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Kong J, Liu AA, Xu X, Tang B, Chen YY, Zhao W, Jia J, Yang LL, Li G, Pang DW. Making Cells as a "Nirvana Phoenix": Precise Coupling of Precursors Prior to ROS Bursts for Intracellular Synthesis of Quantum Dots. J Am Chem Soc 2025; 147:15645-15653. [PMID: 40259718 DOI: 10.1021/jacs.5c02861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Rationally coupling natural biochemical reactions for live-cell synthesis of inorganic nanocrystals with fluorescence, such as quantum dots (QDs) especially near-infrared (NIR), holds significant potential for in situ labeling and bioimaging. However, the introduced exogenous reactants and intracellularly produced species, e.g., reactive oxygen species (ROS), often cause cell damage, decreasing the fluorescence of the QDs. Herein, we have found that cell-adaptable selenocystine ((Cys-Se)2) can be reduced to biocompatible low-valence Se precursors, which could be subsequently hijacked by timely added Ag-glutathione (AgSG) to be transformed into NIR Ag2Se QDs. Such a comprehensive control strategy can inhibit the production of cytotoxic Se species and ROS bursts, significantly increasing the cell viability from 4 to 80% and enhancing the fluorescence of intracellularly synthesized Ag2Se QDs by over 8.7 times. Notably, the proliferative and in vivo tumorigenic capacities of the cells with strong NIR fluorescence-emitting functions could be maintained, enabling long-term tracking of cell division and disease progression. This work has provided new insights into fully excavating the potential of cells for the synthesis of inorganic nanocrystals by designing biocompatible precursors and also opened a new window for conventional synthetic biology from organic to inorganic.
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Affiliation(s)
- Juan Kong
- College of Chemistry and Molecular Sciences, The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - An-An Liu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Xia Xu
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Bo Tang
- College of Chemistry and Molecular Sciences, The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Yan-Yan Chen
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Wei Zhao
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Jianhong Jia
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Ling-Ling Yang
- College of Chemistry and Molecular Sciences, The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Gongyu Li
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
| | - Dai-Wen Pang
- College of Chemistry and Molecular Sciences, The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Frontiers Science Center for Cell Responses, Haihe Laboratory of Sustainable Chemical Transformations, and Engineering Research Center of Thin Film Optoelectronics Technology (Ministry of Education), Nankai University, Tianjin 300071, P. R. China
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Chen L, Kadoya K, Endo T, Iwasaki N, Terkawi MA. Efferocytosis at the frontline of homeostasis: Shaping the bone microenvironment and therapeutic implications in related diseases. Cytokine Growth Factor Rev 2025:S1359-6101(25)00048-6. [PMID: 40368727 DOI: 10.1016/j.cytogfr.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Accepted: 05/02/2025] [Indexed: 05/16/2025]
Abstract
Bone is a dynamic tissue that constantly undergoes remodeling processes throughout life to maintain its structure and integrity. During this process, physiological bone turnover, which is shaped by apoptosis, occurs in cells in the bone microenvironment. The clearance of these apoptotic cells (ACs) is executed by phagocytes through a process called efferocytosis, which simply means taking to the grave "burial." Efferocytosis is a multistage process involving the recognition, binding, internalization, and digestion of ACs, culminating in the resolution of inflammation. Critically, aberrations in efferocytosis lead to the accumulation of apoptotic corpses, impairing tissue homeostasis and contributing to various pathologies as well as bone-related diseases. Emerging evidence suggests that modulating/activating efferocytosis at any stage represents a promising therapeutic strategy for managing bone-related diseases, especially those associated with aging and inflammation. This review discusses the current understanding of the cellular and molecular mechanisms of efferocytosis, its roles within the bone microenvironment, and potential therapeutic interventions targeting efferocytosis in age-related bone diseases.
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Affiliation(s)
- Liyile Chen
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
| | - Ken Kadoya
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
| | - Tsutomu Endo
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
| | - M Alaa Terkawi
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan.
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3
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Barneda-Zahonero B, Almenara-Fuentes L, Perna-Barrull D, Vives-Pi M. Toward a cure for type 1 diabetes: the innovative potential of Phosphatidylserine-rich liposomes. Nanomedicine (Lond) 2025; 20:1077-1079. [PMID: 40018767 PMCID: PMC12068347 DOI: 10.1080/17435889.2025.2473872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 02/26/2025] [Indexed: 03/01/2025] Open
Affiliation(s)
| | | | - David Perna-Barrull
- Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | - Marta Vives-Pi
- Ahead Therapeutics SL, Barcelona, Spain
- Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
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4
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Huse M. Mechanoregulation of lymphocyte cytotoxicity. Nat Rev Immunol 2025:10.1038/s41577-025-01173-2. [PMID: 40312550 DOI: 10.1038/s41577-025-01173-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 05/03/2025]
Abstract
Cytotoxic lymphocytes counter intracellular pathogens and cancer by recognizing and destroying infected or transformed target cells. The basis for their function is the cytolytic immune synapse, a structurally stereotyped cell-cell interface through which lymphocytes deliver toxic proteins to target cells. The immune synapse is a highly dynamic contact capable of exerting nanonewton-scale forces against the target cell. In recent years, it has become clear that the interplay between these forces and the biophysical properties of the target influences the entirety of the cytotoxic response, from the initial activation of cytotoxic lymphocytes to the release of dying target cells. As a result, cellular cytotoxicity has become an exemplar of the ways in which biomechanics can regulate immune cell activation and effector function. This Review covers recent progress in this area, which has prompted a reconsideration of target cell killing from a more mechanobiological perspective.
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Affiliation(s)
- Morgan Huse
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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5
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Zhu DYD, Castrillon C, Carroll MC. Innate Immune Receptors as Dynamic Modulators of Extrafollicular Autoimmune B Cell Response. Immunol Rev 2025; 330:e70005. [PMID: 39917856 DOI: 10.1111/imr.70005] [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: 12/07/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 05/08/2025]
Abstract
The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.
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Affiliation(s)
- Danni Yi-Dan Zhu
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Graduate Program in Virology, Boston, Massachusetts, USA
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Carlos Castrillon
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Michael C Carroll
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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Jiang C, Miao T, Xing X, Schilling KJ, Lenhard N, Wang L, McDowell S, Nilsson BL, Wang H, Zhang X. Masquelet Inspired in Vivo Engineered Extracellular Matrix as Functional Periosteum for Bone Defect Repair and Reconstruction. Adv Healthc Mater 2025; 14:e2404975. [PMID: 39840608 PMCID: PMC11913577 DOI: 10.1002/adhm.202404975] [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: 12/10/2024] [Revised: 01/09/2025] [Indexed: 01/23/2025]
Abstract
The Masquelet technique that combines a foreign body reaction (FBR)-induced vascularized tissue membrane with staged bone grafting for reconstruction of segmental bone defect has gained wide attention in Orthopedic surgery. The success of Masquelet hinges on its ability to promote formation of a "periosteum-like" FBR-induced membrane at the bone defect site. Inspired by Masquelet's technique, here a novel approach is devised to create periosteum mimetics from decellularized extracellular matrix (dECM), engineered in vivo through FBR, for reconstruction of segmental bone defects. The approach involved 3D printing of polylactic acid (PLA) template with desired pattern/architecture, followed by subcutaneous implantation of the template to form tissue, and depolymerization and decellularization to generate dECM with interconnected channels. The dECM matrices produces from the same mice (autologous) or from different mice (allogenic) are used as a functional periosteum for repair of structural bone allograft in a murine segmental bone defect model. This study shows that autologous dECM performed better than allogenic dECM, further permitting local delivery of low dose BMP-2 to enhance allograft incorporation. The success of this current approach can establish a new line of versatile, patient-specific, and periosteum-like autologous dECM for bone regeneration, offering personalized therapeutics to patients with impaired healing.
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Affiliation(s)
- Chen Jiang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Tianfeng Miao
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Xiaojie Xing
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Kevin J Schilling
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Nicholas Lenhard
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Lichen Wang
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, 07030, USA
| | - Susan McDowell
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Bradley L Nilsson
- Department of Chemistry, University of Rochester, Rochester, NY, 14627, USA
| | - Hongjun Wang
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, 07030, USA
| | - Xinping Zhang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA
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Morsy MM, Hassan HA, Morsi RM, Nafea OE, Farag AI, Ramadan RS. Alogliptin attenuates testicular damage induced by monosodium glutamate in both juvenile and adult male rats by activating autophagy: ROS dependent AMPK/mTOR. Reprod Toxicol 2025; 132:108826. [PMID: 39725177 DOI: 10.1016/j.reprotox.2024.108826] [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: 08/05/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024]
Abstract
Monosodium glutamate (MSG) is one of the most commonly used food additives, known for its adverse health effects. Alogliptin (ALO) is a highly selective dipeptidyl peptidase-4 inhibitor, but its role in male reproductive function remains debated. The study was designed to evaluate and compare the potential of ALO in mitigating MSG-induced testicular toxicity in juvenile and adult male rats. Juvenile and adult male rats were treated with either MSG or pretreated with ALO before MSG administration. The rats then received ALO and MSG concurrently for 28 days. Testicular tissues were isolated and subjected to histo-biochemical and molecular assessments. Our results demonstrated that ALO reversed MSG-induced testicular injury, as evidenced by the restoration of reproductive hormone balance (increased serum luteinizing hormone and testosterone concentrations), suppression of oxidative stress injury (decreased testicular malondialdehyde, increased superoxide dismutase activity, and minimal 8-hydroxy-2'-deoxyguanosine immunoreactivity), inflammation (reduced testicular tumor necrosis factor-alpha levels), and fibrosis (decreased testicular collagen fiber deposition). Additionally, ALO impeded apoptosis and activated autophagy by decreasing caspase-3 activity, stimulating the AMPK/mTOR pathway, downregulating Bax and SQSTM-1/p62 expression, upregulating Bcl2 and Beclin 1, promoting testicular proliferation (increased number of proliferating cell nuclear antigen-positive cells in the testis), restoring glycogen content in the testis (mild to moderate periodic acid-Schiff reaction), and preserving testicular architecture. MSG induced more severe adverse testicular effects in juvenile rats, while ALO pretreatment was more protective in adult rats. ALO's anti-inflammatory, antioxidant, antiapoptotic, pro-autophagic, antifibrotic, and proliferative actions in the testis suggest its promising potential for combating male reproductive dysfunction.
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Affiliation(s)
- Manal Mohammad Morsy
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Heba A Hassan
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Pharmacology Department, Faculty of Medicine, Mutah University, Mutah 61710, Jordan
| | - Reham M Morsi
- Biological Application Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Ola Elsayed Nafea
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
| | - Azza I Farag
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Department of Physical Therapy, College of Applied Medical Sciences, Qassim University, P.O. Box 6666, Buraydah 51452, Saudi Arabia
| | - Rania Saad Ramadan
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, College of Medicine, Al-Baha University, Al-Baha 65525, Saudi Arabia
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8
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Rong B, Jiang H, Zhu W, Yang G, Zhou X, Lyu Z, Li X, Zhang J. Unraveling the role of macrophages in diabetes: Impaired phagocytic function and therapeutic prospects. Medicine (Baltimore) 2025; 104:e41613. [PMID: 39993124 PMCID: PMC11856964 DOI: 10.1097/md.0000000000041613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/28/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025] Open
Abstract
The rising aging population and changing lifestyles have led to a global increase in diabetes and its complications, making it one of the most prevalent diseases worldwide. Chronic inflammation is a key pathogenic feature of diabetes and its complications, yet the precise mechanisms remain unclear, impeding the development of targeted therapies. Recent studies have highlighted the β cell-macrophage crosstalk pathway as a crucial factor in chronic low-grade inflammation and glucose homeostasis imbalance in both type 1 and type 2 diabetes. Furthermore, impaired macrophage phagocytic functions, including pathogen phagocytosis, efferocytosis, and autophagy, play a significant role in diabetes complications. Given their high plasticity, macrophages represent a promising research target. This review summarizes recent findings on macrophage phagocytic dysfunction in diabetes and its complications, and explores emerging therapies targeting macrophage phagocytic function. We also discuss the current challenges in translating basic research to clinical practice, aiming to guide researchers in developing targeted treatments to regulate macrophage status and phagocytic function, thus preventing and treating metabolic inflammatory diseases.
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Affiliation(s)
- Bing Rong
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hailun Jiang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Weiming Zhu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH
| | - Xuancheng Zhou
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Zhongxi Lyu
- School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiangyi Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jieying Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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9
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Wu H, Sun X, Li K, Li J, Jiang H, Yan D, Lin Y, Ding Y, Lu Y, Zhu X, Chen X, Li X, Liang G, Xu H. Pyruvate Kinase M2-Responsive Release of Paclitaxel and Indoleamine 2,3-Dioxygenase Inhibitor for Immuno-Chemotherapy of Nonsmall Cell Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409790. [PMID: 39716923 PMCID: PMC11831488 DOI: 10.1002/advs.202409790] [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: 08/16/2024] [Revised: 12/05/2024] [Indexed: 12/25/2024]
Abstract
Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap-Phe-Phe-Phe-Lys-Ser-Thr(H2PO3)-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-Tp), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.
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Affiliation(s)
- Haisi Wu
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
- The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu SchoolNanjing Medical UniversitySuzhou215002China
| | - Xianbao Sun
- State Key Laboratory of Digital Medical EngineeringSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing211189China
| | - Kaiming Li
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Jinyu Li
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Hui Jiang
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Dan Yan
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Ya Lin
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Yan Ding
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Yawen Lu
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
| | - Xiaole Zhu
- Department of EmergencyThe First Affiliated Hospital of Nanjing Medical UniversityNanjing210029China
| | - Xufeng Chen
- Department of EmergencyThe First Affiliated Hospital of Nanjing Medical UniversityNanjing210029China
| | - Xiaolin Li
- Department of Geriatric GastroenterologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjing210029China
| | - Gaolin Liang
- State Key Laboratory of Digital Medical EngineeringSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing211189China
| | - Huae Xu
- Department of PharmaceuticsSchool of PharmacyNanjing Medical UniversityNanjing211166China
- The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu SchoolNanjing Medical UniversitySuzhou215002China
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Wang Z, Li X, Moura AK, Hu JZ, Wang YT, Zhang Y. Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target. Cells 2025; 14:183. [PMID: 39936975 PMCID: PMC11816498 DOI: 10.3390/cells14030183] [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: 12/16/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 02/13/2025] Open
Abstract
Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy-lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.
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Affiliation(s)
- Zhengchao Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
- Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China
| | - Xiang Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
| | - Alexandra K. Moura
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
| | - Jenny Z. Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
| | - Yun-Ting Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
| | - Yang Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA; (Z.W.); (A.K.M.); (J.Z.H.); (Y.-T.W.)
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11
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Morawski M, Krasnodębski M, Rochoń J, Kubiszewski H, Marzęcki M, Topyła D, Murat K, Staszewski M, Szczytko J, Maleszewski M, Grąt M. Decellularized Liver Matrices for Expanding the Donor Pool-An Evaluation of Existing Protocols and Future Trends. Biomolecules 2025; 15:98. [PMID: 39858491 PMCID: PMC11762870 DOI: 10.3390/biom15010098] [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: 12/15/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Liver transplantation is the only curative option for end-stage liver disease and is necessary for an increasing number of patients with advanced primary or secondary liver cancer. Many patient groups can benefit from this treatment, however the shortage of liver grafts remains an unsolved problem. Liver bioengineering offers a promising method for expanding the donor pool through the production of acellular scaffolds that can be seeded with recipient cells. Decellularization protocols involve the removal of cells using various chemical, physical, and enzymatic steps to create a collagenous network that provides support for introduced cells and future vascular and biliary beds. However, the removal of the cells causes varying degrees of matrix damage, that can affect cell seeding and future organ performance. The main objective of this review is to present the existing techniques of producing decellularized livers, with an emphasis on the assessment and definition of acellularity. Decellularization agents are discussed, and the standard process of acellular matrix production is evaluated. We also introduce the concept of the stepwise assessment of the matrix during decellularization through decellularization cycles. This method may lead to shorter detergent exposure times and less scaffold damage. The introduction of apoptosis induction in the field of organ engineering may provide a valuable alternative to existing long perfusion protocols, which lead to significant matrix damage. A thorough understanding of the decellularization process and the action of the various factors influencing the final composition of the scaffold is essential to produce a biocompatible matrix, which can be the basis for further studies regarding recellularization and retransplantation.
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Affiliation(s)
- Marcin Morawski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Maciej Krasnodębski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Jakub Rochoń
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Hubert Kubiszewski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Michał Marzęcki
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Dominik Topyła
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Kacper Murat
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Mikołaj Staszewski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Jacek Szczytko
- Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland;
| | - Marek Maleszewski
- Department of Embryology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland;
| | - Michał Grąt
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
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12
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Han L, Wu T, Zhang Q, Qi A, Zhou X. Immune Tolerance Regulation Is Critical to Immune Homeostasis. J Immunol Res 2025; 2025:5006201. [PMID: 39950084 PMCID: PMC11824399 DOI: 10.1155/jimr/5006201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/07/2024] [Indexed: 02/16/2025] Open
Abstract
The body's immune response plays a critical role in defending against external or foreign antigens while also preserving tolerance to self-antigens. This equilibrium, referred to as immune homeostasis, is paramount for overall health. The regulatory mechanisms governing the maintenance of this delicate immune balance are notably complex. It is currently accepted that immune tolerance is a dynamic outcome regulated by multiple factors, including central and peripheral mechanisms. Its induction or elimination plays a significant role in autoimmune diseases, organ transplantation, and cancer therapy, markedly impacting various major diseases in modern clinical practice. Overall, our current understanding of immune tolerance is still very limited. In this review article, we summarized the main mechanisms that have been known to mediate immune tolerance so far, including endogenous immune tolerance, adaptive immune tolerance, other immune tolerance mechanisms, and the homeostasis of immune tolerance, identified the key factors that regulate immune tolerance, and provided new clues for immune system recovery in many autoimmune diseases, organ transplantation, and tumor therapy.
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Affiliation(s)
- Lei Han
- Department of Pharmacy, Jiangsu Health Vocational College, Nanjing 211800, Jiangsu, China
| | - Tianxiang Wu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Qin Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Anning Qi
- Medical Laboratory, Liuhe People's Hospital of Jiangsu Province, Nanjing, Jiangsu 211500, China
| | - Xiaohui Zhou
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
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13
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Manon J, Evrard R, Maistriaux L, Fieve L, Xhema D, Heller U, Broeck LVD, Vettese J, Boisson J, Schubert T, Lengele B, Behets C, Cornu O. HLA Awareness in tissue decellularization: A paradigm shift for enhanced biocompatibility, studied on the model of the human fascia lata graft. Biomaterials 2025; 312:122741. [PMID: 39121727 DOI: 10.1016/j.biomaterials.2024.122741] [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: 01/18/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024]
Abstract
Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.
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Affiliation(s)
- Julie Manon
- UCLouvain - IREC, Neuromusculoskeletal Lab (NMSK), Avenue Emmanuel Mounier 53 - B1.53.07, 1200 Brussels, Belgium; Cliniques Universitaires Saint-Luc, Centre de Thérapie Cellulaire et Tissulaire Locomoteur, Brussels, Belgium; Cliniques universitaires Saint-Luc, Department of Orthopaedic and Trauma Surgery, Brussels 1200, Belgium.
| | - Robin Evrard
- UCLouvain - IREC, Neuromusculoskeletal Lab (NMSK), Avenue Emmanuel Mounier 53 - B1.53.07, 1200 Brussels, Belgium; Cliniques Universitaires Saint-Luc, Centre de Thérapie Cellulaire et Tissulaire Locomoteur, Brussels, Belgium; Cliniques universitaires Saint-Luc, Department of Orthopaedic and Trauma Surgery, Brussels 1200, Belgium
| | - Louis Maistriaux
- UCLouvain - IREC, Morphology Lab (MORF), Avenue Emmanuel Mounier 52 - B1.52.04, 1200 Brussels, Belgium
| | - Lies Fieve
- UCLouvain - IREC, Morphology Lab (MORF), Avenue Emmanuel Mounier 52 - B1.52.04, 1200 Brussels, Belgium
| | - Daela Xhema
- UCLouvain - IREC, Transplantation and Experimental Surgery Lab (CHEX), Avenue Hippocrate 55 - B1.55.04, 1200 Brussels, Belgium
| | - Ugo Heller
- APHP, Necker Enfants Malades, Unit of Maxillofacial Surgery and Plastic Surgery, Paris, France; IMSIA, ENSTA Paris-Tech, Department of Mechanical Engineering, Palaiseau, Paris, France
| | - Lucien Van Den Broeck
- UCLouvain - IREC, Morphology Lab (MORF), Avenue Emmanuel Mounier 52 - B1.52.04, 1200 Brussels, Belgium
| | - Julia Vettese
- UCLouvain - IREC, Neuromusculoskeletal Lab (NMSK), Avenue Emmanuel Mounier 53 - B1.53.07, 1200 Brussels, Belgium
| | - Jean Boisson
- IMSIA, ENSTA Paris-Tech, Department of Mechanical Engineering, Palaiseau, Paris, France
| | - Thomas Schubert
- UCLouvain - IREC, Neuromusculoskeletal Lab (NMSK), Avenue Emmanuel Mounier 53 - B1.53.07, 1200 Brussels, Belgium; Cliniques Universitaires Saint-Luc, Centre de Thérapie Cellulaire et Tissulaire Locomoteur, Brussels, Belgium; Cliniques universitaires Saint-Luc, Department of Orthopaedic and Trauma Surgery, Brussels 1200, Belgium
| | - Benoît Lengele
- UCLouvain - IREC, Morphology Lab (MORF), Avenue Emmanuel Mounier 52 - B1.52.04, 1200 Brussels, Belgium; Cliniques universitaires Saint-Luc, Department of Plastic and Reconstructive Surgery, Brussels 1200, Belgium
| | - Catherine Behets
- UCLouvain - IREC, Morphology Lab (MORF), Avenue Emmanuel Mounier 52 - B1.52.04, 1200 Brussels, Belgium
| | - Olivier Cornu
- UCLouvain - IREC, Neuromusculoskeletal Lab (NMSK), Avenue Emmanuel Mounier 53 - B1.53.07, 1200 Brussels, Belgium; Cliniques Universitaires Saint-Luc, Centre de Thérapie Cellulaire et Tissulaire Locomoteur, Brussels, Belgium; Cliniques universitaires Saint-Luc, Department of Orthopaedic and Trauma Surgery, Brussels 1200, Belgium
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14
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Li F, Bai Y, Guan Z, Ji X, Zhan X, Gao Y, Zhong W, Rao Z. Dexmedetomidine attenuates sepsis-associated acute lung injury by regulating macrophage efferocytosis through the ROS/ADAM10/AXL pathway. Int Immunopharmacol 2024; 142:112832. [PMID: 39362816 DOI: 10.1016/j.intimp.2024.112832] [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: 01/21/2024] [Revised: 03/20/2024] [Accepted: 07/26/2024] [Indexed: 10/05/2024]
Abstract
BACKGROUND The lungs are highly susceptible to damage during sepsis, with severe lung injury potentially progressing to acute respiratory distress syndrome and even fatal sepsis. Effective efferocytosis of apoptotic cells is crucial in alleviating inflammation and tissue injury. METHODS We established a septic lung injury mouse model via intraperitoneal injection of lipopolysaccharide. Lung injury was assessed by histology, immunofluorescence, neutrophil immunohistochemistry staining, and cytokine detection. We extracted alveolar macrophages by bronchoalveolar lavage and primary macrophages from mouse bone marrow to investigate the regulatory effects of Dexmedetomidine (DEX) on efferocytosis. We further validated the molecular mechanisms underlying the regulation of macrophage efferocytosis by DEX through knockdown of AXL expression. Additionally, we examined the efferocytic ability of monocytes isolated from patients. RESULTS We discovered that DEX treatment effectively alleviated pulmonary injury and inflammation. Lipopolysaccharide reduced macrophage efferocytosis and AXL expression which were reversed by DEX. We also found DEX inhibited the increased activation of A Disintegrin And Metalloproteinase 10 (ADAM10) and the production of soluble AXL. Moreover, our findings demonstrated that DEX decreased the elevated ROS production linked to higher ADAM10 activation. Blocking AXL negated DEX's benefits on efferocytosis and lung protection. Efferocytosis in monocytes from septic lung injury patients was notably lower than in healthy individuals. CONCLUSION Our findings demonstrated that DEX treatment effectively reduces septic lung injury by promoting macrophage efferocytosis through ROS/ADAM10/AXL signaling pathwway.
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Affiliation(s)
- Fei Li
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China; Department of Anesthesiology, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China
| | - Yan Bai
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China
| | - Zhu Guan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China
| | - Xingyue Ji
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China
| | - Xinyu Zhan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029 Nanjing, China
| | - Yiyun Gao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029 Nanjing, China
| | - Weizhe Zhong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 210029 Nanjing, China.
| | - Zhuqing Rao
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China.
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15
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Guillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Fregel Lorenzo RI, Dyall SD, Isenberg D, D'Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, Miller WT, Casanova JL, Geissmann F. ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis. eLife 2024; 13:RP96085. [PMID: 39570652 PMCID: PMC11581429 DOI: 10.7554/elife.96085] [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] [Indexed: 11/22/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
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Affiliation(s)
- Stephanie Guillet
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Ecole doctorale Bio Sorbonne Paris Cité, Université Paris Descartes-Sorbonne Paris CitéParisFrance
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
| | - Natasha Jordan
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
| | - Maria Tello
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Barbara Craddock
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Chihiro Nishi
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka UniversityOsakaJapan
| | - Rohan Bareja
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical CollegeNew YorkUnited States
| | - Hairu Yang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | | | | | - Sabrina D Dyall
- Department of Biosciences and Ocean Studies, Faculty of Science, University of MauritiusReduitMauritius
| | - David Isenberg
- Bioinformatics Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - David D'Cruz
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
| | - Nico Lachmann
- Centre for Rheumatology, Division of Medicine, University College London, The Rayne BuildingLondonUnited Kingdom
| | - Olivier Elemento
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical CollegeNew YorkUnited States
| | - Agnes Viale
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical SchoolHannoverGermany
| | - Nicholas D Socci
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical SchoolHannoverGermany
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
| | - Shigekazu Nagata
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka UniversityOsakaJapan
| | - Morgan Huse
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - W Todd Miller
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Department of Physiology and Biophysics, Stony Brook University School of MedicineStony BrookUnited States
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
- Howard Hughes Medical InstituteNew YorkUnited States
- Lab of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick ChildrenParisFrance
- Department of Pediatrics, Necker Hospital for Sick ChildrenParisFrance
| | - Frédéric Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
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16
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Choi SJ, Han J, Shin YH, Kim JK. Increased efficiency of peripheral nerve regeneration using supercritical carbon dioxide-based decellularization in acellular nerve graft. Sci Rep 2024; 14:23696. [PMID: 39389997 PMCID: PMC11467423 DOI: 10.1038/s41598-024-72672-w] [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: 04/12/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Acellular nerve grafts (ANGs) are a promising therapeutic for patients with nerve defects caused by injuries. Conventional decellularization methods utilize a variety of detergents and enzymes. However, these methods have disadvantages, such as long processing times and the presence of detergents that remain on the graft. In this study, we aimed to reduce process time and minimize the risks associated with residual detergents by replacing them with supercritical carbon dioxide (scCO2) and compared the effectiveness to Hudson's decellularization method, which uses several detergents. The dsDNA and the expression of MHC1 and 2 were significantly reduced in both decellularized groups, which confirmed the effective removal of cellular debris. The extracellular matrix proteins and various factors were found to be better preserved in the scCO2 ANGs compared to the detergent-ANGs. We conducted behavioral tests and histological analyses to assess the impact of scCO2 ANGs on peripheral nerve regeneration in animal models. Compared with Hudson's method, the scCO2 method effectively improved the efficacy of peripheral nerve regeneration. Therefore, the decellularization method using scCO2 is not only beneficial for ANG synthesis, but it may also be helpful for therapeutics by enhancing the efficacy of peripheral nerve regeneration.
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Affiliation(s)
| | | | - Young Ho Shin
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jae Kwang Kim
- Asan Institute for Life Sciences, Seoul, Korea.
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-gil, Songpa-gu, Seoul, 05505, South Korea.
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17
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Rockenfeller P. Phospholipid Scramblase Activity of VDAC Dimers: New Implications for Cell Death, Autophagy and Ageing. Biomolecules 2024; 14:1218. [PMID: 39456151 PMCID: PMC11506367 DOI: 10.3390/biom14101218] [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: 08/27/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024] Open
Abstract
Voltage-dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their beta-barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. VDACs have further been implicated in the control of regulated cell death. Historically, VDACs have been pictured as part of the mitochondrial permeability transition pore (MPTP). New concepts of regulated cell death involving VDACs include its oligomerisation to form a large pore complex in the OMM; however, alternative VDAC localisation to the plasma membrane has been suggested in the literature and will be discussed regarding its potential role during cell death. Very recently, a phospholipid scramblase activity has been attributed to VDAC dimers, which explains the manifold lipidomic changes observed in VDAC-deficient yeast strains. In this review, I highlight the recent advances regarding VDAC's phospholipid scramblase function and discuss how this new insight sheds new light on VDAC's implication in regulated cell death, autophagy, and ageing.
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Affiliation(s)
- Patrick Rockenfeller
- Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
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18
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Bhattacharya T, Kumari M, Kaur K, Kaity S, Arumugam S, Ravichandiran V, Roy S. Decellularized extracellular matrix-based bioengineered 3D breast cancer scaffolds for personalized therapy and drug screening. J Mater Chem B 2024; 12:8843-8867. [PMID: 39162395 DOI: 10.1039/d4tb00680a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2024]
Abstract
Breast cancer (BC) is the second deadliest cancer after lung cancer. Similar to all cancers, it is also driven by a 3D microenvironment. The extracellular matrix (ECM) is an essential component of the 3D tumor micro-environment, wherein it functions as a scaffold for cells and provides metabolic support. BC is characterized by alterations in the ECM. Various studies have attempted to mimic BC-specific ECMs using artificial materials, such as Matrigel. Nevertheless, research has proven that naturally derived decellularized extracellular matrices (dECMs) are superior in providing the essential in vivo-like cues needed to mimic a cancer-like environment. Developing in vitro 3-D BC models is not straightforward and requires extensive analysis of the data established by researchers. For the benefit of researchers, in this review, we have tried to highlight all developmental studies that have been conducted by various scientists so far. The analysis of the conclusions drawn from these studies is also discussed. The advantages and drawbacks of the decellularization methods employed for generating BC scaffolds will be covered, and the review will shed light on how dECM scaffolds help develop a BC environment. The later stages of the article will also focus on immunogenicity issues arising from decellularization and the origin of the tissue. Finally, this review will also discuss the biofabrication of matrices, which is the core part of the bioengineering process.
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Affiliation(s)
- Teeshyo Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Mamta Kumari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Kulwinder Kaur
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine a Health Sciences, Dublin, Ireland
- Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Somasundaram Arumugam
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Velayutham Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
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19
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Hu Z, Qian S, Zhao Q, Lu B, Lu Q, Wang Y, Zhang L, Mao X, Wang D, Cui W, Sun X. Engineering strategies for apoptotic bodies. SMART MEDICINE 2024; 3:e20240005. [PMID: 39420952 PMCID: PMC11425054 DOI: 10.1002/smmd.20240005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/06/2024] [Indexed: 10/19/2024]
Abstract
Extracellular vesicles (EVs) are lipid bilayer vesicles containing proteins, lipids, nucleic acids, and metabolites secreted by cells under various physiological and pathological conditions that mediate intercellular communication. The main types of EVs include exosomes, microvesicles, and apoptotic bodies (ABs). ABs are vesicles released during the terminal stages of cellular apoptosis, enriched with diverse biological entities and characterized by distinct morphological features. As a result, ABs possess great potential in fields like disease diagnosis, immunotherapy, regenerative therapy, and drug delivery due to their specificity, targeting capacity, and biocompatibility. However, their therapeutic efficacy is notably heterogeneous, and an overdose can lead to side effects such as accumulation in the liver, spleen, lungs, and gastrointestinal system. Through bioengineering, the properties of ABs can be optimized to enhance drug-loading efficiency, targeting precision, and multifunctionality for clinical implementations. This review focuses on strategies such as transfection, sonication, electroporation, surface engineering, and integration with biomaterials to enable ABs to load cargoes and enhance targeting, providing insights into the engineering of ABs.
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Affiliation(s)
- Zheyuan Hu
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shutong Qian
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Department of Plastic SurgeryThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Qiuyu Zhao
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Bolun Lu
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qian Lu
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuhuan Wang
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Liucheng Zhang
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiyuan Mao
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Danru Wang
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenguo Cui
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiaoming Sun
- Department of Plastic and Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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20
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Li X, Li C, Kang Y, Zhang R, Li P, Zheng Q, Wang H, Xiao H, Yuan L. G protein coupled receptor in apoptosis and apoptotic cell clearance. FASEB Bioadv 2024; 6:289-297. [PMID: 39399480 PMCID: PMC11467729 DOI: 10.1096/fba.2024-00067] [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: 04/30/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 10/15/2024] Open
Abstract
Apoptosis is a genetically programmed form of cell death that is substantially conserved across the evolutionary tree. Apoptotic cell elimination includes recognition, phagocytosis, and degradation. Failure to clear apoptotic cells can ultimately cause a series of human diseases, such as systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and cancer. Consequently, the timely and effective removal of apoptotic cells is crucial to maintaining the body's homeostasis. GPCRs belong to the largest membrane receptor family. Its intracellular domain exerts an effect on the trimer G protein. By combining with a variety of ligands, the extracellular domain of G protein initiates the dissociation of G protein trimers and progressively transmits signals downstream. Presently, numerous G protein-coupled receptors (GPCRs) have been identified as participants in the apoptosis signal transduction pathway and the apoptotic cell clearance pathway. Therefore, studies on the mechanism of GPCRs in the clearance of apoptotic cells is important for the development of GPCRs therapeutics.
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Affiliation(s)
- Xinyan Li
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Chao Li
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Yang Kang
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Rui Zhang
- Emergency Department The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an China
| | - Peiyao Li
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Qian Zheng
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Hui Wang
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Hui Xiao
- College of Life Sciences, Shaanxi Normal University Xi'an China
| | - Lei Yuan
- College of Life Sciences, Shaanxi Normal University Xi'an China
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21
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Yin M, Liu Z, Zhou Y, Li W, Yan J, Cao D, Yin L. Two-pronged anti-cancer nanovaccines enpowered by exogenous/endogenous tumor-associated antigens. J Control Release 2024; 373:358-369. [PMID: 39009083 DOI: 10.1016/j.jconrel.2024.07.024] [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: 04/30/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/17/2024]
Abstract
Cancer vaccines based on single-source (exogenous or endogenous) tumor-associated antigens (TAAs) are often challenged by the insufficient T cell response and the immunosuppressive tumor microenvironment (TME). Herein, a dual TAAs-boosted nanovaccine based on cancer cell (4T1) membrane-cloaked, CO-immobilized Prussian blue nanoparticles (4T1-PB-CO NPs) is developed and coupled with anti-interleukin (IL)-10 therapy to maximize the efficacy of antitumor immunotherapy. 4T1 cell membrane not only endows NPs with tumor targeting ability, but also serves as exogenous TAAs to trigger CD4+ T cell response and M1-phenotype polarization of tumor-associated macrophages. Under near-infrared light irradiation, 4T1-PB-CO NPs release CO to induce immunogenic cell death (ICD) of tumor cells, thus generating endogenous TAAs to activate CD8+ T cell response. Meanwhile, ICD triggers release of damage-associated molecular patterns, which can promote DC maturation to amplify the antitumor T cell response. When combined with anti-IL-10 that reverses the immunosuppressive TME, 4T1-PB-CO NPs efficiently suppress the primary tumors and produce an abscopal effect to inhibit distant tumors in a breast tumor-bearing mouse model. Such a two-pronged cancer vaccine represents a promising paradigm for robust antitumor immunotherapy.
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Affiliation(s)
- Mengyuan Yin
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China
| | - Zhongmin Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China
| | - Yang Zhou
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China.
| | - Wei Li
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China
| | - Jing Yan
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China
| | - Desheng Cao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China
| | - Lichen Yin
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China.
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22
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Arizanovska D, Dallera CA, Folorunso OO, Bush GF, Frye JB, Doyle KP, Jagid JR, Wolosker H, Monaco BA, Cordeiro JG, Atkins CM, Griswold AJ, Liebl DJ. Cognitive dysfunction following brain trauma results from sex-specific reactivation of the developmental pruning processes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.13.607610. [PMID: 39211262 PMCID: PMC11360988 DOI: 10.1101/2024.08.13.607610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Cognitive losses resulting from severe brain trauma have long been associated with the focal region of tissue damage, leading to devastating functional impairment. For decades, researchers have focused on the sequelae of cellular alterations that exist within the perilesional tissues; however, few clinical trials have been successful. Here, we employed a mouse brain injury model that resulted in expansive synaptic damage to regions outside the focal injury. Our findings demonstrate that synaptic damage results from the prolonged increase in D-serine release from activated microglia and astrocytes, which leads to hyperactivation of perisynaptic NMDARs, tagging of damaged synapses by complement components, and the reactivation of developmental pruning processes. We show that this mechanistic pathway is reversible at several stages within a prolonged and progressive period of synaptic loss. Importantly, these key factors are present in acutely injured brain tissue acquired from patients with brain injury, which supports a therapeutic neuroprotective strategy.
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23
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Lee JR, Boothe T, Mauksch C, Thommen A, Rink JC. Epidermal turnover in the planarian Schmidtea mediterranea involves basal cell extrusion and intestinal digestion. Cell Rep 2024; 43:114305. [PMID: 38906148 DOI: 10.1016/j.celrep.2024.114305] [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: 11/06/2023] [Revised: 03/21/2024] [Accepted: 05/15/2024] [Indexed: 06/23/2024] Open
Abstract
Planarian flatworms undergo continuous internal turnover, wherein old cells are replaced by the division progeny of adult pluripotent stem cells (neoblasts). How cell turnover is carried out at the organismal level remains an intriguing question in planarians and other systems. While previous studies have predominantly focused on neoblast proliferation, little is known about the processes that mediate cell loss during tissue homeostasis. Here, we use the planarian epidermis as a model to study the mechanisms of cell removal. We established a covalent dye-labeling assay and image analysis pipeline to quantify the cell turnover rate in the planarian epidermis. Our findings indicate that the ventral epidermis is highly dynamic and epidermal cells undergo internalization via basal extrusion, followed by a relocation toward the intestine and ultimately digestion by intestinal phagocytes. Overall, our study reveals a complex homeostatic process of cell clearance that may generally allow planarians to catabolize their own cells.
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Affiliation(s)
- Jun-Ru Lee
- Department of Tissue Dynamics and Regeneration, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany; Graduate Center for Neurosciences, Biophysics, and Molecular Biosciences, University of Göttingen, 37077 Göttingen, Germany
| | - Tobias Boothe
- Department of Tissue Dynamics and Regeneration, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany
| | - Clemens Mauksch
- Department of Tissue Dynamics and Regeneration, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany
| | - Albert Thommen
- Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Jochen C Rink
- Department of Tissue Dynamics and Regeneration, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany; Faculty of Biology and Psychology, Georg-August-University, Göttingen, Germany.
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24
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He F, Yu J, Ma S, Zhao W, Zhang M, Wang J, Zhang C, Wu J, Zhu L. γδT Cells Induce the Inflammatory Response of Human Fibroblast-Like Synoviocytes Directly or by Stimulating B Cells to Activate IL-17/STAT3 Signaling Pathway. Int Arch Allergy Immunol 2024; 185:1154-1165. [PMID: 38991517 DOI: 10.1159/000539703] [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: 01/16/2024] [Accepted: 06/03/2024] [Indexed: 07/13/2024] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) combined with hashimoto thyroiditis (HT) is an important cause of various fatal comorbidities of RA. There is no precise conclusion about the cause of this disease. METHODS Peripheral blood and synovial tissue were collected from healthy participants, patients with RA, and patients with both RA and HT. Immunofluorescence staining and Pearson correlation analysis were used to detect the levels of γδTCR and the correlation between IL-17 and p-STAT3, respectively. ELISA, chemiluminescence assays, qRT-PCR and Western blot were performed to detect the levels of IgG, IgM, IFN-γ, IL-1β, TNF-α, Tg-Ab, Tpo-Ab, IL-17, IL-2, p-SATA3, and STAT3, respectively. RESULTS There was increased proportion of γδT cells, IL-17, and p-STAT3 levels in RA and HT patients. IL-17 was positively correlated with p-STAT3. γδT cells significantly promoted the expression of IgG, Tg-Ab, Tpo-Ab, and IL-17. When γδT and human fibroblast-like synoviocytes (FLSs) were co-cultured, the levels of IL-2, IFN-γ, IL-1β, TNF-α, and IL-17 were increased, and the IL-17/STAT3 signaling pathway was activated. When IL-17-silenced γδT cells and STAT3-silenced FLSs were co-cultured, the levels of IL-1β and TNF-α in FLSs were significantly decreased. Furthermore, when STAT3-silenced FLSs were added to the co-culture medium of B cells and γδT cells, the levels of IL-1β and TNF-α were also decreased significantly. CONCLUSION γδT cells induced RA directly or by stimulating B cells to activate STAT3 through IL-17.
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Affiliation(s)
- Fang He
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Juan Yu
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Sha Ma
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Weiqing Zhao
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Mingxing Zhang
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Juan Wang
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Chunpan Zhang
- Department of Pain, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jiangping Wu
- Department of Pain, The First People's Hospital of Yunnan Province, Kunming, China
| | - Lixuan Zhu
- Department of Pain, The First People's Hospital of Yunnan Province, Kunming, China
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25
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An Y, Wang Z, Wu FG. Fluorescent carbon dots for discriminating cell types: a review. Anal Bioanal Chem 2024; 416:3945-3962. [PMID: 38886239 DOI: 10.1007/s00216-024-05328-3] [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: 01/30/2024] [Revised: 04/26/2024] [Accepted: 05/06/2024] [Indexed: 06/20/2024]
Abstract
Carbon dots (CDs) are quasi-spherical carbon nanoparticles with excellent photoluminescence, good biocompatibility, favorable photostability, and easily modifiable surfaces. CDs, serving as fluorescent probes, have emerged as an ideal tool for cellular differentiation owing to their outstanding luminescence performance and tunable surface properties. In this review, we summarize the recent research progress with CDs in the differentiation of cancer/normal cells, Gram-positive/Gram-negative bacteria, and live/dead cells, as well as the cellular differences used for differentiation. Additionally, we summarize the preparation methods, raw materials, and properties of the CDs used for cell discrimination. The differentiation mechanisms and the advantages or limitations of the differentiation methods are also introduced. Finally, we propose several research challenges in this field and future research directions that require extensive investigation. It is hoped that this review will help researchers in the design of new CDs as ideal fluorescent probes for realizing diverse cell differentiation applications.
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Affiliation(s)
- Yaolong An
- State Key Laboratory of Digital Medical Engineering, Key Laboratory for Biomaterials and Devices of Jiangsu Province, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 211189, China
| | - Zihao Wang
- State Key Laboratory of Digital Medical Engineering, Key Laboratory for Biomaterials and Devices of Jiangsu Province, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 211189, China
| | - Fu-Gen Wu
- State Key Laboratory of Digital Medical Engineering, Key Laboratory for Biomaterials and Devices of Jiangsu Province, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 211189, China.
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26
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Han Y, Hu J, Pan J, Song X, Zhou Y, Zhang J, Yang Y, Shi X, Yang J, Sun M. LPS exposure alleviates multiple tissues damage by facilitating macrophage efferocytosis. Int Immunopharmacol 2024; 135:112283. [PMID: 38772299 DOI: 10.1016/j.intimp.2024.112283] [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: 04/02/2024] [Revised: 05/05/2024] [Accepted: 05/14/2024] [Indexed: 05/23/2024]
Abstract
Toll-like receptors (TLRs) play a crucial role in mediating immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), as well as facilitating apoptotic cell (ACs) clearance (efferocytosis), thus contributing significantly to maintaining homeostasis and promoting tissue resolution. In this study, we investigate the impact of TLR agonists on macrophage efferocytosis. Our findings demonstrate that pretreatment with the TLR agonist lipopolysaccharide (LPS) significantly enhances macrophage phagocytic ability, thereby promoting efferocytosis both in vitro and in vivo. Moreover, LPS pretreatment confers tissue protection against damage by augmenting macrophage efferocytic capacity in murine models. Further examination reveals that LPS modulates efferocytosis by upregulating the expression of Tim4.These results underscore the pivotal role of TLR agonists in regulating the efferocytosis process and suggest potential therapeutic avenues for addressing inflammatory diseases. Overall, our study highlights the intricate interplay between LPS pretreatment and efferocytosis in maintaining tissue homeostasis and resolving inflammation.
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Affiliation(s)
- Yuwen Han
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Jiukun Hu
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Jinlin Pan
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Xueyan Song
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Yuanshuai Zhou
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Jun Zhang
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China
| | - Yue Yang
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China; Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Xiaohua Shi
- Department of Gastroenterology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 1 Lijiang Road, Suzhou 215153, China
| | - Jiao Yang
- Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Lijiang Road No. 1, Suzhou 215153, China.
| | - Minxuan Sun
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No. 88, Suzhou 215163, China.
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27
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Guillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Lorenzo RIF, Dyall SD, Isenberg D, D’Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, Miller WT, Casanova JL, Geissmann F. ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.02.15.24302255. [PMID: 38883731 PMCID: PMC11177913 DOI: 10.1101/2024.02.15.24302255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
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Affiliation(s)
- Stephanie Guillet
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Ecole doctorale Bio Sorbonne Paris Cité, Université Paris Descartes-Sorbonne Paris Cité.Paris, France
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of MedicalSciences, New York, New York 10065, USA
| | - Natasha Jordan
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
| | - Maria Tello
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Barbara Craddock
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Chihiro Nishi
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871
| | - Rohan Bareja
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, New York 10065, USA
| | - Hairu Yang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | | | | | - Sabrina D. Dyall
- Department of Biosciences and Ocean Studies, Faculty of Science, University of Mauritius, Reduit, Mauritius
| | - David Isenberg
- Centre for Rheumatology, Division of Medicine, University College London, The Rayne Building, University College London
| | - David D’Cruz
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
| | - Nico Lachmann
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany
| | - Olivier Elemento
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, New York 10065, USA
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Nicholas D. Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
| | - Shigekazu Nagata
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871
| | - Morgan Huse
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - W. Todd Miller
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
- Howard Hughes Medical Institute, New York, 10065 NY, USA
- Lab of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France, EU
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France, EU
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of MedicalSciences, New York, New York 10065, USA
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
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28
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Yamada Y, Zheng Z, Jad AK, Yamashita M. Lethal and sublethal effects of programmed cell death pathways on hematopoietic stem cells. Exp Hematol 2024; 134:104214. [PMID: 38582294 DOI: 10.1016/j.exphem.2024.104214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Programmed cell death is an evolutionally conserved cellular process in multicellular organisms that eliminates unnecessary or rogue cells during development, infection, and carcinogenesis. Hematopoietic stem cells (HSCs) are a rare, self-renewing, and multipotent cell population necessary for the establishment and regeneration of the hematopoietic system. Counterintuitively, key components necessary for programmed cell death induction are abundantly expressed in long-lived HSCs, which often survive myeloablative stress by engaging a prosurvival response that counteracts cell death-inducing stimuli. Although HSCs are well known for their apoptosis resistance, recent studies have revealed their unique vulnerability to certain types of programmed necrosis, such as necroptosis and ferroptosis. Moreover, emerging evidence has shown that programmed cell death pathways can be sublethally activated to cause nonlethal consequences such as innate immune response, organelle dysfunction, and mutagenesis. In this review, we summarized recent findings on how divergent cell death programs are molecularly regulated in HSCs. We then discussed potential side effects caused by sublethal activation of programmed cell death pathways on the functionality of surviving HSCs.
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Affiliation(s)
- Yuta Yamada
- Division of Stem Cell and Molecular Medicine, Centre for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Zhiqian Zheng
- Division of Stem Cell and Molecular Medicine, Centre for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Alaa K Jad
- Division of Stem Cell and Molecular Medicine, Centre for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masayuki Yamashita
- Division of Stem Cell and Molecular Medicine, Centre for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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Le T, Ferling I, Qiu L, Nabaile C, Assunção L, Roskelley CD, Grinstein S, Freeman SA. Redistribution of the glycocalyx exposes phagocytic determinants on apoptotic cells. Dev Cell 2024; 59:853-868.e7. [PMID: 38359833 DOI: 10.1016/j.devcel.2024.01.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 11/08/2023] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Phagocytes remove dead and dying cells by engaging "eat-me" ligands such as phosphatidylserine (PtdSer) on the surface of apoptotic targets. However, PtdSer is obscured by the bulky exofacial glycocalyx, which also exposes ligands that activate "don't-eat-me" receptors such as Siglecs. Clearly, unshielding the juxtamembrane "eat-me" ligands is required for the successful engulfment of apoptotic cells, but the mechanisms underlying this process have not been described. Using human and murine cells, we find that apoptosis-induced retraction and weakening of the cytoskeleton that anchors transmembrane proteins cause an inhomogeneous redistribution of the glycocalyx: actin-depleted blebs emerge, lacking the glycocalyx, while the rest of the apoptotic cell body retains sufficient actin to tether the glycocalyx in place. Thus, apoptotic blebs can be engaged by phagocytes and are targeted for engulfment. Therefore, in cells with an elaborate glycocalyx, such as mucinous cancer cells, this "don't-come-close-to-me" barrier must be removed to enable clearance by phagocytosis.
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Affiliation(s)
- Trieu Le
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Iuliia Ferling
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Lanhui Qiu
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Clement Nabaile
- Department of Learning and Research in Biology, Ecole Normale Supérieure Paris-Saclay, Gif-sur-Yvette, France
| | - Leonardo Assunção
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Calvin D Roskelley
- Department of Cellular and Physiological Sciences, the Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Sergio Grinstein
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Spencer A Freeman
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
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30
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Mann V, Sundaresan A, Shishodia S. Overnutrition and Lipotoxicity: Impaired Efferocytosis and Chronic Inflammation as Precursors to Multifaceted Disease Pathogenesis. BIOLOGY 2024; 13:241. [PMID: 38666853 PMCID: PMC11048223 DOI: 10.3390/biology13040241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024]
Abstract
Overnutrition, driven by the consumption of high-fat, high-sugar diets, has reached epidemic proportions and poses a significant global health challenge. Prolonged overnutrition leads to the deposition of excessive lipids in adipose and non-adipose tissues, a condition known as lipotoxicity. The intricate interplay between overnutrition-induced lipotoxicity and the immune system plays a pivotal role in the pathogenesis of various diseases. This review aims to elucidate the consequences of impaired efferocytosis, caused by lipotoxicity-poisoned macrophages, leading to chronic inflammation and the subsequent development of severe infectious diseases, autoimmunity, and cancer, as well as chronic pulmonary and cardiovascular diseases. Chronic overnutrition promotes adipose tissue expansion which induces cellular stress and inflammatory responses, contributing to insulin resistance, dyslipidemia, and metabolic syndrome. Moreover, sustained exposure to lipotoxicity impairs the efferocytic capacity of macrophages, compromising their ability to efficiently engulf and remove dead cells. The unresolved chronic inflammation perpetuates a pro-inflammatory microenvironment, exacerbating tissue damage and promoting the development of various diseases. The interaction between overnutrition, lipotoxicity, and impaired efferocytosis highlights a critical pathway through which chronic inflammation emerges, facilitating the development of severe infectious diseases, autoimmunity, cancer, and chronic pulmonary and cardiovascular diseases. Understanding these intricate connections sheds light on potential therapeutic avenues to mitigate the detrimental effects of overnutrition and lipotoxicity on immune function and tissue homeostasis, thereby paving the way for novel interventions aimed at reducing the burden of these multifaceted diseases on global health.
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Affiliation(s)
| | | | - Shishir Shishodia
- Department of Biology, Texas Southern University, Houston, TX 77004, USA; (V.M.); (A.S.)
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31
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Pugazhendhi AS, Seal A, Hughes M, Kumar U, Kolanthai E, Wei F, Schwartzman JD, Coathup MJ. Extracellular Proteins Isolated from L. acidophilus as an Osteomicrobiological Therapeutic Agent to Reduce Pathogenic Biofilm Formation, Regulate Chronic Inflammation, and Augment Bone Formation In Vitro. Adv Healthc Mater 2024; 13:e2302835. [PMID: 38117082 DOI: 10.1002/adhm.202302835] [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: 08/25/2023] [Revised: 10/31/2023] [Indexed: 12/21/2023]
Abstract
Periprosthetic joint infection (PJI) is a challenging complication that can occur following joint replacement surgery. Efficacious strategies to prevent and treat PJI and its recurrence remain elusive. Commensal bacteria within the gut convey beneficial effects through a defense strategy named "colonization resistance" thereby preventing pathogenic infection along the intestinal surface. This blueprint may be applicable to PJI. The aim is to investigate Lactobacillus acidophilus spp. and their isolated extracellular-derived proteins (LaEPs) on PJI-relevant Staphylococcus aureus, methicillin-resistant S. aureus, and Escherichia coli planktonic growth and biofilm formation in vitro. The effect of LaEPs on cultured macrophages and osteogenic, and adipogenic human bone marrow-derived mesenchymal stem cell differentiation is analyzed. Data show electrostatically-induced probiotic-pathogen species co-aggregation and pathogenic growth inhibition together with LaEP-induced biofilm prevention. LaEPs prime macrophages for enhanced microbial phagocytosis via cathepsin K, reduce lipopolysaccharide-induced DNA damage and receptor activator nuclear factor-kappa B ligand expression, and promote a reparative M2 macrophage morphology under chronic inflammatory conditions. LaEPs also significantly augment bone deposition while abating adipogenesis thus holding promise as a potential multimodal therapeutic strategy. Proteomic analyses highlight high abundance of lysyl endopeptidase, and urocanate reductase. Further, in vivo analyses are warranted to elucidate their role in the prevention and treatment of PJIs.
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Affiliation(s)
| | - Anouska Seal
- Biionix Cluster, University of Central Florida, Orlando, FL, 32827, USA
| | | | - Udit Kumar
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), University of Central Florida, Orlando, FL, 32826, USA
| | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), University of Central Florida, Orlando, FL, 32826, USA
| | - Fei Wei
- Biionix Cluster, University of Central Florida, Orlando, FL, 32827, USA
| | | | - Melanie J Coathup
- Biionix Cluster, University of Central Florida, Orlando, FL, 32827, USA
- College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
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32
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Lo WCJ, Luther DG. Detection of Granzyme B-associated Binding Targets in Peripheral Blood Samples of Hosts in Sickness and in Health Using a Granzyme B-like Peptide Fluorescent Conjugate (GP1R). J Fluoresc 2024; 34:691-711. [PMID: 37347422 DOI: 10.1007/s10895-023-03320-1] [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: 03/07/2023] [Accepted: 06/16/2023] [Indexed: 06/23/2023]
Abstract
Granzyme B, mostly expressed by cytotoxic T lymphocytes in the fight against cancer and infection, is known to induce cell death based on its active enzymatic activity as a serine protease. Recent studies showed cytotoxicity of a non-enzymatic granzyme B-like peptide (also referred to as granzyme B-associated peptide or GP1 in this report) in tumor cells and presence of binding targets for GP1R (i.e., GP1 conjugated with rhodamine fluorochrome) in tumor cells, bacteria, and circulating platelets/neutrophils of healthy hosts. But there were no data on "sick" hosts to help substantiate any potential GP1 based medical applications. Thus, we adopted similar GP1R binding protocols to further study binding of GP1 in different biological samples (including different blood samples of hosts in sickness and in health, cancer cell lines, and trigeminal ganglia culture of infected hosts treated with and without GP1) and determine if any binding patterns might have any associations with different health conditions. The overall preliminary results appear to show certain GP1R + binding patterns in certain blood components (especially neutrophils) have potential correlations with certain health conditions of hosts at sampling times, indicating potential GP1R applications for diagnostic purposes. Findings of different GP1R binding patterns in different cancer cell lines, whole blood samples and trigeminal ganglia culture of experimental mice infected with HSV-1 virus (might cause neuropathy) within a week post-infection, and blood samples of GP1-treated mouse survivors on day 21 post-infection provided preliminary evidence of potential GP1-led tumor cell-specific cell death and treatment efficacy for greater survival.
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33
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Barreda D, Grinstein S, Freeman SA. Target lysis by cholesterol extraction is a rate limiting step in the resolution of phagolysosomes. Eur J Cell Biol 2024; 103:151382. [PMID: 38171214 DOI: 10.1016/j.ejcb.2023.151382] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/22/2023] [Accepted: 12/25/2023] [Indexed: 01/05/2024] Open
Abstract
The ongoing phagocytic activity of macrophages necessitates an extraordinary capacity to digest and resolve incoming material. While the initial steps leading to the formation of a terminal phagolysosome are well studied, much less is known about the later stages of this process, namely the degradation and resolution of the phagolysosomal contents. We report that the degradation of targets such as splenocytes and erythrocytes by phagolysosomes occurs in a stepwise fashion, requiring lysis of their plasmalemmal bilayer as an essential initial step. This is achieved by the direct extraction of cholesterol facilitated by Niemann-Pick protein type C2 (NPC2), which in turn hands off cholesterol to NPC1 for export from the phagolysosome. The removal of cholesterol ulimately destabilizes and permeabilizes the membrane of the phagocytic target, allowing access of hydrolases to its internal compartments. In contrast, we found that saposins, which activate the hydrolysis of sphingolipids, are required for lysosomal tubulation, yet are dispensable for the resolution of targets by macrophages. The extraction of cholesterol by NPC2 is therefore envisaged as rate-limiting in the clearance of membrane-bound targets such as apoptotic cells. Selective cholesterol removal appears to be a primary mechanism that enables professional phagocytes to distinguish the target membrane from the phagolysosomal membrane and may be conserved in the resolution of autolysosomes.
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Affiliation(s)
- Dante Barreda
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Sergio Grinstein
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Biochemistry and the University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Spencer A Freeman
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Biochemistry and the University of Toronto, Toronto, ON M5S 1A8, Canada.
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34
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Liu Y, Huang Q, He M, Chen T, Chu X. A nano-bioconjugate modified with anti-SIRPα antibodies and antisense oligonucleotides of mTOR for anti-atherosclerosis therapy. Acta Biomater 2024; 176:356-366. [PMID: 38160854 DOI: 10.1016/j.actbio.2023.12.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/02/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
Atherosclerosis is the main cause of a series of fatal cardiovascular diseases, characterized by pathological accumulation of apoptotic cells and lipids. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. The specific nano-bioconjugate utilized acid-responsive calcium phosphate (CaP) as a carrier to load mTOR ASOs, coated with lipid on the surface of CaP nanoparticles (ASOs@CaP), and subsequently modified with aSIRPα. The resulting nano-bioconjugates could accumulate within atherosclerotic plaques, target to macrophages and reactivate lesional phagocytosis through blocking the CD47-SIRPα signaling axis. In addition, efficient delivery of mTOR ASOs inhibited mTOR expression, which significantly restored impaired autophagy. The combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease. STATEMENT OF SIGNIFICANCE: Atherosclerosis is the main cause of a series of fatal cardiovascular diseases. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. Our study demonstrated that the combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Yi Liu
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
| | - Qian Huang
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
| | - Mengyun He
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
| | - Tingting Chen
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
| | - Xia Chu
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China.
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35
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Killarney ST, Tait SWG, Green DR, Wood KC. Sublethal engagement of apoptotic pathways in residual cancer. Trends Cell Biol 2024; 34:225-238. [PMID: 37573235 PMCID: PMC10858294 DOI: 10.1016/j.tcb.2023.07.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 08/14/2023]
Abstract
Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).
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Affiliation(s)
- Shane T Killarney
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Stephen W G Tait
- Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
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36
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Gadre M, Kasturi M, Agarwal P, Vasanthan KS. Decellularization and Their Significance for Tissue Regeneration in the Era of 3D Bioprinting. ACS OMEGA 2024; 9:7375-7392. [PMID: 38405516 PMCID: PMC10883024 DOI: 10.1021/acsomega.3c08930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/19/2023] [Accepted: 01/10/2024] [Indexed: 02/27/2024]
Abstract
Three-dimensional bioprinting is an emerging technology that has high potential application in tissue engineering and regenerative medicine. Increasing advancement and improvement in the decellularization process have led to an increase in the demand for using a decellularized extracellular matrix (dECM) to fabricate tissue engineered products. Decellularization is the process of retaining the extracellular matrix (ECM) while the cellular components are completely removed to harvest the ECM for the regeneration of various tissues and across different sources. Post decellularization of tissues and organs, they act as natural biomaterials to provide the biochemical and structural support to establish cell communication. Selection of an effective method for decellularization is crucial, and various factors like tissue density, geometric organization, and ECM composition affect the regenerative potential which has an impact on the end product. The dECM is a versatile material which is added as an important ingredient to formulate the bioink component for constructing tissue and organs for various significant studies. Bioink consisting of dECM from various sources is used to generate tissue-specific bioink that is unique and to mimic different biometric microenvironments. At present, there are many different techniques applied for decellularization, and the process is not standardized and regulated due to broad application. This review aims to provide an overview of different decellularization procedures, and we also emphasize the different dECM-derived bioinks present in the current global market and the major clinical outcomes. We have also highlighted an overview of benefits and limitations of different decellularization methods and various characteristic validations of decellularization and dECM-derived bioinks.
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Affiliation(s)
- Mrunmayi Gadre
- Manipal
Centre for Biotherapeutics Research, Manipal
Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Meghana Kasturi
- Department
of Mechanical Engineering, University of
Michigan, Dearborn, Michigan 48128, United States
| | - Prachi Agarwal
- Manipal
Centre for Biotherapeutics Research, Manipal
Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Kirthanashri S. Vasanthan
- Manipal
Centre for Biotherapeutics Research, Manipal
Academy of Higher Education, Manipal 576104, Karnataka, India
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37
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Tevlek A. The role of decellularized cell derived extracellular matrix in the establishment and culture of in vitrobreast cancer tumor model. Biomed Mater 2024; 19:025037. [PMID: 38286003 DOI: 10.1088/1748-605x/ad2378] [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: 11/18/2023] [Accepted: 01/29/2024] [Indexed: 01/31/2024]
Abstract
Decades of research have shown that two-dimensional cell culture studies are insufficient for preclinical cancer diagnosis and treatment, and that cancer cells in three-dimensional (3D) culture systems have better cell-cell and cell-matrix interactions, gene expression, heterogeneity, and structural complexity that more closely resemblein vivotumors. Researchers are still optimizing 3D culturing settings for different cancers. Despite promising tumor spheroid research, tumor cell-only aggregates lack the tumor microenvironment and cannot model tumors. Here, MCF-7 breast cancer cell derived decellularized extracellular matrix (CD-dECMs) were obtained and converted into autologous, biologically active, biocompatible, and non-immunogenic hydrogels to be used as micro-environment in both organoid formation and culture. For the production of organoids, CD-dECM doping concentrations ranging from 0.1 mg ml-1to 1.5 mg ml-1were evaluated, and the lowest concentration was found to be the most effective. For organoid culture, 8 mg ml-1CD-dECM, 4 mg ml-1rat tendon collagen type I (Col I) (4 mg ml-1) and a 1:1 (v/v) mixture of these two were used and the most viable and the biggest organoids were discovered in CD-dECM/Col I (1:1) group. The results show that autologous CD-dECM can replace hydrogels in tumor organoid generation and culture at low and high concentrations, respectively.
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Affiliation(s)
- Atakan Tevlek
- Middle East Technical University (METU), MEMS Research and Application Center, 06530 Ankara, Turkey
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38
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Hao L, Khajouei F, Rodriguez J, Kim S, Lee EJA. Unlocking the Promise of Decellularized Pancreatic Tissue: A Novel Approach to Support Angiogenesis in Engineered Tissue. Bioengineering (Basel) 2024; 11:183. [PMID: 38391669 PMCID: PMC10886056 DOI: 10.3390/bioengineering11020183] [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: 01/10/2024] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 02/24/2024] Open
Abstract
Advancements in regenerative medicine have highlighted the potential of decellularized extracellular matrix (ECM) as a scaffold for organ bioengineering. Although the potential of ECM in major organ systems is well-recognized, studies focusing on the angiogenic effects of pancreatic ECM are limited. This study investigates the capabilities of pancreatic ECM, particularly its role in promoting angiogenesis. Using a Triton-X-100 solution, porcine pancreas was successfully decellularized, resulting in a significant reduction in DNA content (97.1% removal) while preserving key pancreatic ECM components. A three-dimensional ECM hydrogel was then created from this decellularized tissue and used for cell culture. Biocompatibility tests demonstrated enhanced adhesion and proliferation of mouse embryonic stem cell-derived endothelial cells (mES-ECs) and human umbilical vein endothelial cells (HUVECs) in this hydrogel compared to conventional scaffolds. The angiogenic potential was evaluated through tube formation assays, wherein the cells showed superior tube formation capabilities in ECM hydrogel compared to rat tail collagen. The RT-PCR analysis further confirmed the upregulation of pro-angiogenic genes in HUVECs cultured within the ECM hydrogel. Specifically, HUVECs cultured in the ECM hydrogel exhibited a significant upregulation in the expression of MMP2, VEGF and PAR-1, compared to those cultured in collagen hydrogel or in a monolayer condition. The identification of ECM proteins, specifically PRSS2 and Decorin, further supports the efficacy of pancreatic ECM hydrogel as an angiogenic scaffold. These findings highlight the therapeutic promise of pancreatic ECM hydrogel as a candidate for vascularized tissue engineering application.
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Affiliation(s)
- Lei Hao
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Fariba Khajouei
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Jaselin Rodriguez
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Soojin Kim
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Eun Jung A Lee
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
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39
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Kandouz M. Cell Death, by Any Other Name…. Cells 2024; 13:325. [PMID: 38391938 PMCID: PMC10886887 DOI: 10.3390/cells13040325] [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: 12/31/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is "cell death", really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell-cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell-cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication.
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Affiliation(s)
- Mustapha Kandouz
- Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, USA;
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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40
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Santavanond JP, Chiu YH, Tixeira R, Liu Z, Yap JKY, Chen KW, Li CL, Lu YR, Roncero-Carol J, Hoijman E, Rutter SF, Shi B, Ryan GF, Hodge AL, Caruso S, Baxter AA, Ozkocak DC, Johnson C, Day ZI, Mayfosh AJ, Hulett MD, Phan TK, Atkin-Smith GK, Poon IKH. The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Cell Death Dis 2024; 15:123. [PMID: 38336804 PMCID: PMC10858176 DOI: 10.1038/s41419-024-06513-z] [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: 07/05/2023] [Revised: 01/16/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024]
Abstract
Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors.
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Affiliation(s)
- Jascinta P Santavanond
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Yu-Hsin Chiu
- Departments of Medical Science, Life Science, and Medicine, National Tsing Hua University, Hsinchu, Taiwan.
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
| | - Rochelle Tixeira
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Zonghan Liu
- Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Jeremy K Y Yap
- Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Kaiwen W Chen
- Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Chen-Lu Li
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yi-Ru Lu
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Joan Roncero-Carol
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Esteban Hoijman
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Stephanie F Rutter
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Bo Shi
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Gemma F Ryan
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Amy L Hodge
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Sarah Caruso
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Amy A Baxter
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Dilara C Ozkocak
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Chad Johnson
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Zoe I Day
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Alyce J Mayfosh
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Mark D Hulett
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
| | - Thanh K Phan
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
- The Walter and Eliza Hall Institute of Medial Research, Parkville, Vic, Australia
| | - Georgia K Atkin-Smith
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia
- The Walter and Eliza Hall Institute of Medial Research, Parkville, Vic, Australia
- University of Melbourne, Melbourne, VIC, Australia
| | - Ivan K H Poon
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
- Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.
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Vecchiarelli HA, Lopes LT, Paolicelli RC, Stevens B, Wake H, Tremblay MÈ. Synapse Regulation. ADVANCES IN NEUROBIOLOGY 2024; 37:179-208. [PMID: 39207693 DOI: 10.1007/978-3-031-55529-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Microglia are the resident immune cells of the brain. As such, they rapidly detect changes in normal brain homeostasis and accurately respond by fine-tuning in a tightly regulated manner their morphology, gene expression, and functional behavior. Depending on the nature of these changes, microglia can thicken and retract their processes, proliferate and migrate, release numerous signaling factors and compounds influencing neuronal physiology (e.g., cytokines and trophic factors), in addition to secreting proteases able to transform the extracellular matrix, and phagocytosing various types of cellular debris, etc. Because microglia also transform rapidly (on a time scale of minutes) during experimental procedures, studying these very special cells requires methods that are specifically non-invasive. The development of such methods has provided unprecedented insights into the roles of microglia during normal physiological conditions. In particular, transcranial two-photon in vivo imaging revealed that presumably "resting" microglia continuously survey the brain parenchyma with their highly motile processes, in addition to modulating their structural and functional interactions with neuronal circuits along the changes in neuronal activity and behavioral experience occurring throughout the lifespan. In this chapter, we will describe how surveillant microglia interact with synaptic elements and modulate the number, maturation, function, and plasticity of synapses in the healthy developing, mature, and aging brain, with consequences on neuronal activity, learning and memory, and the behavioral outcome.
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Affiliation(s)
| | | | - Rosa C Paolicelli
- Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland
| | - Beth Stevens
- Department of Neurology, Harvard Medical School, Center for Life Science, Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA
| | - Hiroaki Wake
- Division of Brain Circuits, National Institute for Basic Biology, Myodaiji-cho, Okazaki, Japan
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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Li Z, Yan M, Wang Z, An Y, Wei X, Li T, Xu M, Xia Y, Wang L, Gao C. Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia. Thromb Haemost 2023; 123:1116-1128. [PMID: 37364609 PMCID: PMC10686749 DOI: 10.1055/a-2117-7890] [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: 09/28/2022] [Accepted: 06/12/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Although thrombosis events are the leading complication of uremia, their mechanism is largely unknown. The interaction between endothelial cells (ECs) and red blood cells (RBCs) in uremic solutes and its prothrombotic role need to be investigated. METHODS AND RESULTS Here, we established an in vitro co-incubation model of uremic RBC and EC as well as a uremic rat model induced by adenine. Using flow cytometry, confocal microscopy, and electron microscopy, we found increased erythrophagocytosis by EC accompanied by increased reactive oxygen species, lipid peroxidation, and impairment of mitochondria, indicating that ECs undergo ferroptosis. Further investigations showed increased proteins' expression of heme oxygenase-1 and ferritin and labile iron pool accumulation in EC, which could be suppressed by deferoxamine (DFO). The ferroptosis-negative regulators glutathione peroxidase 4 and SLC7A11 were decreased in our erythrophagocytosis model and could be enhanced by ferrostatin-1 or DFO. In vivo, we observed that vascular EC phagocytosed RBC and underwent ferroptosis in the kidney of the uremic rat, which could be inhibited by blocking the phagocytic pathway or inhibiting ferroptosis. Next, we found that the high tendency of thrombus formation was accompanied by erythrophagocytosis-induced ferroptosis in vitro and in vivo. Importantly, we further revealed that upregulated TMEM16F expression mediated phosphatidylserine externalization on ferroptotic EC, which contributed to a uremia-associated hypercoagulable state. CONCLUSION Our results indicate that erythrophagocytosis-triggered ferroptosis followed by phosphatidylserine exposure of EC may play a key role in uremic thrombotic complications, which may be a promising target to prevent thrombogenesis of uremia.
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Affiliation(s)
- Zhanni Li
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Meishan Yan
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Zelong Wang
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Yao An
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Xinyu Wei
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Tingting Li
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Minghui Xu
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Yanshi Xia
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
| | - Liqiu Wang
- Department of Clinical Laboratory, The Fifth Hospital, Harbin Medical University, Daqing, China
| | - Chunyan Gao
- Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
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Na K, Oh BC, Jung Y. Multifaceted role of CD14 in innate immunity and tissue homeostasis. Cytokine Growth Factor Rev 2023; 74:100-107. [PMID: 37661484 DOI: 10.1016/j.cytogfr.2023.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/05/2023]
Abstract
CD14 is a co-receptor of Toll-like receptor (TLR)- 4, with a critical role in innate immune responses. CD14 recognizes bacterial lipopolysaccharides, pathogen-, and damage-associated molecular patterns, thereby facilitating inflammatory immune responses. In addition to its well-established association with TLR4, CD14 is also implicated in TLR4-independent signaling, which leads to the apoptotic death of differentiated dendritic cells and activation of the noncanonical inflammasome pathway. CD14 also has a role beyond that of the immune responses. It contributes to tissue homeostasis by promoting the clearance of various apoptotic cells via recognizing externalized phosphatidylinositol phosphates. CD14 also has context-dependent roles, particularly in barrier tissues that include the skin and gastrointestinal tract. For example, CD14+ dendritic cells in the skin can induce immunostimulatory or immunosuppressive responses. In the gastrointestinal system, CD14 is involved in producing inflammatory cytokines in inflammatory bowel disease and maintaining of intestinal integrity. This review focuses on the multifaceted roles of CD14 in innate immunity and its potential regulatory functions in barrier tissues characterized by rapid cell renewal. By providing insights into the diverse functions of CD14, this review offers potential therapeutic implications for this versatile molecule in immune modulation and tissue homeostasis.
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Affiliation(s)
- Kunhee Na
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon 21999, the Republic of Korea
| | - Byung-Chul Oh
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon 21999, the Republic of Korea; Department of Physiology, College of Medicine, Gachon University, Incheon 21999, the Republic of Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, the Republic of Korea.
| | - YunJae Jung
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon 21999, the Republic of Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, the Republic of Korea; Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, the Republic of Korea.
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Chen TA, Sharma D, Jia W, Ha D, Man K, Zhang J, Yang Y, Zhou Y, Kamp TJ, Zhao F. Detergent-Based Decellularization for Anisotropic Cardiac-Specific Extracellular Matrix Scaffold Generation. Biomimetics (Basel) 2023; 8:551. [PMID: 37999192 PMCID: PMC10669368 DOI: 10.3390/biomimetics8070551] [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: 08/09/2023] [Revised: 09/19/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
Cell-derived extracellular matrix (ECM) has become increasingly popular in tissue engineering applications due to its ability to provide tailored signals for desirable cellular responses. Anisotropic cardiac-specific ECM scaffold decellularized from human induced pluripotent stem cell (hiPSC)-derived cardiac fibroblasts (hiPSC-CFs) mimics the native cardiac microenvironment and provides essential biochemical and signaling cues to hiPSC-derived cardiomyocytes (hiPSC-CMs). The objective of this study was to assess the efficacy of two detergent-based decellularization methods: (1) a combination of ethylenediaminetetraacetic acid and sodium dodecyl sulfate (EDTA + SDS) and (2) a combination of sodium deoxycholate and deoxyribonuclease (SD + DNase), in preserving the composition and bioactive substances within the aligned ECM scaffold while maximumly removing cellular components. The decellularization effects were evaluated by characterizing the ECM morphology, quantifying key structural biomacromolecules, and measuring preserved growth factors. Results showed that both treatments met the standard of cell removal (less than 50 ng/mg ECM dry weight) and substantially preserved major ECM biomacromolecules and growth factors. The EDTA + SDS treatment was more time-efficient and has been determined to be a more efficient method for generating an anisotropic ECM scaffold from aligned hiPSC-CFs. Moreover, this cardiac-specific ECM has demonstrated effectiveness in supporting the alignment of hiPSC-CMs and their expression of mature structural and functional proteins in in vitro cultures, which is crucial for cardiac tissue engineering.
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Affiliation(s)
- Te-An Chen
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Dhavan Sharma
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Wenkai Jia
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Donggi Ha
- Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Kun Man
- Department of Biomedical Engineering, University of North Texas, Denton, TX 76203, USA
| | - Jianhua Zhang
- Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Yong Yang
- Department of Biomedical Engineering, University of North Texas, Denton, TX 76203, USA
| | - Yuxiao Zhou
- Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Timothy J. Kamp
- Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Feng Zhao
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
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Kafili G, Kabir H, Jalali Kandeloos A, Golafshan E, Ghasemi S, Mashayekhan S, Taebnia N. Recent advances in soluble decellularized extracellular matrix for heart tissue engineering and organ modeling. J Biomater Appl 2023; 38:577-604. [PMID: 38006224 PMCID: PMC10676626 DOI: 10.1177/08853282231207216] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2023]
Abstract
Despite the advent of tissue engineering (TE) for the remodeling, restoring, and replacing damaged cardiovascular tissues, the progress is hindered by the optimal mechanical and chemical properties required to induce cardiac tissue-specific cellular behaviors including migration, adhesion, proliferation, and differentiation. Cardiac extracellular matrix (ECM) consists of numerous structural and functional molecules and tissue-specific cells, therefore it plays an important role in stimulating cell proliferation and differentiation, guiding cell migration, and activating regulatory signaling pathways. With the improvement and modification of cell removal methods, decellularized ECM (dECM) preserves biochemical complexity, and bio-inductive properties of the native matrix and improves the process of generating functional tissue. In this review, we first provide an overview of the latest advancements in the utilization of dECM in in vitro model systems for disease and tissue modeling, as well as drug screening. Then, we explore the role of dECM-based biomaterials in cardiovascular regenerative medicine (RM), including both invasive and non-invasive methods. In the next step, we elucidate the engineering and material considerations in the preparation of dECM-based biomaterials, namely various decellularization techniques, dECM sources, modulation, characterizations, and fabrication approaches. Finally, we discuss the limitations and future directions in fabrication of dECM-based biomaterials for cardiovascular modeling, RM, and clinical translation.
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Affiliation(s)
- Golara Kafili
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
| | - Hannaneh Kabir
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, CA, USA
| | | | - Elham Golafshan
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
| | - Sara Ghasemi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Shohreh Mashayekhan
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Nayere Taebnia
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
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Burstyn-Cohen T, Fresia R. TAM receptors in phagocytosis: Beyond the mere internalization of particles. Immunol Rev 2023; 319:7-26. [PMID: 37596991 DOI: 10.1111/imr.13267] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/18/2023] [Indexed: 08/21/2023]
Abstract
TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, activated by their ligands GAS6 and PROS1. TAMs are necessary for adult homeostasis in the immune, nervous, reproductive, skeletal, and vascular systems. Among additional cellular functions employed by TAMs, phagocytosis is central for tissue health. TAM receptors are dominant in providing phagocytes with the molecular machinery necessary to engulf diverse targets, including apoptotic cells, myelin debris, and portions of live cells in a phosphatidylserine-dependent manner. Simultaneously, TAMs drive the release of anti-inflammatory and tissue repair molecules. Disruption of the TAM-driven phagocytic pathway has detrimental consequences, resulting in autoimmunity, male infertility, blindness, and disrupted vascular integrity, and which is thought to contribute to neurodegenerative diseases. Although structurally and functionally redundant, the TAM receptors and ligands underlie complex signaling cascades, of which several key aspects are yet to be elucidated. We discuss similarities and differences between TAMs and other phagocytic pathways, highlight future directions and how TAMs can be harnessed therapeutically to modulate phagocytosis.
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Affiliation(s)
- Tal Burstyn-Cohen
- The Institute for Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel
| | - Roberta Fresia
- The Institute for Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel
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47
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Gregory CD. Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis. Immunol Rev 2023; 319:100-127. [PMID: 37553811 PMCID: PMC10952466 DOI: 10.1111/imr.13259] [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: 04/25/2023] [Accepted: 07/18/2023] [Indexed: 08/10/2023]
Abstract
Cancers are genetically driven, rogue tissues which generate dysfunctional, obdurate organs by hijacking normal, homeostatic programs. Apoptosis is an evolutionarily conserved regulated cell death program and a profoundly important homeostatic mechanism that is common (alongside tumor cell proliferation) in actively growing cancers, as well as in tumors responding to cytotoxic anti-cancer therapies. Although well known for its cell-autonomous tumor-suppressive qualities, apoptosis harbors pro-oncogenic properties which are deployed through non-cell-autonomous mechanisms and which generally remain poorly defined. Here, the roles of apoptosis in tumor biology are reviewed, with particular focus on the secreted and fragmentation products of apoptotic tumor cells and their effects on tumor-associated macrophages, key supportive cells in the aberrant homeostasis of the tumor microenvironment. Historical aspects of cell loss in tumor growth kinetics are considered and the impact (and potential impact) on tumor growth of apoptotic-cell clearance (efferocytosis) as well as released soluble and extracellular vesicle-associated factors are discussed from the perspectives of inflammation, tissue repair, and regeneration programs. An "apoptosis-centric" view is proposed in which dying tumor cells provide an important platform for intricate intercellular communication networks in growing cancers. The perspective has implications for future research and for improving cancer diagnosis and therapy.
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Affiliation(s)
- Christopher D. Gregory
- Centre for Inflammation ResearchInstitute for Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarterEdinburghUK
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48
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Khalaji A, Yancheshmeh FB, Farham F, Khorram A, Sheshbolouki S, Zokaei M, Vatankhah F, Soleymani-Goloujeh M. Don't eat me/eat me signals as a novel strategy in cancer immunotherapy. Heliyon 2023; 9:e20507. [PMID: 37822610 PMCID: PMC10562801 DOI: 10.1016/j.heliyon.2023.e20507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 09/04/2023] [Accepted: 09/27/2023] [Indexed: 10/13/2023] Open
Abstract
Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer treatment has seen the development of various strategies, each carrying its drawbacks that can negatively impact the quality of life for cancer patients. The challenge remains significant within the medical field to establish a definitive cancer treatment that minimizes complications and limitations. In the forthcoming years, exploring new strategies to surmount the failures in cancer treatment appears to be an unavoidable pursuit. Among these strategies, immunology-based ones hold substantial promise in combatting cancer and immune-related disorders. A particular subset of this approach identifies "eat me" and "Don't eat me" signals in cancer cells, contrasting them with their counterparts in non-cancerous cells. This distinction could potentially mark a significant breakthrough in treating diverse cancers. By delving into signal transduction and engineering novel technologies that utilize distinct "eat me" and "Don't eat me" signals, a valuable avenue may emerge for advancing cancer treatment methodologies. Macrophages, functioning as vital components of the immune system, regulate metabolic equilibrium, manage inflammatory disorders, oversee fibrosis, and aid in the repair of injuries. However, in the context of tumor cells, the overexpression of "Don't eat me" signals like CD47, PD-L1, and beta-2 microglobulin (B2M), an anti-phagocytic subunit of the primary histocompatibility complex class I, enables these cells to evade macrophages and proliferate uncontrollably. Conversely, the presentation of an "eat me" signal, such as Phosphatidylserine (PS), along with alterations in charge and glycosylation patterns on the cellular surface, modifications in intercellular adhesion molecule-1 (ICAM-1) epitopes, and the exposure of Calreticulin and PS on the outer layer of the plasma membrane represent universally observed changes on the surface of apoptotic cells, preventing phagocytosis from causing harm to adjacent non-tumoral cells. The current review provides insight into how signaling pathways and immune cells either stimulate or obstruct these signals, aiming to address challenges that may arise in future immunotherapy research. A potential solution lies in combination therapies targeting the "eat me" and "Don't eat me" signals in conjunction with other targeted therapeutic approaches. This innovative strategy holds promise as a novel avenue for the future treatment of cancer.
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Affiliation(s)
- Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatereh Baharlouei Yancheshmeh
- Cardiac Rehabilitation Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Farham
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arya Khorram
- Department of Laboratory Sciences, School of Allied Medical Sciences, Alborz University of Medical Sciences, Karaj, Iran
| | - Shiva Sheshbolouki
- Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Veterinary Medicine, Beyza Branch, Islamic Azad University, Beyza, Iran
| | - Fatemeh Vatankhah
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Soleymani-Goloujeh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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49
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Wang X, Elbahrawi RT, Abdukadir AM, Ali ZM, Chan V, Corridon PR. A proposed model of xeno-keratoplasty using 3D printing and decellularization. Front Pharmacol 2023; 14:1193606. [PMID: 37799970 PMCID: PMC10548234 DOI: 10.3389/fphar.2023.1193606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 09/06/2023] [Indexed: 10/07/2023] Open
Abstract
Corneal opacity is a leading cause of vision impairment and suffering worldwide. Transplantation can effectively restore vision and reduce chronic discomfort. However, there is a considerable shortage of viable corneal graft tissues. Tissue engineering may address this issue by advancing xeno-keratoplasty as a viable alternative to conventional keratoplasty. In particular, livestock decellularization strategies offer the potential to generate bioartificial ocular prosthetics in sufficient supply to match existing and projected needs. To this end, we have examined the best practices and characterizations that have supported the current state-of-the-art driving preclinical and clinical applications. Identifying the challenges that delimit activities to supplement the donor corneal pool derived from acellular scaffolds allowed us to hypothesize a model for keratoprosthesis applications derived from livestock combining 3D printing and decellularization.
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Affiliation(s)
- Xinyu Wang
- Biomedical Engineering and Healthcare Engineering Innovation Center, Khalifa University, Abu Dhabi, United Arab Emirates
- Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Rawdah Taha Elbahrawi
- Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Azhar Mohamud Abdukadir
- Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Zehara Mohammed Ali
- Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Vincent Chan
- Biomedical Engineering and Healthcare Engineering Innovation Center, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Peter R. Corridon
- Biomedical Engineering and Healthcare Engineering Innovation Center, Khalifa University, Abu Dhabi, United Arab Emirates
- Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University, Abu Dhabi, United Arab Emirates
- Hleathcare, Engineering and Innovation Center, Khalifa University, Abu Dhabi, United Arab Emirates
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50
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Cao L, Ma L, Zhao J, Wang X, Fang X, Li W, Qi Y, Tang Y, Liu J, Peng S, Yang L, Zhou L, Li L, Hu X, Ji Y, Hou Y, Zhao Y, Zhang X, Zhao YY, Zhao Y, Wei Y, Malik AB, Saiyin H, Xu J. An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo. eLife 2023; 12:RP86591. [PMID: 37728612 PMCID: PMC10511239 DOI: 10.7554/elife.86591] [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] [Indexed: 09/21/2023] Open
Abstract
Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.
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Affiliation(s)
- Luyang Cao
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL)GuangzhouChina
| | - Lixiang Ma
- Department of Anatomy, Histology & Embryology, Shanghai Medical CollegeShanghaiChina
| | - Juan Zhao
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Xiangyu Wang
- Department of Anatomy, Histology & Embryology, Shanghai Medical CollegeShanghaiChina
| | - Xinzou Fang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Wei Li
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL)GuangzhouChina
| | - Yawen Qi
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL)GuangzhouChina
| | - Yingkui Tang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Jieya Liu
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Shengxian Peng
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Li Yang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Liangxue Zhou
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Li Li
- Department of Anatomy, Histology & Embryology, Shanghai Medical CollegeShanghaiChina
| | - Xiaobo Hu
- Clinical Laboratory, Longhua Hospital, Shanghai University of Traditional MedicineShanghaiChina
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital Fudan UniversityShanghaiChina
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital Fudan UniversityShanghaiChina
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan UniversityChengduChina
| | - Xianming Zhang
- Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of MedicineChicagoUnited States
| | - You-yang Zhao
- Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of MedicineChicagoUnited States
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesBeijingChina
| | - Yuquan Wei
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
| | - Asrar B Malik
- Department of Pharmacology, University of Illinois, College of MedicineChicagoUnited States
| | - Hexige Saiyin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityShanghaiChina
| | - Jingsong Xu
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengduChina
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