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Fonseca-Pereira D, Bae S, Clay SL, Michaud M, MacDonald MH, Glickman JN, Garrett WS. The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function. Cell Rep 2025; 44:115456. [PMID: 40120107 DOI: 10.1016/j.celrep.2025.115456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/06/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025] Open
Abstract
Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.
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Affiliation(s)
- Diogo Fonseca-Pereira
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Sena Bae
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Slater L Clay
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Monia Michaud
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Meghan H MacDonald
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA
| | - Jonathan N Glickman
- Gastrointestinal Pathology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Wendy S Garrett
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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2
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Karimpur-Zahmatkesh A, Khalaj-Kondori M. The perspective of targeting cancer cell metabolism: combination therapy approaches. Mol Biol Rep 2025; 52:375. [PMID: 40202553 DOI: 10.1007/s11033-025-10472-9] [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: 12/23/2024] [Accepted: 03/25/2025] [Indexed: 04/10/2025]
Abstract
Cancer cells are considered the most adaptable for their metabolic status, which supports growth, survival, rapid proliferation, invasiveness, and metastasis in a nutrient-deficient microenvironment. Since the discovery of altered glucose metabolism (aerobic glycolysis), which is generally known as a part of metabolic reprogramming and an innate trait of cancer cells, in 1930 via Dr. Otto Warburg, numerous studies have endeavored to recognize various aspects of cancer cell metabolism and find new methods for efficiently eradicating described cells by targeting their energy metabolism. In this way, the outcomes have mainly been promising. Accordingly, outlining the related results will indeed assist us in making a definitive path for developing targeted therapy strategies based on cancer cell-altered metabolism. The present study reviews the key features of cancer cell metabolism and treatment strategies based on them. It emphasizes the importance of targeting cancer cell dysregulated metabolic pathways that influence the cell energy supply and manage cancer cell growth and survival. This trial also introduces a multimodal therapeutic strategy hypothesis, a potential next-generation combination therapy approach, and suggests interdisciplinary research to recognize the complexities of cancer metabolism and exploit them for designing more efficacious cancer therapeutic strategies.
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Affiliation(s)
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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3
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Bozkurt AS, Yılmaz ŞG, Kaplan DS, Bal R. The regenerative effect of exosomes isolated from mouse embryonic fibroblasts in mice created as a sciatic nerve crush injury model. Mol Biol Rep 2024; 51:1046. [PMID: 39388029 DOI: 10.1007/s11033-024-09962-z] [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: 08/13/2024] [Accepted: 09/20/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Exosomes (Exos) are candidates for functional recovery and regeneration following sciatic nerve crushed (SNC) injury due to their composition which can accelerate tissue regeneration. Therefore, mouse embryonic fibroblast-derived exosomes were evaluated for their regenerative capacity in SNC injury. METHODS AND RESULTS In the study, 40 Balb/c males (20 ± 5 g) and two pregnant mice (for embryonic fibroblast tissue) were used and crushed injury was induced in the left sciatic nerve with an aneurysm clamp. Sciatic nerve model mice were randomly divided into 5 groups (n = 8; control, n = 8; sham, n = 8; SNC, n = 8; Mouse embryonic fibroblast exosome (mExo), n = 8; SNC + Mouse embryonic fibroblast exosome (SNC + mExo). Rotarod tests for motor functions and hot plate and von Frey tests for sensory functions were analyzed in the groups. Expression changes of exosome genes (RARRES1, NAGS, HOXA13, and MEIS1) immunohistochemical analysis of these gene proteins, and structural exosome NF-200 and S100 proteins were evaluated by confocal microscopy. Behavioral analyses showed that the damage in SNC was significant between groups on day14 and day28 (P < 0.05). In behavioral analyses, it was determined that motor functions and mechanical sensitivity lost in SNC were regained after mExo treatment. While expression of all genes was detected in MEF-derived exosomes, the high expression was MESI1 and the low expression was HOXA13. NF200, an indicator of axon number and neurofilament density, was found to decrease in SNC (P < 0.001) and increase after treatment, but not significantly. The decreased S100 protein levels in SNC and the increase detected after treatment were not significant. CONCLUSION The expression of four mRNAs in mExos indicates that these genes may have an effect on regenerative processes after SNC injury. The regenerative process supported by tissue protein expressions demonstrates the therapeutic potential of mExo treatment.
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Affiliation(s)
- Ahmet Sarper Bozkurt
- Physiology Department, Medicine Faculty, Gaziantep University, Gaziantep, Turkey.
| | - Şenay Görücü Yılmaz
- Nutrition and Dietetics Department, Health Science Faculty, Gaziantep University, Gaziantep, Turkey
| | - Davut Sinan Kaplan
- Physiology Department, Medicine Faculty, Gaziantep University, Gaziantep, Turkey
| | - Ramazan Bal
- Physiology Department, Medicine Faculty, Gaziantep University, Gaziantep, Turkey
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4
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Xu H, Li Y, Gao Y. The role of immune cells settled in the bone marrow on adult hematopoietic stem cells. Cell Mol Life Sci 2024; 81:420. [PMID: 39367881 PMCID: PMC11456083 DOI: 10.1007/s00018-024-05445-3] [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: 11/29/2023] [Revised: 09/09/2024] [Accepted: 09/09/2024] [Indexed: 10/07/2024]
Abstract
Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis.
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Affiliation(s)
- Hui Xu
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Yinghui Li
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
| | - Yingdai Gao
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
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5
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Özgüldez HÖ, Bulut-Karslioğlu A. Dormancy, Quiescence, and Diapause: Savings Accounts for Life. Annu Rev Cell Dev Biol 2024; 40:25-49. [PMID: 38985838 DOI: 10.1146/annurev-cellbio-112122-022528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration.
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Affiliation(s)
- Hatice Özge Özgüldez
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
| | - Aydan Bulut-Karslioğlu
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
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Zhou C, Kuang M, Tao Y, Wang J, Luo Y, Fu Y, Chen Z, Liu Y, Li Z, Wu W, Wang L, Dou Y, Wang J, Hou Y. Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening. Cell Stem Cell 2024; 31:1359-1375.e8. [PMID: 38955185 DOI: 10.1016/j.stem.2024.06.007] [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: 11/21/2023] [Revised: 04/22/2024] [Accepted: 06/07/2024] [Indexed: 07/04/2024]
Abstract
Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.
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Affiliation(s)
- Chengfang Zhou
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Mei Kuang
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yin Tao
- Department of Gynecology, The affiliated ZhuZhou Hospital (ZhuZhou Central Hospital), Xiangya Medical College of Central South University, Zhuzhou, Hunan 412007, China
| | - Jianming Wang
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yu Luo
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yinghao Fu
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhe Chen
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yuanyuan Liu
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhigang Li
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Weiru Wu
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong Qu, Chongqing 400016, China
| | - Ying Dou
- Department of Hematology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
| | - Junping Wang
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
| | - Yu Hou
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Department of Hematology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing Medical University, Chongqing 400016, China.
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7
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Kovale L, Singh MK, Kim J, Ha J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int J Mol Sci 2024; 25:8647. [PMID: 39201332 PMCID: PMC11354724 DOI: 10.3390/ijms25168647] [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: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
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Affiliation(s)
- Lochana Kovale
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Joungmok Kim
- Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
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8
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Liu M, Gu L, Zhang Y, Li Y, Zhang L, Xin Y, Wang Y, Xu ZX. LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma. Cancer Lett 2024; 595:217025. [PMID: 38844063 DOI: 10.1016/j.canlet.2024.217025] [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: 12/22/2023] [Revised: 05/15/2024] [Accepted: 06/02/2024] [Indexed: 06/10/2024]
Abstract
Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.
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Affiliation(s)
- Mingdi Liu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China
| | - Liting Gu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China
| | - Yuning Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China
| | - Yunkuo Li
- Department of Urology, the First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Lihong Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China.
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China.
| | - Zhi-Xiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, China.
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9
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Li M, Kong X, Jian X, Bo Y, Miao X, Chen H, Shang P, Zhou X, Wang L, Zhang Q, Deng Q, Xue Y, Feng F. Fatty acids metabolism in ozone-induced pulmonary inflammatory injury: Evidence, mechanism and prevention. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 933:173222. [PMID: 38750750 DOI: 10.1016/j.scitotenv.2024.173222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/20/2024]
Abstract
Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.
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Affiliation(s)
- Mengyuan Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xiangbing Kong
- College of Public Health, Qingdao University, Qingdao, Shandong Province, China
| | - Xiaotong Jian
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yacong Bo
- College of Public Health, Qingdao University, Qingdao, Shandong Province, China
| | - Xinyi Miao
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Pingping Shang
- Key Laboratory of Tobacco Chemistry, Zhengzhou Tobacco Research Institute, CNC, Zhengzhou, Henan, China
| | - Xiaolei Zhou
- Department of Pulmonary Medicine, Chest Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ling Wang
- Faculty of Medicine, Macau University of Science and Technology, Macau
| | - Qiao Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Qihong Deng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yuan Xue
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.
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10
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Sun J, Zhang Y, Zhang Q, Hu L, Zhao L, Wang H, Yuan Y, Niu H, Wang D, Zhang H, Liu J, Feng X, Su X, Qiu J, Sun J, Xu H, Zhang C, Wang K, Bi Y, Engleman EG, Shen L. Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance. Immunity 2024; 57:1289-1305.e9. [PMID: 38772366 DOI: 10.1016/j.immuni.2024.04.024] [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: 08/18/2023] [Revised: 02/06/2024] [Accepted: 04/25/2024] [Indexed: 05/23/2024]
Abstract
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
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Affiliation(s)
- Jiping Sun
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Youqin Zhang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qingbing Zhang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lin Hu
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Linfeng Zhao
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital affiliated with Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China
| | - Yue Yuan
- Department of Endocrinology, Drum Tower Hospital affiliated with Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China
| | - Hongshen Niu
- Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Dongdi Wang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Huasheng Zhang
- Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jianyue Liu
- Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xujiao Feng
- Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaohui Su
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ju Qiu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Heping Xu
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Catherine Zhang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Kathleen Wang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital affiliated with Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China
| | - Edgar G Engleman
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Lei Shen
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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11
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Xiao Z, Wang S, Luo L, Lv W, Feng P, Sun Y, Yang Q, He J, Cao G, Yin Z, Yang M. Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis. Cell Mol Immunol 2024; 21:546-560. [PMID: 38641698 PMCID: PMC11143210 DOI: 10.1038/s41423-024-01163-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 04/02/2024] [Indexed: 04/21/2024] Open
Abstract
γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.
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Affiliation(s)
- Zhiqiang Xiao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shanshan Wang
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Liang Luo
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Wenkai Lv
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Peiran Feng
- Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China
| | - Yadong Sun
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Quanli Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China
| | - Jun He
- Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application. Institute of Laboratory Animal Science, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Guangchao Cao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhinan Yin
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China.
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Meixiang Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China.
- The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China.
- Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application. Institute of Laboratory Animal Science, School of Medicine, Jinan University, Guangzhou, 510632, China.
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12
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Watanuki S, Kobayashi H, Sugiura Y, Yamamoto M, Karigane D, Shiroshita K, Sorimachi Y, Fujita S, Morikawa T, Koide S, Oshima M, Nishiyama A, Murakami K, Haraguchi M, Tamaki S, Yamamoto T, Yabushita T, Tanaka Y, Nagamatsu G, Honda H, Okamoto S, Goda N, Tamura T, Nakamura-Ishizu A, Suematsu M, Iwama A, Suda T, Takubo K. Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis. eLife 2024; 12:RP87674. [PMID: 38573813 PMCID: PMC10994660 DOI: 10.7554/elife.87674] [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: 04/06/2024] Open
Abstract
Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.
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Affiliation(s)
- Shintaro Watanuki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Division of Hematology, Department of Medicine, Keio University School of MedicineTokyoJapan
| | - Hiroshi Kobayashi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Department of Cell Fate Biology and Stem Cell Medicine, Tohoku University Graduate School of MedicineSendaiJapan
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of MedicineTokyoJapan
- Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of MedicineKyotoJapan
| | - Masamichi Yamamoto
- Department of Research Promotion and Management, National Cerebral and Cardiovascular CenterOsakaJapan
| | - Daiki Karigane
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Division of Hematology, Department of Medicine, Keio University School of MedicineTokyoJapan
| | - Kohei Shiroshita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Division of Hematology, Department of Medicine, Keio University School of MedicineTokyoJapan
| | - Yuriko Sorimachi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and EngineeringTokyoJapan
| | - Shinya Fujita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Division of Hematology, Department of Medicine, Keio University School of MedicineTokyoJapan
| | - Takayuki Morikawa
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
| | - Shuhei Koide
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of TokyoTokyoJapan
| | - Motohiko Oshima
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of TokyoTokyoJapan
| | - Akira Nishiyama
- Department of Immunology, Yokohama City University Graduate School of MedicineKanagawaJapan
| | - Koichi Murakami
- Department of Immunology, Yokohama City University Graduate School of MedicineKanagawaJapan
- Advanced Medical Research Center, Yokohama City UniversityKanagawaJapan
| | - Miho Haraguchi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
| | - Shinpei Tamaki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
| | - Takehiro Yamamoto
- Department of Biochemistry, Keio University School of MedicineTokyoJapan
| | - Tomohiro Yabushita
- Division of Cellular Therapy, The Institute of Medical Science, The University of TokyoTokyoJapan
| | - Yosuke Tanaka
- International Research Center for Medical Sciences, Kumamoto UniversityKumamotoJapan
| | - Go Nagamatsu
- Center for Advanced Assisted Reproductive Technologies, University of YamanashiYamanashiJapan
- Precursory Research for Embryonic Science and Technology, Japan Science and Technology AgencySaitamaJapan
| | - Hiroaki Honda
- Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical UniversityTokyoJapan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Medicine, Keio University School of MedicineTokyoJapan
| | - Nobuhito Goda
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and EngineeringTokyoJapan
| | - Tomohiko Tamura
- Department of Immunology, Yokohama City University Graduate School of MedicineKanagawaJapan
- Advanced Medical Research Center, Yokohama City UniversityKanagawaJapan
| | - Ayako Nakamura-Ishizu
- Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical UniversityTokyoJapan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of MedicineTokyoJapan
- Live Imaging Center, Central Institute for Experimental AnimalsKanagawaJapan
| | - Atsushi Iwama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of TokyoTokyoJapan
| | - Toshio Suda
- International Research Center for Medical Sciences, Kumamoto UniversityKumamotoJapan
- Cancer Science Institute of Singapore, National University of SingaporeSingaporeSingapore
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and MedicineTokyoJapan
- Department of Cell Fate Biology and Stem Cell Medicine, Tohoku University Graduate School of MedicineSendaiJapan
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13
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Bonora M, Morganti C, van Gastel N, Ito K, Calura E, Zanolla I, Ferroni L, Zhang Y, Jung Y, Sales G, Martini P, Nakamura T, Lasorsa FM, Finkel T, Lin CP, Zavan B, Pinton P, Georgakoudi I, Romualdi C, Scadden DT, Ito K. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate. Cell Stem Cell 2024; 31:359-377.e10. [PMID: 38458178 PMCID: PMC10957094 DOI: 10.1016/j.stem.2024.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 11/16/2023] [Accepted: 02/08/2024] [Indexed: 03/10/2024]
Abstract
Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
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Affiliation(s)
- Massimo Bonora
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Claudia Morganti
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Nick van Gastel
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; de Duve Institute, UCLouvain, 1200 Brussels, Belgium
| | - Kyoko Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Enrica Calura
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - Ilaria Zanolla
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy
| | - Yang Zhang
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA
| | - Yookyung Jung
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Gabriele Sales
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - Paolo Martini
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Takahisa Nakamura
- Divisions of Endocrinology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Metabolic Bioregulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
| | - Francesco Massimo Lasorsa
- Department of Biosciences Biotechnologies and Environment University of Bari and Institute of Biomembranes Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70125 Bari, Italy
| | - Toren Finkel
- Aging Institute and Department of Medicine, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Charles P Lin
- Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Barbara Zavan
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; Translational Medicine Department, University of Ferrara, 44121 Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Irene Georgakoudi
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA
| | - Chiara Romualdi
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - David T Scadden
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Keisuke Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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14
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Xu Y, Chiang YH, Ho PC, Vannini N. Mitochondria Dictate Function and Fate of HSCs and T Cells. Cancer Immunol Res 2023; 11:1303-1313. [PMID: 37789763 DOI: 10.1158/2326-6066.cir-22-0685] [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: 08/27/2022] [Revised: 01/23/2023] [Accepted: 08/16/2023] [Indexed: 10/05/2023]
Abstract
Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.
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Affiliation(s)
- Yingxi Xu
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Yi-Hsuan Chiang
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Nicola Vannini
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
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15
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Pizzato HA, Wang Y, Wolfgang MJ, Finck BN, Patti GJ, Bhattacharya D. Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis. J Exp Med 2023; 220:e20221373. [PMID: 37249600 PMCID: PMC10227646 DOI: 10.1084/jem.20221373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 03/23/2023] [Accepted: 05/10/2023] [Indexed: 05/31/2023] Open
Abstract
To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. In contrast, deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient and specific increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, while glutaminolysis in progenitors promotes emergency myelopoiesis.
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Affiliation(s)
- Hannah A. Pizzato
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
- Department of Immunobiology, University of Arizona, Tucson, AZ, USA
| | - Yahui Wang
- Department of Chemistry, Washington University, Saint Louis, MO, USA
| | - Michael J. Wolfgang
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian N. Finck
- Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, Saint Louis, MO, USA
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Gary J. Patti
- Department of Chemistry, Washington University, Saint Louis, MO, USA
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- Siteman Cancer Center, Washington University, Saint Louis, MO, USA
| | - Deepta Bhattacharya
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
- Department of Immunobiology, University of Arizona, Tucson, AZ, USA
- BIO5 Institute, University of Arizona, Tucson, AZ, USA
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16
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Girotra M, Chiang YH, Charmoy M, Ginefra P, Hope HC, Bataclan C, Yu YR, Schyrr F, Franco F, Geiger H, Cherix S, Ho PC, Naveiras O, Auwerx J, Held W, Vannini N. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems. NATURE AGING 2023; 3:1057-1066. [PMID: 37653255 DOI: 10.1038/s43587-023-00473-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 07/24/2023] [Indexed: 09/02/2023]
Abstract
Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
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Affiliation(s)
- Mukul Girotra
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Yi-Hsuan Chiang
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Melanie Charmoy
- Department of Oncology, University of Lausanne, Epalinges, Switzerland
| | - Pierpaolo Ginefra
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Helen Carrasco Hope
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Charles Bataclan
- Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences, University of Lausanne and ISREC, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Yi-Ru Yu
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Frederica Schyrr
- Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences, University of Lausanne and ISREC, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Fabien Franco
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Hartmut Geiger
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Stephane Cherix
- Orthopedic and Traumatology Service, Lausanne University Hospital, Lausanne, Switzerland
| | - Ping-Chih Ho
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Olaia Naveiras
- Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences, University of Lausanne and ISREC, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Hematology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Werner Held
- Department of Oncology, University of Lausanne, Epalinges, Switzerland
| | - Nicola Vannini
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
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17
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Yan Y, Teng H, Hang Q, Kondiparthi L, Lei G, Horbath A, Liu X, Mao C, Wu S, Zhuang L, James You M, Poyurovsky MV, Ma L, Olszewski K, Gan B. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells. Nat Commun 2023; 14:3673. [PMID: 37339981 PMCID: PMC10281978 DOI: 10.1038/s41467-023-39401-9] [Citation(s) in RCA: 123] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 06/09/2023] [Indexed: 06/22/2023] Open
Abstract
The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.
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Affiliation(s)
- Yuelong Yan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hongqi Teng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Qinglei Hang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Lavanya Kondiparthi
- Kadmon Corporation, LLC (A Sanofi Company), New York, NY, 10016, USA
- Sanofi US Services Inc, 270 Albany St, Cambridge, MA, 02139, USA
| | - Guang Lei
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Amber Horbath
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xiaoguang Liu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Chao Mao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Shiqi Wu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li Zhuang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - M James You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | | | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Kellen Olszewski
- Kadmon Corporation, LLC (A Sanofi Company), New York, NY, 10016, USA
- The Barer Institute, Philadelphia, PA, 19104, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
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18
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de Morree A, Rando TA. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. Nat Rev Mol Cell Biol 2023; 24:334-354. [PMID: 36922629 PMCID: PMC10725182 DOI: 10.1038/s41580-022-00568-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 03/18/2023]
Abstract
Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.
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Affiliation(s)
- Antoine de Morree
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Thomas A Rando
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
- Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
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19
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Nguyen K, Hebert K, McConnell E, Cullen N, Cheng T, Awoyode S, Martin E, Chen W, Wu T, Alahari SK, Izadpanah R, Collins-Burow BM, Lee SB, Drewry DH, Burow ME. LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma. Pharmacol Res 2023; 192:106757. [PMID: 37023992 DOI: 10.1016/j.phrs.2023.106757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
The liver is a major organ that is involved in essential biological functions such as digestion, nutrient storage, and detoxification. Furthermore, it is one of the most metabolically active organs with active roles in regulating carbohydrate, protein, and lipid metabolism. Hepatocellular carcinoma is a cancer of the liver that is associated in settings of chronic inflammation such as viral hepatitis, repeated toxin exposure, and fatty liver disease. Furthermore, liver cancer is the most common cause of death associated with cirrhosis and is the 3rd leading cause of global cancer deaths. LKB1 signaling has been demonstrated to play a role in regulating cellular metabolism under normal and nutrient deficient conditions. Furthermore, LKB1 signaling has been found to be involved in many cancers with most reports identifying LKB1 to have a tumor suppressive role. In this review, we use the KMPlotter database to correlate RNA levels of LKB1 signaling genes and hepatocellular carcinoma patient survival outcomes with the hopes of identifying potential biomarkers clinical usage. Based on our results STRADß, CAB39L, AMPKα, MARK2, SIK1, SIK2, BRSK1, BRSK2, and SNRK expression has a statistically significant impact on patient survival.
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Affiliation(s)
- Khoa Nguyen
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Katherine Hebert
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Emily McConnell
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Nicole Cullen
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Thomas Cheng
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Susanna Awoyode
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Elizabeth Martin
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Suresh K Alahari
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, LA, USA
| | - Reza Izadpanah
- Applied Stem Cell Laboratory, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | | | - Sean B Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - David H Drewry
- UNC Eshelman School of Pharmacy and UNC Lineberger Comprehensive Cancer Center, Chemical Biology and Medicinal Chemistry Division, SGC-UNC, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Matthew E Burow
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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20
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Liu X, Nie L, Zhang Y, Yan Y, Wang C, Colic M, Olszewski K, Horbath A, Chen X, Lei G, Mao C, Wu S, Zhuang L, Poyurovsky MV, James You M, Hart T, Billadeau DD, Chen J, Gan B. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol 2023; 25:404-414. [PMID: 36747082 PMCID: PMC10027392 DOI: 10.1038/s41556-023-01091-2] [Citation(s) in RCA: 548] [Impact Index Per Article: 274.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 01/12/2023] [Indexed: 02/08/2023]
Abstract
SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.
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Affiliation(s)
- Xiaoguang Liu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Litong Nie
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yilei Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuelong Yan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chao Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Medina Colic
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kellen Olszewski
- Kadmon Corporation (A Sanofi Company), LLC, New York, NY, USA
- The Barer Institute, Philadelphia, PA, USA
| | - Amber Horbath
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiong Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guang Lei
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chao Mao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shiqi Wu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Li Zhuang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - M James You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Traver Hart
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel D Billadeau
- Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
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21
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Conserva MR, Redavid I, Anelli L, Zagaria A, Tarantini F, Cumbo C, Tota G, Parciante E, Coccaro N, Minervini CF, Minervini A, Specchia G, Musto P, Albano F. IKAROS in Acute Leukemia: A Positive Influencer or a Mean Hater? Int J Mol Sci 2023; 24:3282. [PMID: 36834692 PMCID: PMC9961161 DOI: 10.3390/ijms24043282] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/31/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
One key process that controls leukemogenesis is the regulation of oncogenic gene expression by transcription factors acting as tumor suppressors. Understanding this intricate mechanism is crucial to elucidating leukemia pathophysiology and discovering new targeted treatments. In this review, we make a brief overview of the physiological role of IKAROS and the molecular pathway that contributes to acute leukemia pathogenesis through IKZF1 gene lesions. IKAROS is a zinc finger transcription factor of the Krüppel family that acts as the main character during hematopoiesis and leukemogenesis. It can activate or repress tumor suppressors or oncogenes, regulating the survival and proliferation of leukemic cells. More than 70% of Ph+ and Ph-like cases of acute lymphoblastic leukemia exhibit IKZF1 gene variants, which are linked to worse treatment outcomes in both childhood and adult B-cell precursor acute lymphoblastic leukemia. In the last few years, much evidence supporting IKAROS involvement in myeloid differentiation has been reported, suggesting that loss of IKZF1 might also be a determinant of oncogenesis in acute myeloid leukemia. Considering the complicated "social" network that IKAROS manages in hematopoietic cells, we aim to focus on its involvement and the numerous alterations of molecular pathways it can support in acute leukemias.
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Affiliation(s)
- Maria Rosa Conserva
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Immacolata Redavid
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Luisa Anelli
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Antonella Zagaria
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Francesco Tarantini
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Cosimo Cumbo
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Giuseppina Tota
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Elisa Parciante
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Nicoletta Coccaro
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Crescenzio Francesco Minervini
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Angela Minervini
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Giorgina Specchia
- School of Medicine, University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Pellegrino Musto
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
| | - Francesco Albano
- Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
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22
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Mistry JJ, Bowles K, Rushworth SA. HSC-derived fatty acid oxidation in steady-state and stressed hematopoiesis. Exp Hematol 2023; 117:1-8. [PMID: 36223830 DOI: 10.1016/j.exphem.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 01/10/2023]
Abstract
Metabolism impacts all cellular functions and plays a fundamental role in physiology. Metabolic regulation of hematopoiesis is dynamically regulated under steady-state and stress conditions. It is clear that hematopoietic stem cells (HSCs) impose different energy demands and flexibility during maintenance compared with stressed conditions. However, the cellular and molecular mechanisms underlying metabolic regulation in HSCs remain poorly understood. In this review, we focus on defining the role of fatty acid oxidation (FAO) in HSCs. We first review the existing literature describing FAO in HSCs under steady-state hematopoiesis. Next, we describe the models used to examine HSCs under stress conditions, and, finally, we describe how infection causes a shift toward FAO in HSCs and the impact of using this pathway on emergency hematopoiesis.
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Affiliation(s)
| | - Kristian Bowles
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom; Department of Haematology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Stuart A Rushworth
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
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23
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Evans AM. Of Mice and Men and Plethysmography Systems: Does LKB1 Determine the Set Point of Carotid Body Chemosensitivity and the Hypoxic Ventilatory Response? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1427:163-173. [PMID: 37322347 DOI: 10.1007/978-3-031-32371-3_18] [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] [Indexed: 06/17/2023]
Abstract
Our recent studies suggest that the level of liver kinase B1 (LKB1) expression in some way determines carotid body afferent discharge during hypoxia and to a lesser extent during hypercapnia. In short, phosphorylation by LKB1 of an as yet unidentified target(s) determines a set point for carotid body chemosensitivity. LKB1 is the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses, but conditional deletion of AMPK in catecholaminergic cells, including therein carotid body type I cells, has little or no effect on carotid body responses to hypoxia or hypercapnia. With AMPK excluded, the most likely target of LKB1 is one or other of the 12 AMPK-related kinases, which are constitutively phosphorylated by LKB1 and, in general, regulate gene expression. By contrast, the hypoxic ventilatory response is attenuated by either LKB1 or AMPK deletion in catecholaminergic cells, precipitating hypoventilation and apnea during hypoxia rather than hyperventilation. Moreover, LKB1, but not AMPK, deficiency causes Cheyne-Stokes-like breathing. This chapter will explore further the possible mechanisms that determine these outcomes.
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Affiliation(s)
- A Mark Evans
- Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.
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24
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Sun B, Sherrin M, Roy R. Unscheduled epigenetic modifications cause genome instability and sterility through aberrant R-loops following starvation. Nucleic Acids Res 2022; 51:84-98. [PMID: 36504323 PMCID: PMC9841415 DOI: 10.1093/nar/gkac1155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
During starvation, organisms modify both gene expression and metabolism to adjust to the energy stress. We previously reported that Caenorhabditis elegans lacing AMP-activated protein kinase (AMPK) exhibit transgenerational reproductive defects associated with abnormally elevated trimethylated histone H3 at lysine 4 (H3K4me3) levels in the germ line following recovery from acute starvation. Here, we show that these H3K4me3 marks are significantly increased at promoters, driving aberrant transcription elongation resulting in the accumulation of R-loops in starved AMPK mutants. DNA-RNA immunoprecipitation followed by high-throughput sequencing (DRIP-seq) analysis demonstrated that a significant proportion of the genome was affected by R-loop formation. This was most pronounced in the promoter-transcription start site regions of genes, in which the chromatin was modified by H3K4me3. Like H3K4me3, the R-loops were also found to be heritable, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK mutant germ lines show considerably more RAD-51 (the RecA recombinase) foci at sites of R-loop formation, potentially sequestering them from their roles at meiotic breaks or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation. The downstream effects of R-loops on DNA damage sensitivity and germline stem cell integrity may account for inappropriate epigenetic modification that occurs in numerous human disorders, including various cancers.
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Affiliation(s)
- Bing Sun
- To whom correspondence should be addressed.
| | - McLean Sherrin
- Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada
| | - Richard Roy
- Correspondence may also be addressed to Richard Roy. Tel: +1 514 398 6437;
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25
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Ma Q, Li X, Wang S, Wang Q, Li Y, Li K, Wang J, Zhang Q, Wu J, Chen H. Niche-Dependent Regulation of Lkb1 in the Proliferation of Lung Epithelial Progenitor Cells. Int J Mol Sci 2022; 23:15065. [PMID: 36499390 PMCID: PMC9735896 DOI: 10.3390/ijms232315065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Lung homeostasis and regeneration depend on lung epithelial progenitor cells. Lkb1 (Liver Kinase B1) has known roles in the differentiation of airway epithelial cells during embryonic development. However, the effects of Lkb1 in adult lung epithelial progenitor cell regeneration and its mechanisms of action have not been determined. In this study, we investigated the mechanism by which Lkb1 regulates lung epithelial progenitor cell regeneration. Organoid culture showed that loss of Lkb1 significantly reduced the proliferation of club cells and alveolar type 2 (AT2) cells in vitro. In the absence of Lkb1, there is a slower recovery rate of the damaged airway epithelium in naphthalene-induced airway epithelial injury and impaired expression of surfactant protein C during bleomycin-induced alveolar epithelial damage. Moreover, the expression of autophagy-related genes was reduced in club cells and increased in AT2 cells, but the expression of Claudin-18 was obviously reduced in AT2 cells after Lkb1 knockdown. On the whole, our findings indicated that Lkb1 may promote the proliferation of lung epithelial progenitor cells via a niche-dependent pathway and is required for the repair of the damaged lung epithelium.
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Affiliation(s)
- Qingwen Ma
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
| | - Xue Li
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Sisi Wang
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
| | - Qi Wang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Yu Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Kuan Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Jianhai Wang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Qiuyang Zhang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Junping Wu
- Department of Tuberculosis, Haihe Hospital, Tianjin University, Jinnan District, Tianjin 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Jinnan District, Tianjin 300350, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Jinnan District, Tianjin 300350, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Jinnan District, Tianjin 300350, China
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26
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White Z, Elagib KE, Gru AA, Goldfarb AN. Liver kinase B1 (LKB1) in murine erythroid progenitors modulates erythropoietin setpoint in association with maturation control. Blood Cells Mol Dis 2022; 97:102688. [PMID: 35717902 PMCID: PMC9436178 DOI: 10.1016/j.bcmd.2022.102688] [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: 04/21/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 11/18/2022]
Abstract
Erythropoiesis is a tightly regulated process. It is stimulated by decreased oxygen in circulation, which leads to the secretion of the hormone erythropoietin (Epo) by the kidneys. An additional layer of control involves the coordinated sensing and use of nutrients. Much cellular machinery contributes to sensing and responding to nutrient status in cells, and one key participant is the kinase LKB1. The current study examines the role of LKB1 in erythropoiesis using a murine in vivo and ex vivo conditional knockout system. In vivo analysis showed erythroid loss of LKB1 to be associated with a robust increase in serum Epo and mild reticulocytosis. Despite these abnormalities, no evidence of anemia or hemolysis was found. Further characterization using an ex vivo progenitor culture assay demonstrated accelerated erythroid maturation in the LKB1-deficient cells. Based on pharmacologic evidence, this phenotype appeared to result from impaired AMP-activated protein kinase (AMPK) signaling downstream of LKB1. These findings reveal a role for LKB1 in fine-tuning Epo-driven erythropoiesis in association with maturational control.
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Affiliation(s)
- Zollie White
- Department of Pathology, University of Virginia School of Medicine, USA
| | | | - Alejandro A Gru
- Department of Pathology, University of Virginia School of Medicine, USA
| | - Adam N Goldfarb
- Department of Pathology, University of Virginia School of Medicine, USA.
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27
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Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness. Blood 2022; 140:1686-1701. [PMID: 35881840 DOI: 10.1182/blood.2022016112] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 07/20/2022] [Indexed: 11/20/2022] Open
Abstract
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
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28
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Pereverzeva L, Otto NA, Roelofs JJTH, de Vos AF, van der Poll T. Myeloid liver kinase B1 contributes to lung inflammation induced by lipoteichoic acid but not by viable Streptococcus pneumoniae. Respir Res 2022; 23:241. [PMID: 36096803 PMCID: PMC9465928 DOI: 10.1186/s12931-022-02168-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 09/05/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Liver kinase B1 (Lkb1, gene name Stk11) functions as a tumor suppressor in cancer. Myeloid cell Lkb1 potentiates lung inflammation induced by the Gram-negative bacterial cell wall component lipopolysaccharide and in host defense during Gram-negative pneumonia. Here, we sought to investigate the role of myeloid Lkb1 in lung inflammation elicited by the Gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during pneumonia caused by the Gram-positive respiratory pathogen Streptococcus pneumoniae (Spneu).
Methods
Alveolar and bone marrow derived macrophages (AMs, BMDMs) harvested from myeloid-specific Lkb1 deficient (Stk11-ΔM) and littermate control mice were stimulated with LTA or Spneu in vitro. Stk11-ΔM and control mice were challenged via the airways with LTA or infected with Spneu in vivo.
Results
Lkb1 deficient AMs and BMDMs produced less tumor necrosis factor (TNF)α upon activation by LTA or Spneu. During LTA-induced lung inflammation, Stk11-ΔM mice had reduced numbers of AMs in the lungs, as well as diminished cytokine release and neutrophil recruitment into the airways. During pneumonia induced by either encapsulated or non-encapsulated Spneu, Stk11-ΔM and control mice had comparable bacterial loads and inflammatory responses in the lung, with the exception of lower TNFα levels in Stk11-ΔM mice after infection with the non-encapsulated strain.
Conclusion
Myeloid Lkb1 contributes to LTA-induced lung inflammation, but is not important for host defense during pneumococcal pneumonia.
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Fujino T, Asada S, Goyama S, Kitamura T. Mechanisms involved in hematopoietic stem cell aging. Cell Mol Life Sci 2022; 79:473. [PMID: 35941268 PMCID: PMC11072869 DOI: 10.1007/s00018-022-04356-5] [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: 01/28/2022] [Revised: 04/27/2022] [Accepted: 05/05/2022] [Indexed: 11/03/2022]
Abstract
Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.
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Affiliation(s)
- Takeshi Fujino
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Shuhei Asada
- The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, 1628666, Japan
| | - Susumu Goyama
- Division of Molecular Oncology Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 1088639, Japan
| | - Toshio Kitamura
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
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30
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Park SR, Kim SK, Kim SR, Yu WJ, Lee SJ, Lee HY. Effects of smoking on the tissue regeneration-associated functions of human endometrial stem cells via a novel target gene SERPINB2. Stem Cell Res Ther 2022; 13:404. [PMID: 35932085 PMCID: PMC9356492 DOI: 10.1186/s13287-022-03061-1] [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: 03/23/2022] [Accepted: 07/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Smokers directly inhale mainstream cigarette smoke, which contains numerous known and potential toxic substances, and thus, smoking is expected to have broad harmful effects that cause tissue injury and dysfunction. Interestingly, many studies have suggested that the recent decline in female fertility and increased rate of spontaneous abortion could be associated with increased smoking rates. Indeed, women that smoked for 10 years or more were reported to have a ~ 20% higher infertility rate than women that had never smoked. However, the reasons for the underlying harmful aspects of smoking on female fertility remain a matter of debate. Importantly, a previous study revealed that resident endometrial stem cell deficiency significantly limits the cyclic regeneration potential of endometrium, which, in turn, decreases successful pregnancy outcomes. In this context, we postulated that exposure to mainstream cigarette smoke extracts might decrease female fertility by inhibiting the functions of resident endometrial stem cells. METHODS We investigated whether cigarette mainstream smoke exposure directly inhibits various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, pluripotency, and differentiation capacity in vitro. Next, we determined whether SERPINB2 mediates cigarette smoke-induced suppressive effects on various tissue regeneration-associated functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. Mice were injected intraperitoneally with low (0.5 mg/kg) or high (1 mg/kg) doses of cigarette smoke extract (10 times for two weeks), and endometrial stem cells were then isolated from mice uterine tissues. RESULTS We found that exposure to cigarette smoke extracts remarkably suppressed various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, multilineage differentiation ability, and pluripotency in vitro and in vivo by activating the SERPINB2 gene. Indeed, cigarette smoke-induced inhibitory effects on various endometrial stem cell functions were significantly abolished by SERPINB2 knockdown. CONCLUSIONS These findings provide valuable information on the harmful effects of cigarette smoking on resident endometrial stem cells and hopefully will facilitate the developments of promising therapeutic strategies for subfertile or infertile women that smoke cigarettes.
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Affiliation(s)
- Se-Ra Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Seong-Kwan Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Soo-Rim Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Wook-Joon Yu
- Developmental and Reproductivoxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Seung-Jin Lee
- Developmental and Reproductivoxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Hwa-Yong Lee
- Division of Science Education, Kangwon National University, Chuncheon, 24341, Republic of Korea.
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31
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An Q, Lin R, Wang D, Wang C. Emerging roles of fatty acid metabolism in cancer and their targeted drug development. Eur J Med Chem 2022; 240:114613. [PMID: 35853429 DOI: 10.1016/j.ejmech.2022.114613] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 11/30/2022]
Abstract
Metabolic reprogramming is now considered as one of hallmark of tumor cells and provides them with a selective survival/growth advantage to resist harsh micro-environmental stress. Fatty acid (FA) metabolism of tumor cells supports the biosynthetic needs and provides fuel sources for energy supply. Since FA metabolic reprogramming is a critical link in tumor metabolism, its various roles in tumors have attracted increasing interest. Herein, we review the mechanisms through which cancer cells rewire their FA metabolism with a focus on the pathway of FA metabolism and its targeting drug development. The failure and successful cases of targeting tumor FA metabolism are expected to bypass the metabolic vulnerability and improve the efficacy of targeted therapy.
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Affiliation(s)
- Qi An
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, 377 Jingming Road, Jinjiang District, Chengdu, Sichuan, 610061, China
| | - Rui Lin
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, 377 Jingming Road, Jinjiang District, Chengdu, Sichuan, 610061, China
| | - Dongmei Wang
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, 377 Jingming Road, Jinjiang District, Chengdu, Sichuan, 610061, China
| | - Chuan Wang
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, 377 Jingming Road, Jinjiang District, Chengdu, Sichuan, 610061, China.
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32
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Park SR, Kim SK, Kim SR, Park JR, Lim S, Hong IS. Novel roles of luteinizing hormone (LH) in tissue regeneration-associated functions in endometrial stem cells. Cell Death Dis 2022; 13:605. [PMID: 35831270 PMCID: PMC9279474 DOI: 10.1038/s41419-022-05054-7] [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: 11/01/2021] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 01/21/2023]
Abstract
Luteinizing hormone (LH) stimulates the synthesis and secretion of the key steroid hormone estrogen, which subsequently promotes ovarian follicular growth and development. Therefore, the administration of exogenous LH to achieve superovulation (multiple ovulations) and an LH surge is commonly used as the most effective therapeutic option in a majority of in vitro fertilization (IVF) clinics. However, a relatively low pregnancy rate (between 20% and 35%) is one of the most challenging aspects of LH-based infertility treatment. Furthermore, the major cause of this low pregnancy rate in LH-based infertility treatment remains unidentified. Recent studies have shown that endometrial stem cell loss or deficiency can significantly decrease tissue regeneration ability during the menstrual cycle and reduce endometrial receptivity. In this context, we postulated that the low pregnancy rates following LH-based ovarian hyperactivation may be the result of the adverse effects of consecutive exogenous LH administration on endometrial stem cells. To the best of our knowledge, this study revealed for the first time that in addition to its previously reported roles in stimulating ovarian functions through the pituitary-gonadal axis, LH brings about the extragonadal suppression of various tissue regeneration-associated functions in endometrial stem cells, such as self-renewal, migration ability, multilineage differentiation potential, and pluripotency/stemness, by inhibiting pro-survival Akt and ERK1/2 signaling pathways in vitro and in vivo, and as a consequence, it decreases the endometrial receptivity.
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Affiliation(s)
- Se-Ra Park
- grid.256155.00000 0004 0647 2973Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999 Republic of Korea ,grid.256155.00000 0004 0647 2973Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840 Republic of Korea
| | - Seong-Kwan Kim
- grid.256155.00000 0004 0647 2973Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999 Republic of Korea ,grid.256155.00000 0004 0647 2973Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840 Republic of Korea
| | - Soo-Rim Kim
- grid.256155.00000 0004 0647 2973Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999 Republic of Korea ,grid.256155.00000 0004 0647 2973Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840 Republic of Korea
| | - Jeong-Ran Park
- grid.412010.60000 0001 0707 9039Division of Science Education, Kangwon National University, Chuncheon, 24341 Republic of Korea
| | - Soyi Lim
- grid.411653.40000 0004 0647 2885Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - In-Sun Hong
- grid.256155.00000 0004 0647 2973Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999 Republic of Korea ,grid.256155.00000 0004 0647 2973Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840 Republic of Korea
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33
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Li C, Wu B, Li Y, Chen J, Ye Z, Tian X, Wang J, Xu X, Pan S, Zheng Y, Cai X, Jiang L, Zhao M. Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis. Cell Stem Cell 2022; 29:1119-1134.e7. [PMID: 35803229 DOI: 10.1016/j.stem.2022.06.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/28/2022] [Accepted: 06/08/2022] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD+ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.
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Affiliation(s)
- Changzheng Li
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Binghuo Wu
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Yishan Li
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Jie Chen
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Zhitao Ye
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Xiaobin Tian
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Jin Wang
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Xi Xu
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Shuai Pan
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Yucan Zheng
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Xiongwei Cai
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing 404100, China
| | - Linjia Jiang
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China
| | - Meng Zhao
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
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LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response. Commun Biol 2022; 5:642. [PMID: 35768580 PMCID: PMC9243028 DOI: 10.1038/s42003-022-03583-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 06/14/2022] [Indexed: 11/08/2022] Open
Abstract
The hypoxic ventilatory response (HVR) is critical to breathing and thus oxygen supply to the body and is primarily mediated by the carotid bodies. Here we reveal that carotid body afferent discharge during hypoxia and hypercapnia is determined by the expression of Liver Kinase B1 (LKB1), the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK had no effect on carotid body responses to hypoxia or hypercapnia. By contrast, the HVR was attenuated by LKB1 and AMPK deletion. However, in LKB1 knockouts hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, while only hypoventilation and apnoea were observed after AMPK deletion. We therefore identify LKB1 as an essential regulator of carotid body chemosensing and uncover a divergence in dependency on LKB1 and AMPK between the carotid body on one hand and the HVR on the other.
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35
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Mann Z, Sengar M, Verma YK, Rajalingam R, Raghav PK. Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects. Front Cell Dev Biol 2022; 10:664261. [PMID: 35399522 PMCID: PMC8987924 DOI: 10.3389/fcell.2022.664261] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 02/14/2022] [Indexed: 01/29/2023] Open
Abstract
Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.
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Affiliation(s)
- Zoya Mann
- Independent Researcher, New Delhi, India
| | - Manisha Sengar
- Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Yogesh Kumar Verma
- Stem Cell and Gene Therapy Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, India
| | - Raja Rajalingam
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Pawan Kumar Raghav
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
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36
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Naidu SR, Capitano M, Ropa J, Cooper S, Huang X, Broxmeyer HE. Chromatin remodeling subunit BRM and valine regulate hematopoietic stem/progenitor cell function and self-renewal via intrinsic and extrinsic effects. Leukemia 2022; 36:821-833. [PMID: 34599272 PMCID: PMC9212754 DOI: 10.1038/s41375-021-01426-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
Little is known of hematopoietic stem (HSC) and progenitor (HPC) cell self-renewal. The role of Brahma (BRM), a chromatin remodeler, in HSC function is unknown. Bone marrow (BM) from Brm-/- mice manifested increased numbers of long- and short-term HSCs, GMPs, and increased numbers and cycling of functional HPCs. However, increased Brm-/- BM HSC numbers had decreased secondary and tertiary engraftment, suggesting BRM enhances HSC self-renewal. Valine was elevated in lineage negative Brm-/- BM cells, linking intracellular valine with Brm expression. Valine enhanced HPC colony formation, replating of human cord blood (CB) HPC-derived colonies, mouse BM and human CB HPC survival in vitro, and ex vivo expansion of normal mouse BM HSCs and HPCs. Valine increased oxygen consumption rates of WT cells. BRM through CD98 was linked to regulated import of branched chain amino acids, such as valine, in HPCs. Brm-/- LSK cells exhibited upregulated interferon response/cell cycle gene programs. Effects of BRM depletion are less apparent on isolated HSCs compared to HSCs in the presence of HPCs, suggesting cell extrinsic effects on HSCs. Thus, intracellular valine is regulated by BRM expression in HPCs, and the BRM/valine axis regulates HSC and HPC self-renewal, proliferation, and possibly differentiation fate decisions.
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Affiliation(s)
- Samisubbu R. Naidu
- Medicine, Indiana University School of Medicine,Indiana University School of Medicine, Department of Microbiology/Immunology, 950 West Walnut Street, Bldg. R2, Room 302, Indianapolis, IN 46202, Indiana University School of Medicine, Department of Medicine, 950 West Walnut Street, Bldg. R2, Room E435,These authors contributed equally to this work
| | - Maegan Capitano
- Departments of Microbiology and Immunology, Indiana University School of Medicine,These authors contributed equally to this work
| | - James Ropa
- Departments of Microbiology and Immunology, Indiana University School of Medicine,These authors contributed equally to this work
| | - Scott Cooper
- Departments of Microbiology and Immunology, Indiana University School of Medicine
| | - Xinxin Huang
- Departments of Microbiology and Immunology, Indiana University School of Medicine
| | - Hal E. Broxmeyer
- Departments of Microbiology and Immunology, Indiana University School of Medicine,Indiana University School of Medicine, Department of Microbiology/Immunology, 950 West Walnut Street, Bldg. R2, Room 302, Indianapolis, IN 46202, Indiana University School of Medicine, Department of Medicine, 950 West Walnut Street, Bldg. R2, Room E435
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Abstract
Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
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38
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Pre-Transplant Serum Leptin Levels and Relapse of Acute Myeloid Leukemia after Allogeneic Transplantation. Int J Mol Sci 2022; 23:ijms23042337. [PMID: 35216457 PMCID: PMC8879842 DOI: 10.3390/ijms23042337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/09/2022] [Accepted: 02/16/2022] [Indexed: 01/27/2023] Open
Abstract
Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59–0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT.
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Potential for Prebiotic Stabilized Cornus mas L. Lyophilized Extract in the Prophylaxis of Diabetes Mellitus in Streptozotocin Diabetic Rats. Antioxidants (Basel) 2022; 11:antiox11020380. [PMID: 35204262 PMCID: PMC8868578 DOI: 10.3390/antiox11020380] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/16/2022] Open
Abstract
As a systemic disease, diabetes mellitus (DM) is characterized by the disruption of many glucose metabolic pathways. Therefore, it seems critical to study new therapies to support treatment to develop therapeutic systems that can operate across a broad metabolic spectrum. The current state of knowledge indicates an essential role of the gut microbiota in the development and course of the disease. Cornus mas fruits have demonstrated a rich biological activity profile and potential for application in the treatment of DM. As part of a preliminary analysis, the activity of four cultivars of Cornus mas fruits was analyzed. The cultivar Wydubieckij was selected as having the highest activity in in vitro conditions for further prebiotic system preparation. The study aimed to develop a unique therapeutic system based, first of all, on the mechanism of α-glucosidase inhibition and the antioxidant effect resulting from the activity of the plant extract used, combined with the prebiotic effect of inulin. The obtained system was characterized in vitro in terms of antioxidant activity and enzyme inhibition capacity, and was then tested on diabetic rats. The study was coupled with an analysis of changes in the intestinal microflora. The system of prebiotic stabilized Cornus mas L. lyophilized extract with inulin offers valuable support for the prophylaxis and treatment of DM.
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Zhao Q, Han YM, Song P, Liu Z, Yuan Z, Zou MH. Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation. Nat Commun 2022; 13:648. [PMID: 35115536 PMCID: PMC8814147 DOI: 10.1038/s41467-022-28316-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 11/29/2021] [Indexed: 11/19/2022] Open
Abstract
In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 (Stk11) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor (Scf) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11-soluble-Scf axis as a potential cause of DC deficiency syndromes.
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Affiliation(s)
- Qiang Zhao
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Young-Min Han
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA
| | - Zhixue Liu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA
| | - Zuyi Yuan
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA.
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Zhao K, Liu J, Zhu Y, Dong X, Yin R, Liu X, Gao H, Xiao F, Gao R, Wang Q, Zhan Y, Yu M, Chen H, Ning H, Zhang C, Yang X, Li C. Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN-γ Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103838. [PMID: 34923767 PMCID: PMC8844507 DOI: 10.1002/advs.202103838] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/14/2021] [Indexed: 06/14/2023]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn-/- HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn-/- HSPCs are enriched for gene sets related to interferon gamma (IFN-γ) signaling. Hemgn-/- HSPCs show enhanced responses to IFN-γ treatment and increased aging over time. Blocking IFN-γ signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn-/- HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-γ-treated Hemgn-/- mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-γ signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.
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Affiliation(s)
- Ke Zhao
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Jin‐Fang Liu
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Ya‐Xin Zhu
- School of Life SciencesHebei UniversityNo. 180 Wusi Dong Road, Lian Chi DistrictBaoding CityHebei Province071000China
| | - Xiao‐Ming Dong
- College of Life SciencesShanxi Normal UniversityNo. 199, South Chang'an Road, Yanta DistrictXi'an710062China
| | - Rong‐Hua Yin
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Xian Liu
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Hui‐Ying Gao
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Feng‐Jun Xiao
- Department of Experimental Hematology and BiochemistryBeijing Institute of Radiation MedicineBeijing100850China
| | - Rui Gao
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Qi Wang
- An Hui Medical UniversitySchool of Basic Medical SciencesHefei230032China
| | - Yi‐Qun Zhan
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Miao Yu
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Hui Chen
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Hong‐Mei Ning
- Department of Hematopoietic Stem Cell TransplantationThe Fifth Medical Center of Chinese PLA General HospitalBeijing100071China
| | - Cai‐Bo Zhang
- Department of Life SciencesQilu Normal UniversityNo. 2, Wenbo Road, Zhangqiu DistrictJinanShandong250013China
| | - Xiao‐Ming Yang
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
| | - Chang‐Yan Li
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijing102206China
- School of Life SciencesHebei UniversityNo. 180 Wusi Dong Road, Lian Chi DistrictBaoding CityHebei Province071000China
- An Hui Medical UniversitySchool of Basic Medical SciencesHefei230032China
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Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism. Stem Cell Reports 2022; 17:599-615. [PMID: 35148846 PMCID: PMC9039836 DOI: 10.1016/j.stemcr.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 01/13/2022] [Accepted: 01/13/2022] [Indexed: 01/25/2023] Open
Abstract
Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c-/-) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.
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Zhang Y, Wu Z, Xi P, Wang H, Zhu W, Tian D. LKB1 on POMC neurons affect the formation of diet-induced obesity by regulating the expression of HDAC1. Genes Genomics 2022; 44:467-475. [DOI: 10.1007/s13258-021-01206-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/08/2021] [Indexed: 11/04/2022]
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Kis D, Csordás IB, Persa E, Jezsó B, Hargitai R, Szatmári T, Sándor N, Kis E, Balázs K, Sáfrány G, Lumniczky K. Extracellular Vesicles Derived from Bone Marrow in an Early Stage of Ionizing Radiation Damage Are Able to Induce Bystander Responses in the Bone Marrow. Cells 2022; 11:cells11010155. [PMID: 35011718 PMCID: PMC8750882 DOI: 10.3390/cells11010155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 02/01/2023] Open
Abstract
Ionizing radiation (IR)-induced bystander effects contribute to biological responses to radiation, and extracellular vesicles (EVs) play important roles in mediating these effects. In this study we investigated the role of bone marrow (BM)-derived EVs in the bystander transfer of radiation damage. Mice were irradiated with 0.1Gy, 0.25Gy and 2Gy, EVs were extracted from the BM supernatant 24 h or 3 months after irradiation and injected into bystander mice. Acute effects on directly irradiated or EV-treated mice were investigated after 4 and 24 h, while late effects were investigated 3 months after treatment. The acute effects of EVs on the hematopoietic stem and progenitor cell pools were similar to direct irradiation effects and persisted for up to 3 months, with the hematopoietic stem cells showing the strongest bystander responses. EVs isolated 3 months after irradiation elicited no bystander responses. The level of seven microRNAs (miR-33a-3p, miR-140-3p, miR-152-3p, miR-199a-5p, miR-200c-5p, miR-375-3p and miR-669o-5p) was altered in the EVs isolated 24 hour but not 3 months after irradiation. They regulated pathways highly relevant for the cellular response to IR, indicating their role in EV-mediated bystander responses. In conclusion, we showed that only EVs from an early stage of radiation damage could transmit IR-induced bystander effects.
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Affiliation(s)
- Dávid Kis
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
- Doctoral School of Pathological Sciences, Semmelweis University, 1085 Budapest, Hungary
| | - Ilona Barbara Csordás
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Eszter Persa
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Bálint Jezsó
- Doctoral School of Biology and Institute of Biology, Eötvös Loránd University, 1053 Budapest, Hungary;
- Research Centre for Natural Sciences, Institute of Enzymology, 1117 Budapest, Hungary
| | - Rita Hargitai
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Tünde Szatmári
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Nikolett Sándor
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Enikő Kis
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Katalin Balázs
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
- Doctoral School of Pathological Sciences, Semmelweis University, 1085 Budapest, Hungary
| | - Géza Sáfrány
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
| | - Katalin Lumniczky
- National Public Health Center, Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, 1097 Budapest, Hungary; (D.K.); (I.B.C.); (E.P.); (R.H.); (T.S.); (N.S.); (E.K.); (K.B.); (G.S.)
- Correspondence:
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Kim Y, Lee S, Kim S, Kim TY, Lee SH, Chang JH, Kweon MN. LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production. Cell Mol Gastroenterol Hepatol 2021; 13:1121-1139. [PMID: 34973477 PMCID: PMC8873961 DOI: 10.1016/j.jcmgh.2021.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis. METHODS We generated mice with IEC-specific deletion of LKB1 (LKB1ΔIEC) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, metagenomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis. RESULTS LKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1ΔIEC mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA synthesis, was found in the small intestine (SI) ileum of LKB1ΔIEC mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-βMCA) were observed in the SI of LKB1ΔIEC mice. Moreover, LKB1ΔIEC mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1ΔIEC mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure. CONCLUSIONS LKB1 in IECs manages BA homeostasis by controlling FGF15/19 production.
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Affiliation(s)
- Yeji Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sohyeon Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungil Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae-Young Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su-Hyun Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Correspondence Address correspondence to: Dr Mi-Na Kweon, Asan Medical Center, Department of Convergence Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505 Republic of Korea. tel: 82-2-3010-2096.
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Li Y, Zhang Q, Li L, Hao D, Cheng P, Li K, Li X, Wang J, Wang Q, Du Z, Ji H, Chen H. LKB1 deficiency upregulates RELM-α to drive airway goblet cell metaplasia. Cell Mol Life Sci 2021; 79:42. [PMID: 34921639 PMCID: PMC8738459 DOI: 10.1007/s00018-021-04044-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 02/08/2023]
Abstract
Targeting airway goblet cell metaplasia is a novel strategy that can potentially reduce the chronic obstructive pulmonary disease (COPD) symptoms. Tumor suppressor liver kinase B1 (LKB1) is an important regulator of the proliferation and differentiation of stem/progenitor cells. In this study, we report that LKB1 expression was downregulated in the lungs of patients with COPD and in those of cigarette smoke-exposed mice. Nkx2.1Cre; Lkb1f/f mice with conditional loss of Lkb1 in mouse lung epithelium displayed airway mucus hypersecretion and pulmonary macrophage infiltration. Single-cell transcriptomic analysis of the lung tissues from Nkx2.1Cre; Lkb1f/f mice further revealed that airway goblet cell differentiation was altered in the absence of LKB1. An organoid culture study demonstrated that Lkb1 deficiency in mouse airway (club) progenitor cells promoted the expression of FIZZ1/RELM-α, which drove airway goblet cell differentiation and pulmonary macrophage recruitment. Additionally, monocyte-derived macrophages in the lungs of Nkx2.1Cre; Lkb1f/f mice exhibited an alternatively activated M2 phenotype, while expressing RELM-α, which subsequently aggravated airway goblet cell metaplasia. Our findings suggest that the LKB1-mediated crosstalk between airway progenitor cells and macrophages regulates airway goblet cell metaplasia. Moreover, our data suggest that LKB1 agonists might serve as a potential therapeutic option to treat respiratory disorders associated with goblet cell metaplasia.
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Affiliation(s)
- Yu Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Qiuyang Zhang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Li Li
- Department of Respiratory Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - De Hao
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
| | - Peiyong Cheng
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
| | - Kuan Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Xue Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Jianhai Wang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Qi Wang
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
| | - Zhongchao Du
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China
| | - Hongbin Ji
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, 300350, China.
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China.
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China.
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China.
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Sarwar Z, Nabi N, Bhat SA, Gillani SQ, Reshi I, Un Nisa M, Adelmant G, Marto J, Andrabi S. Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis. J Biol Chem 2021; 298:101496. [PMID: 34921839 PMCID: PMC8784333 DOI: 10.1016/j.jbc.2021.101496] [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: 05/15/2021] [Revised: 11/09/2021] [Accepted: 12/10/2021] [Indexed: 12/05/2022] Open
Abstract
Deleted in Breast Cancer 1 (DBC1) is an important metabolic sensor. Previous studies have implicated DBC1 in various cellular functions, notably cell proliferation, apoptosis, histone modification, and adipogenesis. However, current reports about the role of DBC1 in tumorigenesis are controversial and designate DBC1 alternatively as a tumor suppressor or a tumor promoter. In the present study, we report that polyoma small T antigen (PyST) associates with DBC1 in mammalian cells, and this interaction leads to the posttranslational downregulation of DBC1 protein levels. When coexpressed, DBC1 overcomes PyST-induced mitotic arrest and promotes the exit of cells from mitosis. Using both transient and stable modes of PyST expression, we also show that cellular DBC1 is subjected to degradation by LKB1, a tumor suppressor and cellular energy sensor kinase, in an AMP kinase-independent manner. Moreover, LKB1 negatively regulates the phosphorylation as well as activity of the prosurvival kinase AKT1 through DBC1 and its downstream pseudokinase substrate, Tribbles 3 (TRB3). Using both transient transfection and stable cell line approaches as well as soft agar assay, we demonstrate that DBC1 has oncogenic potential. In conclusion, our study provides insight into a novel signaling axis that connects LKB1, DBC1, TRB3, and AKT1. We propose that the LKB1–DBC1–AKT1 signaling paradigm may have an important role in the regulation of cell cycle and apoptosis and consequently tumorigenesis.
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Affiliation(s)
- Zarka Sarwar
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006
| | - Nusrat Nabi
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006
| | - Sameer Ahmed Bhat
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006
| | | | - Irfana Reshi
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006
| | - Misbah Un Nisa
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006
| | - Guillaume Adelmant
- Blais Proteomics Centre, Dana Farber Cancer Institute, Harvard University, Boston, USA
| | - Jarrod Marto
- Blais Proteomics Centre, Dana Farber Cancer Institute, Harvard University, Boston, USA
| | - Shaida Andrabi
- Department of Biochemistry, University of Kashmir, Srinagar, India, 190006.
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48
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Ala M, Ala M. Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next? ACS Pharmacol Transl Sci 2021; 4:1747-1770. [PMID: 34927008 DOI: 10.1021/acsptsci.1c00167] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Indexed: 12/15/2022]
Abstract
Diabetes is accompanied by several complications. Higher prevalence of cancers, cardiovascular diseases, chronic kidney disease (CKD), obesity, osteoporosis, and neurodegenerative diseases has been reported among patients with diabetes. Metformin is the oldest oral antidiabetic drug and can improve coexisting complications of diabetes. Clinical trials and observational studies uncovered that metformin can remarkably prevent or alleviate cardiovascular diseases, obesity, polycystic ovarian syndrome (PCOS), osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and COVID-19. In addition, metformin has been proposed as an antiaging agent. Numerous mechanisms were shown to be involved in the protective effects of metformin. Metformin activates the LKB1/AMPK pathway to interact with several intracellular signaling pathways and molecular mechanisms. The drug modifies the biologic function of NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/β-catenin, Nrf2, JNK, and other major molecules in the intracellular signaling network. It also regulates the expression of noncoding RNAs. Thereby, metformin can regulate metabolism, growth, proliferation, inflammation, tumorigenesis, and senescence. Additionally, metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects. Furthermore, metformin protects against oxidative stress and genomic instability, preserves telomere length, and prevents stem cell exhaustion. In this review, the protective effects of metformin on each disease will be discussed using the results of recent meta-analyses, clinical trials, and observational studies. Thereafter, it will be meticulously explained how metformin reprograms intracellular signaling pathways and alters molecular and cellular interactions to modify the clinical presentations of several diseases.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), 1416753955 Tehran, Iran
| | - Mahan Ala
- School of Dentistry, Golestan University of Medical Sciences (GUMS), 4814565589 Golestan, Iran
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49
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Schuster T, Geiger H. Septins in Stem Cells. Front Cell Dev Biol 2021; 9:801507. [PMID: 34957123 PMCID: PMC8695968 DOI: 10.3389/fcell.2021.801507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/24/2021] [Indexed: 12/01/2022] Open
Abstract
Septins were first described in yeast. Due to extensive research in non-yeast cells, Septins are now recognized across all species as important players in the regulation of the cytoskeleton, in the establishment of polarity, for migration, vesicular trafficking and scaffolding. Stem cells are primarily quiescent cells, and this actively maintained quiescent state is critical for proper stem cell function. Equally important though, stem cells undergo symmetric or asymmetric division, which is likely linked to the level of symmetry found in the mother stem cell. Due to the ability to organize barriers and be able to break symmetry in cells, Septins are thought to have a significant impact on organizing quiescence as well as the mode (symmetric vs asymmetric) of stem cell division to affect self-renewal versus differentiation. Mechanisms of regulating mammalian quiescence and symmetry breaking by Septins are though still somewhat elusive. Within this overview article, we summarize current knowledge on the role of Septins in stem cells ranging from yeast to mice especially with respect to quiescence and asymmetric division, with a special focus on hematopoietic stem cells.
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Affiliation(s)
| | - Hartmut Geiger
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
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50
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Park SR, Lee JW, Kim SK, Yu WJ, Lee SJ, Kim D, Kim KW, Jung JW, Hong IS. The impact of fine particulate matter (PM) on various beneficial functions of human endometrial stem cells through its key regulator SERPINB2. Exp Mol Med 2021; 53:1850-1865. [PMID: 34857902 PMCID: PMC8741906 DOI: 10.1038/s12276-021-00713-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/30/2021] [Accepted: 09/29/2021] [Indexed: 12/25/2022] Open
Abstract
Fine particulate matter (PM) has a small diameter but a large surface area; thus, it may have broad toxic effects that subsequently damage many tissues of the human body. Interestingly, many studies have suggested that the recent decline in female fertility could be associated with increased PM exposure. However, the precise mechanisms underlying the negative effects of PM exposure on female fertility are still a matter of debate. A previous study demonstrated that resident stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases the pregnancy failure rate. Therefore, we hypothesized that PM exposure induces endometrial tissue damage and subsequently reduces the pregnancy rate by inhibiting various beneficial functions of local endometrial stem cells. Consistent with our hypothesis, we showed for the first time that PM exposure significantly inhibits various beneficial functions of endometrial stem cells, such as their self-renewal, transdifferentiation, and migratory capacities, in vitro and in vivo through the PM target gene SERPINB2, which has recently been shown to be involved in multiple stem cell functions. In addition, the PM-induced inhibitory effects on the beneficial functions of endometrial stem cells were significantly diminished by SERPINB2 depletion. Our findings may facilitate the development of promising therapeutic strategies for improving reproductive outcomes in infertile women. Airborne pollutants may reduce female fertility through their debilitating effects on the stem cells that maintain the endometrium, the interior lining of the uterus. Recent evidence suggests that toxic byproducts from fossil fuels known as ‘particulate matter’ represent a danger to women’s reproductive health. South Korean researchers led by Ji-Won Jung, Korea Centers for Disease Control and Prevention, and In-Sun Hong, Gachon University, Incheon, have investigated this risk by exposing cultured human endometrial stem cells to diesel-derived particulate matter. These stem cells normally maintain the endometrium, allowing embryonic implantation to take place, but exposure to particulate matter greatly impaired the cells’ regenerative function. Mice exposed to particulate matter exhibited similar impairments of endometrial maintenance. The researchers identified a molecular pathway associated with this response that could guide development of fertility-restoring treatments.
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Affiliation(s)
- Se-Ra Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Joong Won Lee
- Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongwon-gun, Republic of Korea
| | - Seong-Kwan Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Wook-Joon Yu
- Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Seung-Jin Lee
- Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Doojin Kim
- Department of Surgery, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Republic of Korea
| | - Kun-Woo Kim
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Ji-Won Jung
- Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongwon-gun, Republic of Korea.
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea. .,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
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