components, and cellular structures such as endosomes and centrosomes. In several types of neural stem cells, these factors show specific patterns of inheritance that correlate to specific cell fates, albeit the underlying mechanism and the potential causal relationship is not always understood. Here, we review these examples of cellular neural stem and progenitor cell asymmetries and will discuss how they fit into our current understanding of neural stem cell function in neurogenesis in developing and adult brains. We will focus mainly on the vertebrate brain, though we will incorporate relevant examples from invertebrate organisms as well. In particular, we will highlight recent advances in our understanding of the complexities related cellular asymmetries in determining division mode outcomes, and how these mechanisms are spatiotemporally regulated to match the different needs for proliferation and differentiation as the brain forms.
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Breaking through the barrier: Modelling and exploiting the physical microenvironment to enhance drug transport and efficacy. Adv Drug Deliv Rev 2022; 184:114183. [PMID: 35278523 DOI: 10.1016/j.addr.2022.114183] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/03/2022] [Accepted: 03/06/2022] [Indexed: 02/08/2023]
Abstract
Pharmaceutical compounds are the main pillar in the treatment of various illnesses. To administer these drugs in the therapeutic setting, multiple routes of administration have been defined, including ingestion, inhalation, and injection. After administration, drugs need to find their way to the intended target for high effectiveness, and this penetration is greatly dependent on obstacles the drugs encounter along their path. Key hurdles include the physical barriers that are present within the body and knowledge of those is indispensable for progress in the development of drugs with increased therapeutic efficacy. In this review, we examine several important physical barriers, such as the blood-brain barrier, the gut-mucosal barrier, and the extracellular matrix barrier, and evaluate their influence on drug transport and efficacy. We explore various in vitro model systems that aid in understanding how parameters within the barrier model affect drug transfer and therapeutic effect. We conclude that physical barriers in the body restrict the quantity of drugs that can pass through, mainly as a consequence of the barrier architecture. In addition, the specific physical properties of the tissue can trigger intracellular changes, altering cell behavior in response to drugs. Though the barriers negatively influence drug distribution, physical stimulation of the surrounding environment may also be exploited as a mechanism to control drug release. This drug delivery approach is explored in this review as a potential alternative to the conventional ways of delivering therapeutics.
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Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases. Int J Mol Sci 2022; 23:ijms23084413. [PMID: 35457230 PMCID: PMC9028019 DOI: 10.3390/ijms23084413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.
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Bierman-Duquette RD, Safarians G, Huang J, Rajput B, Chen JY, Wang ZZ, Seidlits SK. Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells. Adv Healthc Mater 2022; 11:e2101577. [PMID: 34808031 PMCID: PMC8986557 DOI: 10.1002/adhm.202101577] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/31/2021] [Indexed: 12/19/2022]
Abstract
Conductive biomaterials provide an important control for engineering neural tissues, where electrical stimulation can potentially direct neural stem/progenitor cell (NS/PC) maturation into functional neuronal networks. It is anticipated that stem cell-based therapies to repair damaged central nervous system (CNS) tissues and ex vivo, "tissue chip" models of the CNS and its pathologies will each benefit from the development of biocompatible, biodegradable, and conductive biomaterials. Here, technological advances in conductive biomaterials are reviewed over the past two decades that may facilitate the development of engineered tissues with integrated physiological and electrical functionalities. First, one briefly introduces NS/PCs of the CNS. Then, the significance of incorporating microenvironmental cues, to which NS/PCs are naturally programmed to respond, into biomaterial scaffolds is discussed with a focus on electrical cues. Next, practical design considerations for conductive biomaterials are discussed followed by a review of studies evaluating how conductive biomaterials can be engineered to control NS/PC behavior by mimicking specific functionalities in the CNS microenvironment. Finally, steps researchers can take to move NS/PC-interfacing, conductive materials closer to clinical translation are discussed.
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Affiliation(s)
| | - Gevick Safarians
- Department of Bioengineering, University of California Los Angeles, USA
| | - Joyce Huang
- Department of Bioengineering, University of California Los Angeles, USA
| | - Bushra Rajput
- Department of Bioengineering, University of California Los Angeles, USA
| | - Jessica Y. Chen
- Department of Bioengineering, University of California Los Angeles, USA
- David Geffen School of Medicine, University of California Los Angeles, USA
| | - Ze Zhong Wang
- Department of Bioengineering, University of California Los Angeles, USA
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Abulaiti X, Wang A, Zhang H, Su H, Gao R, Chen J, Gao S, Li L. Disrupted mossy fiber connections from defective embryonic neurogenesis contribute to SOX11-associated schizophrenia. Cell Mol Life Sci 2022; 79:180. [PMID: 35254515 PMCID: PMC11072709 DOI: 10.1007/s00018-022-04206-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/29/2022] [Accepted: 02/09/2022] [Indexed: 11/26/2022]
Abstract
Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.
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Affiliation(s)
- Xianmixinuer Abulaiti
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Shanghai Advanced Research Institute Chinese Academy of Sciences, Shanghai, 201210, China
| | - Aifang Wang
- Shanghai Advanced Research Institute Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Han Zhang
- Shanghai Advanced Research Institute Chinese Academy of Sciences, Shanghai, 201210, China
| | - Hang Su
- Shanghai Advanced Research Institute Chinese Academy of Sciences, Shanghai, 201210, China
- Henan Provincial People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
| | - Rui Gao
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jiayu Chen
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Shaorong Gao
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Lingsong Li
- Shanghai Advanced Research Institute Chinese Academy of Sciences, Shanghai, 201210, China.
- Henan Provincial People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers (Basel) 2021; 13:5203. [PMID: 34680351 PMCID: PMC8534074 DOI: 10.3390/cancers13205203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/28/2022] Open
Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
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Affiliation(s)
- Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah 11211, Saudi Arabia;
| | - Mahnaz Ghaebi
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan 4513956184, Iran;
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, 2418 Hamar, Norway;
| | - Martin R. Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
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Almasoudi SH, Schlosser G. Otic Neurogenesis in Xenopus laevis: Proliferation, Differentiation, and the Role of Eya1. Front Neuroanat 2021; 15:722374. [PMID: 34616280 PMCID: PMC8488300 DOI: 10.3389/fnana.2021.722374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/27/2021] [Indexed: 11/15/2022] Open
Abstract
Using immunostaining and confocal microscopy, we here provide the first detailed description of otic neurogenesis in Xenopus laevis. We show that the otic vesicle comprises a pseudostratified epithelium with apicobasal polarity (apical enrichment of Par3, aPKC, phosphorylated Myosin light chain, N-cadherin) and interkinetic nuclear migration (apical localization of mitotic, pH3-positive cells). A Sox3-immunopositive neurosensory area in the ventromedial otic vesicle gives rise to neuroblasts, which delaminate through breaches in the basal lamina between stages 26/27 and 39. Delaminated cells congregate to form the vestibulocochlear ganglion, whose peripheral cells continue to proliferate (as judged by EdU incorporation), while central cells differentiate into Islet1/2-immunopositive neurons from stage 29 on and send out neurites at stage 31. The central part of the neurosensory area retains Sox3 but stops proliferating from stage 33, forming the first sensory areas (utricular/saccular maculae). The phosphatase and transcriptional coactivator Eya1 has previously been shown to play a central role for otic neurogenesis but the underlying mechanism is poorly understood. Using an antibody specifically raised against Xenopus Eya1, we characterize the subcellular localization of Eya1 proteins, their levels of expression as well as their distribution in relation to progenitor and neuronal differentiation markers during otic neurogenesis. We show that Eya1 protein localizes to both nuclei and cytoplasm in the otic epithelium, with levels of nuclear Eya1 declining in differentiating (Islet1/2+) vestibulocochlear ganglion neurons and in the developing sensory areas. Morpholino-based knockdown of Eya1 leads to reduction of proliferating, Sox3- and Islet1/2-immunopositive cells, redistribution of cell polarity proteins and loss of N-cadherin suggesting that Eya1 is required for maintenance of epithelial cells with apicobasal polarity, progenitor proliferation and neuronal differentiation during otic neurogenesis.
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Affiliation(s)
| | - Gerhard Schlosser
- School of Natural Sciences, National University of Galway, Galway, Ireland
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The Effects of Bilirubin and Lumirubin on the Differentiation of Human Pluripotent Cell-Derived Neural Stem Cells. Antioxidants (Basel) 2021; 10:antiox10101532. [PMID: 34679668 PMCID: PMC8532948 DOI: 10.3390/antiox10101532] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 11/23/2022] Open
Abstract
The ‘gold standard’ treatment of severe neonatal jaundice is phototherapy with blue–green light, which produces more polar photo-oxidation products that are easily excreted via the bile or urine. The aim of this study was to compare the effects of bilirubin (BR) and its major photo-oxidation product lumirubin (LR) on the proliferation, differentiation, morphology, and specific gene and protein expressions of self-renewing human pluripotent stem cell-derived neural stem cells (NSC). Neither BR nor LR in biologically relevant concentrations (12.5 and 25 µmol/L) affected cell proliferation or the cell cycle phases of NSC. Although none of these pigments affected terminal differentiation to neurons and astrocytes, when compared to LR, BR exerted a dose-dependent cytotoxicity on self-renewing NSC. In contrast, LR had a substantial effect on the morphology of the NSC, inducing them to form highly polar rosette-like structures associated with the redistribution of specific cellular proteins (β-catenin/N-cadherin) responsible for membrane polarity. This observation was accompanied by lower expressions of NSC-specific proteins (such as SOX1, NR2F2, or PAX6) together with the upregulation of phospho-ERK. Collectively, the data indicated that both BR and LR affect early human neurodevelopment in vitro, which may have clinical relevance in phototherapy-treated hyperbilirubinemic neonates.
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Noronha C, Ribeiro AS, Taipa R, Castro DS, Reis J, Faria C, Paredes J. Cadherin Expression and EMT: A Focus on Gliomas. Biomedicines 2021; 9:biomedicines9101328. [PMID: 34680444 PMCID: PMC8533397 DOI: 10.3390/biomedicines9101328] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 12/13/2022] Open
Abstract
Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.
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Affiliation(s)
- Carolina Noronha
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal; (C.N.); (J.R.)
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Ana Sofia Ribeiro
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
| | - Ricardo Taipa
- Neuropathology Unit, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal;
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Diogo S. Castro
- Stem Cells & Neurogenesis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
| | - Joaquim Reis
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal; (C.N.); (J.R.)
- Anatomy Department, Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Cláudia Faria
- Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, 1649-028 Lisboa, Portugal;
- IMM—Instituto de Medicina Molecular Joao Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Joana Paredes
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Correspondence:
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Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity. Cells 2021; 10:cells10081911. [PMID: 34440681 PMCID: PMC8393895 DOI: 10.3390/cells10081911] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 12/19/2022] Open
Abstract
Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP.
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Punovuori K, Malaguti M, Lowell S. Cadherins in early neural development. Cell Mol Life Sci 2021; 78:4435-4450. [PMID: 33796894 PMCID: PMC8164589 DOI: 10.1007/s00018-021-03815-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/04/2021] [Accepted: 03/18/2021] [Indexed: 11/12/2022]
Abstract
During early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type" (Waddington in Nature 183: 1654-1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772-774, 1988; Lander in Cell 144: 955-969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.
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Affiliation(s)
- Karolina Punovuori
- Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
| | - Mattias Malaguti
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Little France Drive, Edinburgh, EH16 4UU, UK
| | - Sally Lowell
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Little France Drive, Edinburgh, EH16 4UU, UK.
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Sbiera I, Kircher S, Altieri B, Fassnacht M, Kroiss M, Sbiera S. Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues? Cancers (Basel) 2021; 13:1736. [PMID: 33917436 PMCID: PMC8038668 DOI: 10.3390/cancers13071736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/02/2021] [Accepted: 04/04/2021] [Indexed: 12/22/2022] Open
Abstract
A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.
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Affiliation(s)
- Iuliu Sbiera
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany; (I.S.); (B.A.); (M.F.)
| | - Stefan Kircher
- Institute for Pathology, University of Würzburg, 97080 Würzburg, Germany;
| | - Barbara Altieri
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany; (I.S.); (B.A.); (M.F.)
| | - Martin Fassnacht
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany; (I.S.); (B.A.); (M.F.)
- Clinical Chemistry and Laboratory Medicine, University Hospital Würzburg, 97080 Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany
| | - Matthias Kroiss
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany; (I.S.); (B.A.); (M.F.)
- Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany
- Department of Internal Medicine IV, University Hospital Munich, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Silviu Sbiera
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany; (I.S.); (B.A.); (M.F.)
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Deng Z, Yan W, Dai X, Chen M, Qu Q, Wu B, Zhao W. N-Cadherin Regulates the Odontogenic Differentiation of Dental Pulp Stem Cells via β-Catenin Activity. Front Cell Dev Biol 2021; 9:661116. [PMID: 33859987 PMCID: PMC8042212 DOI: 10.3389/fcell.2021.661116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
Dental pulp stem cell (DPSC) transplantation has shown new prospects in dental pulp regeneration, and is of great significance in the treatment of pulpitis and pulp necrosis. The fate and regenerative potential of stem cells are dependent, to a great extent, on their microenvironment, which is composed of various tissue components, cell populations, and soluble factors. N-cadherin-mediated cell–cell interaction has been implicated as an important factor in controlling the cell-fate commitment of mesenchymal stem cells. In this study, the effect of N-cadherin on odontogenic differentiation of DPSCs and the potential underlying mechanisms, both in vitro and in vivo, was investigated using a cell culture model and a subcutaneous transplantation mouse model. It was found that the expression of N-cadherin was reversely related to the expression of odontogenic markers (dentin sialophosphoprotein, DSPP, and runt-related transcription factor 2, Runx2) during the differentiation process of DPSCs. Specific shRNA-mediated knockdown of N-cadherin expression in DPSCs significantly increased the expression of DSPP and Runx2, alkaline phosphatase (ALP) activity, and the formation of mineralized nodules. Notably, N-cadherin silencing promoted nucleus translocation and accumulation of β-catenin. Inhibition of β-catenin by a specific inhibitor XAV939, reversed the facilitating effects of N-cadherin downregulation on odontogenic differentiation of DPSCs. In addition, knockdown of N-cadherin promoted the formation of odontoblast-like cells and collagenous matrix in β-tricalcium phosphate/DPSCs composites transplanted into mice. In conclusion, N-cadherin acted as a negative regulator via regulating β-catenin activity during odontogenic differentiation of DPSCs. These data may help to guide DPSC behavior by tuning the N-cadherin-mediated cell–cell interactions, with implications for pulp regeneration.
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Affiliation(s)
- Zilong Deng
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjuan Yan
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xingzhu Dai
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ming Chen
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Qian Qu
- Stomatology Healthcare Center, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
| | - Buling Wu
- Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, China
| | - Wanghong Zhao
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Osuka S, Zhu D, Zhang Z, Li C, Stackhouse CT, Sampetrean O, Olson JJ, Gillespie GY, Saya H, Willey CD, Van Meir EG. N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. J Clin Invest 2021; 131:136098. [PMID: 33720050 PMCID: PMC7954595 DOI: 10.1172/jci136098] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 01/22/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which suppressed Wnt/β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.
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Affiliation(s)
- Satoru Osuka
- Department of Neurosurgery, School of Medicine and O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Dan Zhu
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Zhaobin Zhang
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Chaoxi Li
- Department of Neurosurgery, School of Medicine and O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Christian T. Stackhouse
- Department of Neurosurgery, School of Medicine and O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, USA
| | - Oltea Sampetrean
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Jeffrey J. Olson
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - G. Yancey Gillespie
- Department of Neurosurgery, School of Medicine and O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Christopher D. Willey
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, USA
| | - Erwin G. Van Meir
- Department of Neurosurgery, School of Medicine and O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Cao X, An J, Cao Y, Lv J, Wang J, Ding Y, Lin X, Zhou X. EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development. Invest Ophthalmol Vis Sci 2021; 62:31. [PMID: 33605987 PMCID: PMC7900856 DOI: 10.1167/iovs.62.2.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 01/18/2021] [Indexed: 12/15/2022] Open
Abstract
Purpose We used a mouse model to explore the role of the endoplasmic reticulum membrane protein complex subunit 3 (EMC3) in mammalian retinal development. Methods The transcription pattern of Emc3 in C57BL/6 mice was analyzed by in situ hybridization. To explore the effects of EMC3 absence on retinal development, the Cre-loxP system was used to generate retina-specific Emc3 in knockout mice (Emc3flox/flox, Six3-cre+; CKO). Morphological changes in the retina of E13.5, E17.5, P0.5, and P7 mice were observed via hematoxylin and eosin staining. Immunofluorescence staining was used to assess protein distribution and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to assess apoptosis changes. Proteins were identified and quantified by Western blotting and proteomic analysis. Electroretinogram (ERG), fundus color photography, and optical coherence tomography were performed on 5-week-old mice to evaluate retinal function and structure. Results The Emc3 mRNA was widely distributed in the whole retina during development. Loss of retinal EMC3 led to retinal rosette degeneration with mislocalization of cell junction molecules (β-catenin, N-cadherin, and zonula occludens-1) and polarity molecules (Par3 and PKCζ). Endoplasmic reticulum stress and TUNEL apoptosis signals were present in retinal rosette-forming cells. Although the absence of EMC3 promoted the production of photoreceptor cells, 5-week-old mice lost all visual function and had severe retinal morphological degeneration. Conclusions EMC3 regulates retinal structure by maintaining the polarity of retinal progenitor cells and regulating retinal cell apoptosis.
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Affiliation(s)
- Xiaowen Cao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Jianhong An
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Yuqing Cao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Juan Lv
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Jiawei Wang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Yang Ding
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
| | - Xinhua Lin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiangtian Zhou
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
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Kunii M, Noguchi Y, Yoshimura SI, Kanda S, Iwano T, Avriyanti E, Atik N, Sato T, Sato K, Ogawa M, Harada A. SNAP23 deficiency causes severe brain dysplasia through the loss of radial glial cell polarity. J Cell Biol 2021; 220:e201910080. [PMID: 33332551 PMCID: PMC7754684 DOI: 10.1083/jcb.201910080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 08/23/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
In the developing brain, the polarity of neural progenitor cells, termed radial glial cells (RGCs), is important for neurogenesis. Intercellular adhesions, termed apical junctional complexes (AJCs), at the apical surface between RGCs are necessary for cell polarization. However, the mechanism by which AJCs are established remains unclear. Here, we show that a SNARE complex composed of SNAP23, VAMP8, and Syntaxin1B has crucial roles in AJC formation and RGC polarization. Central nervous system (CNS)-specific ablation of SNAP23 (NcKO) results in mice with severe hypoplasia of the neocortex and no hippocampus or cerebellum. In the developing NcKO brain, RGCs lose their polarity following the disruption of AJCs and exhibit reduced proliferation, increased differentiation, and increased apoptosis. SNAP23 and its partner SNAREs, VAMP8 and Syntaxin1B, are important for the localization of an AJC protein, N-cadherin, to the apical plasma membrane of RGCs. Altogether, SNARE-mediated localization of N-cadherin is essential for AJC formation and RGC polarization during brain development.
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Affiliation(s)
- Masataka Kunii
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | - Yuria Noguchi
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shin-ichiro Yoshimura
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Satoshi Kanda
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tomohiko Iwano
- Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Erda Avriyanti
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Dermatology and Venereology, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Nur Atik
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Biomedical Sciences, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Takashi Sato
- Laboratory of Developmental Biology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | - Ken Sato
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | | | - Akihiro Harada
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
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Manohar S, Camacho-Magallanes A, Echeverria C, Rogers CD. Cadherin-11 Is Required for Neural Crest Specification and Survival. Front Physiol 2020; 11:563372. [PMID: 33192560 PMCID: PMC7662130 DOI: 10.3389/fphys.2020.563372] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/06/2020] [Indexed: 01/06/2023] Open
Abstract
Neural crest (NC) cells are multipotent embryonic cells that form melanocytes, craniofacial bone and cartilage, and the peripheral nervous system in vertebrates. NC cells express many cadherin proteins, which control their specification, epithelial to mesenchymal transition (EMT), migration, and mesenchymal to epithelial transition. Abnormal NC development leads to congenital defects including craniofacial clefts as well as NC-derived cancers. Here, we identify the role of the type II cadherin protein, Cadherin-11 (CDH11), in early chicken NC development. CDH11 is known to play a role in NC cell migration in amphibian embryos as well as cell survival, proliferation, and migration in cancer cells. It has also been linked to the complex neurocristopathy disorder, Elsahy-Waters Syndrome, in humans. In this study, we knocked down CDH11 translation at the onset of its expression in the NC domain during NC induction. Loss of CDH11 led to a reduction of bonafide NC cells in the dorsal neural tube combined with defects in cell survival and migration. Loss of CDH11 increased p53-mediated programmed-cell death, and blocking the p53 pathway rescued the NC phenotype. Our findings reveal an early requirement for CDH11 in NC development and demonstrated the complexity of the mechanisms that regulate NC development, where a single cell-cell adhesion protein simultaneous controls multiple essential cellular functions to ensure proper specification, survival, and transition to a migratory phase in the dorsal neural tube. Our findings may also increase our understanding of early cadherin-related NC developmental defects.
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Affiliation(s)
- Subrajaa Manohar
- Department of Biology, School of Math and Science, California State University Northridge, Northridge, CA, United States
| | - Alberto Camacho-Magallanes
- Department of Biology, School of Math and Science, California State University Northridge, Northridge, CA, United States
| | - Camilo Echeverria
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA, United States
| | - Crystal D Rogers
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA, United States
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Ferent J, Zaidi D, Francis F. Extracellular Control of Radial Glia Proliferation and Scaffolding During Cortical Development and Pathology. Front Cell Dev Biol 2020; 8:578341. [PMID: 33178693 PMCID: PMC7596222 DOI: 10.3389/fcell.2020.578341] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/08/2020] [Indexed: 01/14/2023] Open
Abstract
During the development of the cortex, newly generated neurons migrate long-distances in the expanding tissue to reach their final positions. Pyramidal neurons are produced from dorsal progenitors, e.g., radial glia (RGs) in the ventricular zone, and then migrate along RG processes basally toward the cortex. These neurons are hence dependent upon RG extensions to support their migration from apical to basal regions. Several studies have investigated how intracellular determinants are required for RG polarity and subsequent formation and maintenance of their processes. Fewer studies have identified the influence of the extracellular environment on this architecture. This review will focus on extracellular factors which influence RG morphology and pyramidal neuronal migration during normal development and their perturbations in pathology. During cortical development, RGs are present in different strategic positions: apical RGs (aRGs) have their cell bodies located in the ventricular zone with an apical process contacting the ventricle, while they also have a basal process extending radially to reach the pial surface of the cortex. This particular conformation allows aRGs to be exposed to long range and short range signaling cues, whereas basal RGs (bRGs, also known as outer RGs, oRGs) have their cell bodies located throughout the cortical wall, limiting their access to ventricular factors. Long range signals impacting aRGs include secreted molecules present in the embryonic cerebrospinal fluid (e.g., Neuregulin, EGF, FGF, Wnt, BMP). Secreted molecules also contribute to the extracellular matrix (fibronectin, laminin, reelin). Classical short range factors include cell to cell signaling, adhesion molecules and mechano-transduction mechanisms (e.g., TAG1, Notch, cadherins, mechanical tension). Changes in one or several of these components influencing the RG extracellular environment can disrupt the development or maintenance of RG architecture on which neuronal migration relies, leading to a range of cortical malformations. First, we will detail the known long range signaling cues impacting RG. Then, we will review how short range cell contacts are also important to instruct the RG framework. Understanding how RG processes are structured by their environment to maintain and support radial migration is a critical part of the investigation of neurodevelopmental disorders.
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Affiliation(s)
- Julien Ferent
- Inserm, U 1270, Paris, France.,Sorbonne University, UMR-S 1270, IFM, Paris, France.,Institut du Fer á Moulin, Paris, France
| | - Donia Zaidi
- Inserm, U 1270, Paris, France.,Sorbonne University, UMR-S 1270, IFM, Paris, France.,Institut du Fer á Moulin, Paris, France
| | - Fiona Francis
- Inserm, U 1270, Paris, France.,Sorbonne University, UMR-S 1270, IFM, Paris, France.,Institut du Fer á Moulin, Paris, France
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Kumar S, Curran JE, DeLeon E, Leandro AC, Howard TE, Lehman DM, Williams-Blangero S, Glahn DC, Blangero J. Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells. Int J Mol Sci 2020; 21:ijms21196980. [PMID: 32977388 PMCID: PMC7582477 DOI: 10.3390/ijms21196980] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 11/16/2022] Open
Abstract
miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA-mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change-absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10-15-1.44 × 10-4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.
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Affiliation(s)
- Satish Kumar
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (E.D.); (S.W.-B.)
- Correspondence:
| | - Joanne E. Curran
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (J.E.C.); (A.C.L.); (T.E.H.); (J.B.)
| | - Erica DeLeon
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (E.D.); (S.W.-B.)
| | - Ana C. Leandro
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (J.E.C.); (A.C.L.); (T.E.H.); (J.B.)
| | - Tom E. Howard
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (J.E.C.); (A.C.L.); (T.E.H.); (J.B.)
| | - Donna M. Lehman
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA;
| | - Sarah Williams-Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (E.D.); (S.W.-B.)
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (J.E.C.); (A.C.L.); (T.E.H.); (J.B.)
| | - David C. Glahn
- Department of Psychiatry, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
- Olin Neuropsychiatric Research Center, Institute of Living, Hartford, CT 06102, USA
| | - John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (J.E.C.); (A.C.L.); (T.E.H.); (J.B.)
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Arzaghi H, Adel B, Jafari H, Askarian-Amiri S, Shiralizadeh Dezfuli A, Akbarzadeh A, Pazoki-Toroudi H. Nanomaterial integration into the scaffolding materials for nerve tissue engineering: a review. Rev Neurosci 2020; 31:/j/revneuro.ahead-of-print/revneuro-2020-0008/revneuro-2020-0008.xml. [PMID: 32776904 DOI: 10.1515/revneuro-2020-0008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 05/21/2020] [Indexed: 12/12/2022]
Abstract
The nervous system, which consists of a complex network of millions of neurons, is one of the most highly intricate systems in the body. This complex network is responsible for the physiological and cognitive functions of the human body. Following injuries or degenerative diseases, damage to the nervous system is overwhelming because of its complexity and its limited regeneration capacity. However, neural tissue engineering currently has some capacities for repairing nerve deficits and promoting neural regeneration, with more developments in the future. Nevertheless, controlling the guidance of stem cell proliferation and differentiation is a challenging step towards this goal. Nanomaterials have the potential for the guidance of the stem cells towards the neural lineage which can overcome the pitfalls of the classical methods since they provide a unique microenvironment that facilitates cell-matrix and cell-cell interaction, and they can manipulate the cell signaling mechanisms to control stem cells' fate. In this article, the suitable cell sources and microenvironment cues for neuronal tissue engineering were examined. Afterward, the nanomaterials that impact stem cell proliferation and differentiation towards neuronal lineage were reviewed.
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Affiliation(s)
- Hamidreza Arzaghi
- Department of Medical Biotechnology, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Hemat Highway Next to Milad Tower, Tehran 1449614535, Islamic Republic of Iran
| | - Bashir Adel
- Department of Biology, Faculty of Sciences, The University of Guilan, Rasht 4199613776, Islamic Republic of Iran
| | - Hossein Jafari
- Institute for Research in Fundamental Sciences (IPM), Artesh Highway, Tehran 1956836681, Islamic Reitutionpublic of Iran
| | - Shaghayegh Askarian-Amiri
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Hemat Highway Next to Milad Tower, Tehran 1449614535, Islamic Republic of Iran
| | - Amin Shiralizadeh Dezfuli
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Hemat Highway Next to Milad Tower, Tehran 1449614535, Islamic Republic of Iran
| | - Abolfazl Akbarzadeh
- Tuberculosis and Lung Disease Research Center of Tabriz, Tabriz University of Medical Sciences, Tabriz 5165665811, Islamic Republic of Iran
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5165665811, Islamic Republic of Iran
- Iran Universal Scientific and Education Network (USERN), Tabriz 5165665811, Islamic Republic of Iran
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Hemat Highway Next to Milad Tower, Tehran 1449614535, Islamic Republic of Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Hemat Highway Next to Milad Tower, Tehran 1449614535, Islamic Republic of Iran
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Castaneyra-Ruiz L, McAllister JP, Morales DM, Brody SL, Isaacs AM, Limbrick DD. Preterm intraventricular hemorrhage in vitro: modeling the cytopathology of the ventricular zone. Fluids Barriers CNS 2020; 17:46. [PMID: 32690048 PMCID: PMC7372876 DOI: 10.1186/s12987-020-00210-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 07/13/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50% developing post-hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a protocol from our accepted in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. METHODS Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1-4 days of age and expanded in proliferation media for 3-5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3-5 days, which corresponded to the onset of EC differentiation based on the appearance of multiciliated cells, phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the EC surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. DISCUSSION This protocol will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis.
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Affiliation(s)
- Leandro Castaneyra-Ruiz
- Department of Neurological Surgery, Washington University School of Medicine and the St. Louis Children's Hospital, Campus Box 8057, 660 South Euclid Ave., St. Louis, MO, 63110, USA.
| | - James P McAllister
- Department of Neurological Surgery, Washington University School of Medicine and the St. Louis Children's Hospital, Campus Box 8057, 660 South Euclid Ave., St. Louis, MO, 63110, USA
| | - Diego M Morales
- Department of Neurological Surgery, Washington University School of Medicine and the St. Louis Children's Hospital, Campus Box 8057, 660 South Euclid Ave., St. Louis, MO, 63110, USA
| | - Steven L Brody
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Albert M Isaacs
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - David D Limbrick
- Department of Neurological Surgery, Washington University School of Medicine and the St. Louis Children's Hospital, Campus Box 8057, 660 South Euclid Ave., St. Louis, MO, 63110, USA
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Liu W, Xu B, Xue W, Yang B, Fan Y, Chen B, Xiao Z, Xue X, Sun Z, Shu M, Zhang Q, Shi Y, Zhao Y, Dai J. A functional scaffold to promote the migration and neuronal differentiation of neural stem/progenitor cells for spinal cord injury repair. Biomaterials 2020; 243:119941. [DOI: 10.1016/j.biomaterials.2020.119941] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/26/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023]
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Pei XD, He SQ, Shen LQ, Wei JC, Li XS, Wei YY, Zhang YM, Wang XY, Lin F, He ZL, Jiang LH. 14,15β-dihydroxyklaineanone inhibits HepG2 cell proliferation and migration through p38MAPK pathway. J Pharm Pharmacol 2020; 72:1165-1175. [PMID: 32419149 DOI: 10.1111/jphp.13289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 04/21/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Eurycoma longifolia Jack (Simaroubaceae) is commonly distributed in the Southeast Asia and Indo China, which has been shown to possess antianxiety, antibacterial, anticancer, antifungal, anti-inflammatory, antimalarial and antioxidant biological activities. 14,15β-dihydroxyklaineanone is a diterpene isolated from E. longifolia Jack, which is cytotoxic against human lung cancer and human breast cancer cell lines. However, the effects and underlying mechanisms of 14,15β-dihydroxyklaineanone on hepatocellular carcinoma remain unknown. METHODS Cell viability assay and colony formation assay were used to measure HepG2 cell proliferation. Flow cytometry was used to analyse cell cycle and apoptosis. Wound-healing assay and transwell assay were used to observe cells migration. RNA sequencing and the enrichment of differentially expressed genes (DEGs) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to find and determine underlying pathways. KEY FINDINGS We found that 14,15β-dihydroxyklaineanone inhibited the growth and migration of HepG2 cells but did not induce cell apoptosis. 14,15β-dihydroxyklaineanone induced S cell cycle arrest by downregulating the expression levels of cyclin A, p-CDK2, cyclin B1, p21, E2F-1 and PCNA. In addition, RNA sequencing showed that 14,15β-dihydroxyklaineanone regulated MAPK pathway by increasing the expression levels of phosphor-p38. Downregulating of p38 via both p38 inhibitor (SB203580) and p38-siRNA could antagonize the inhibition of cell proliferation and migration and reverse the changes in p-p38, E-cadherin, N-cadherin and PCNA expression induced by 14,15β-dihydroxyklaineanone treatment. CONCLUSIONS 14,15β-dihydroxyklaineanone inhibited cell proliferation and migration through regulating p38 MAPK pathway in HCC cells.
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Affiliation(s)
- Xiao-Dong Pei
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, China
| | - Song-Qing He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li-Qun Shen
- Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi University for Nationalities, Nanning, China
| | - Jing-Chen Wei
- Department of Pharmacology, Guilin Medical University, Guilin, China
| | - Xue-Sheng Li
- Institute of Pesticide and Environmental Toxicology, College of Agriculture, Guangxi University, Nanning, China
| | - Yan-Yan Wei
- Cultivation Base of Guangxi Key Laboratory for Agro-Environment and Agro-Products Safety, National Demonstration Center for Experimental Plant Science Education, College of Agriculture, Guangxi University, Nanning, China
| | - Yu-Meng Zhang
- Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
| | - Xin-Yu Wang
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Feng Lin
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Zhi-Long He
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Li-He Jiang
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, China
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50
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Moore R, Alexandre P. Delta-Notch Signaling: The Long and The Short of a Neuron's Influence on Progenitor Fates. J Dev Biol 2020; 8:jdb8020008. [PMID: 32225077 PMCID: PMC7345741 DOI: 10.3390/jdb8020008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/20/2020] [Accepted: 03/24/2020] [Indexed: 01/16/2023] Open
Abstract
Maintenance of the neural progenitor pool during embryonic development is essential to promote growth of the central nervous system (CNS). The CNS is initially formed by tightly compacted proliferative neuroepithelial cells that later acquire radial glial characteristics and continue to divide at the ventricular (apical) and pial (basal) surface of the neuroepithelium to generate neurons. While neural progenitors such as neuroepithelial cells and apical radial glia form strong connections with their neighbours at the apical and basal surfaces of the neuroepithelium, neurons usually form the mantle layer at the basal surface. This review will discuss the existing evidence that supports a role for neurons, from early stages of differentiation, in promoting progenitor cell fates in the vertebrates CNS, maintaining tissue homeostasis and regulating spatiotemporal patterning of neuronal differentiation through Delta-Notch signalling.
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Affiliation(s)
- Rachel Moore
- Centre for Developmental Neurobiology, King’s College London, London SE1 1UL, UK
- Correspondence: (R.M.); (P.A.)
| | - Paula Alexandre
- Developmental Biology and Cancer, University College London Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
- Correspondence: (R.M.); (P.A.)
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