|
1
|
Yue F, Gu L, Qiu J, Oprescu SN, Beckett LM, Ellis JM, Donkin SS, Kuang S. Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation. EMBO J 2025; 44:2566-2595. [PMID: 40065099 PMCID: PMC12048568 DOI: 10.1038/s44318-025-00397-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/31/2025] [Accepted: 02/10/2025] [Indexed: 05/04/2025] Open
Abstract
During homeostasis and regeneration, satellite cells, the resident stem cells of skeletal muscle, have distinct metabolic requirements for fate transitions between quiescence, proliferation and differentiation. However, the contribution of distinct energy sources to satellite cell metabolism and function remains largely unexplored. Here, we uncover a role of mitochondrial fatty acid oxidation (FAO) in satellite cell integrity and function. Single-cell RNA sequencing revealed progressive enrichment of mitochondrial FAO and downstream pathways during activation, proliferation and myogenic commitment of satellite cells. Deletion of Carnitine palmitoyltransferase 2 (Cpt2), the rate-limiting enzyme in FAO, hampered muscle stem cell expansion and differentiation upon acute muscle injury, markedly delaying regeneration. Cpt2 deficiency reduces acetyl-CoA levels in satellite cells, impeding the metabolic flux and acetylation of selective proteins including Pax7, the central transcriptional regulator of satellite cells. Notably, acetate supplementation restored cellular metabolic flux and partially rescued the regenerative defects of Cpt2-null satellite cells. These findings highlight an essential role of fatty acid oxidation in controlling satellite cell function and suggest an integration of lipid metabolism and protein acetylation in adult stem cells.
Collapse
Affiliation(s)
- Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Department of Animal Sciences, University of Florida, Gainesville, FL, 32611, USA.
| | - Lijie Gu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephanie N Oprescu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Linda M Beckett
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Jessica M Ellis
- East Carolina Diabetes and Obesity Institute and Department of Physiology, East Carolina University, Greenville, NC, 27858, USA
| | - Shawn S Donkin
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, 27710, USA.
| |
Collapse
|
|
2
|
Zhao C, Zhou H, Wang P, Zhang S, Lin X, Pan Y, Zhu H. Hexokinase 2-driven aerobic glycolysis modulates YAP1 in placental trophoblast development. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167872. [PMID: 40286881 DOI: 10.1016/j.bbadis.2025.167872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 02/21/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
Recurrent pregnancy loss (RPL) is a severe complication, and its risk is heightened by dysregulated trophoblast development. However, the underlying mechanisms remain unclear. Herein, we show that a portion of villous samples from patients with RPL display reduced hexokinase II (HK2) and Yes-associated protein 1 (YAP1) expression compared with healthy controls. Moreover, in human trophoblast stem (TS) cell models, blocking HK2 activities via exposure to 3-bromopyruvate markedly reduced cell proliferation and induced cell cycle arrest by regulating YAP1 phosphorylation and localization. This was partially reversed by the YAP signaling activator TT-10. Moreover, YAP1 contributes to aerobic glycolysis regulation by influencing HK2 activity. Together, these findings demonstrate an interplay between the Hippo/YAP1 pathway and glucose metabolism in placental trophoblast development and highlight an approach for RPL intervention.
Collapse
Affiliation(s)
- Chenqiong Zhao
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
| | - Hanjing Zhou
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
| | - Peixing Wang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
| | - Yibin Pan
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China.
| | - Haiyan Zhu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China; Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China.
| |
Collapse
|
|
3
|
Jing Y, Kobayashi M, Shoulkamy MI, Zhou M, Thi Vu H, Arakawa H, Sabit H, Iwabuchi S, Quang Vu C, Kasahara A, Ueno M, Tadokoro Y, Kurayoshi K, Chen X, Yan Y, Arai S, Hashimoto S, Soga T, Todo T, Nakada M, Hirao A. Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma. Nat Commun 2025; 16:2876. [PMID: 40169552 PMCID: PMC11962137 DOI: 10.1038/s41467-025-56946-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 02/06/2025] [Indexed: 04/03/2025] Open
Abstract
Recent advances in cancer therapy have underscored the importance of targeting specific metabolic pathways. In this study, we propose a precision nutrition approach aimed at lysosomal function in glioblastoma multiforme (GBM). Using patient-derived GBM cells, we identify lysosomal activity as a unique metabolic biomarker of tumorigenesis, controlling the efficacy of temozolomide (TMZ), a standard GBM therapy. Employing combined analyses of clinical patient samples and xenograft models, we further elucidate the pivotal role of Transcription Factor Binding To IGHM Enhancer 3 (TFE3), a master regulator of lysosomal biogenesis, in modulating malignant properties, particularly TMZ tolerance, by regulating peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α)-mediated mitochondrial activity. Notably, we find that lysine protects GBM cells from lysosomal stress by counteracting arginine's effects on nitric oxide production. The lysine restriction mimetic, homoarginine administration, significantly enhances the efficacy of anticancer therapies through lysosomal dysfunction. This study underscores the critical role of lysosomal function modulated by amino acid metabolism in GBM pathogenesis and treatment.
Collapse
Affiliation(s)
- Yongwei Jing
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masahiko Kobayashi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mahmoud I Shoulkamy
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
- Department of Zoology, Faculty of Science, Minia University, Minia, Egypt
| | - Meiqi Zhou
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Ha Thi Vu
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
- Department of Medical Biology and Genetics, Hanoi Medical University, Ha Noi, Vietnam
| | - Hiroshi Arakawa
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hemragul Sabit
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Cong Quang Vu
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Atsuko Kasahara
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
- Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masaya Ueno
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuko Tadokoro
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Xi Chen
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuhang Yan
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Satoshi Arai
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
- Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mitsutoshi Nakada
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Atsushi Hirao
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
- WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan.
| |
Collapse
|
|
4
|
Sun H, Xia T, Ma S, Lv T, Li Y. Intercellular communication is crucial in the regulation of healthy aging via exosomes. Pharmacol Res 2025; 212:107591. [PMID: 39800177 DOI: 10.1016/j.phrs.2025.107591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/23/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.
Collapse
Affiliation(s)
- Huifang Sun
- College of Biological and Food Engineering, Qujing Normal University, Qujing, Yunnan 655011, China
| | - Tengyuan Xia
- College of Biological and Food Engineering, Qujing Normal University, Qujing, Yunnan 655011, China
| | - Shuting Ma
- College of Biological and Food Engineering, Qujing Normal University, Qujing, Yunnan 655011, China
| | - Tao Lv
- College of Biological and Food Engineering, Qujing Normal University, Qujing, Yunnan 655011, China.
| | - Yuhong Li
- College of Biological and Food Engineering, Qujing Normal University, Qujing, Yunnan 655011, China.
| |
Collapse
|
|
5
|
Yu Z, Zhu Y, Chen Y, Feng C, Zhang Z, Guo X, Chen H, Liu X, Yuan Y, Chen H. Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction. Nat Commun 2024; 15:9243. [PMID: 39455549 PMCID: PMC11512028 DOI: 10.1038/s41467-024-53675-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Nutrient-sensing pathways undergo deregulation in aged animals, exerting a pivotal role in regulating the cell cycle and subsequent stem cell division. Nevertheless, their precise functions in governing pluripotent stem cell differentiation remain largely elusive. Here, we uncovered a significant alteration in the cellular constituents of the intestinal epithelium in aged humans and mice. Employing Drosophila midgut and mouse organoid culture models, we made an observation regarding the altered trajectory of differentiation in intestinal stem cells (ISC) during overnutrition or aging, which stems from the erroneous activation of the insulin receptor signaling pathway. Through genetic analyses, we ascertained that the nutrient-sensing pathway regulated the direction of ISC differentiation by modulating the maturation of endosomes and SOX21A transcription factor. This study elucidates a nutrient-sensing pathway-mediated mechanism underlying stem cell differentiation, offering insights into the etiology of stem cell dysfunction in aged animals, including humans.
Collapse
Affiliation(s)
- Zihua Yu
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuedan Zhu
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenxi Feng
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zehong Zhang
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoxin Guo
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haiou Chen
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xingzhu Liu
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Yuan
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haiyang Chen
- West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| |
Collapse
|
|
6
|
Guo T, Zhang Q, Wang X, Xu X, Wang Y, Wei L, Li N, Liu H, Hu L, Zhao N, Xu S. Targeted and untargeted metabolomics reveals meat quality in grazing yak during different phenology periods on the Qinghai-Tibetan Plateau. Food Chem 2024; 447:138855. [PMID: 38520902 DOI: 10.1016/j.foodchem.2024.138855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 02/20/2024] [Accepted: 02/24/2024] [Indexed: 03/25/2024]
Abstract
Yak meat is more popular among consumers because of its high nutritional value, but little attention has been paid to its meat quality, which is affected by different phenology periods grass. We hypothesized that seasonal variations in grass composition influenced the ruminal bacteria community, and eventually affected the meat quality of yaks. This study aims to investigate the relationship of meat quality in grazing yak as well as the key rumen bacteria using targeted and untargeted metabolomics and 16S rRNA during different phenology periods. The main three altered metabolic pathways in grazing yak, including amino acids biosynthesis, glutathione metabolism, and fatty acids biosynthesis, were found in the grass period (GP) group compared to the regreen period (RP) and hay period (HP) groups. The GP group had higher concentrations of flavor amino acids (FAA), polyunsaturated fatty acids (PUFA), and a lower ratio of n-6/n-3 compared with the RP group. Correlation analysis results showed that Rikenellaceae_RC9_gut_group was positively correlated with fatty acids and lipid metabolites, which might be involved in lipid metabolism. Pediococcus had a positive correlation with biological peptides, which could be involved in the metabolism of bioactive compounds. In conclusion, grass in different phenology periods was associated with modified amino acids and fatty acids composition of yak meat as well as altered regulation of biological pathways, which was correlated with changes in rumen bacterial communities.
Collapse
Affiliation(s)
- Tongqing Guo
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qian Zhang
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xungang Wang
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
| | - Xianli Xu
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yalin Wang
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lin Wei
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Na Li
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongjin Liu
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
| | - Linyong Hu
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
| | - Na Zhao
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
| | - Shixiao Xu
- Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.
| |
Collapse
|
|
7
|
Zutshi N, Mohapatra BC, Mondal P, An W, Goetz BT, Wang S, Li S, Storck MD, Mercer DF, Black AR, Thayer SP, Black JD, Lin C, Band V, Band H. Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance. iScience 2024; 27:109912. [PMID: 38974465 PMCID: PMC11225835 DOI: 10.1016/j.isci.2024.109912] [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: 05/23/2023] [Revised: 02/29/2024] [Accepted: 05/03/2024] [Indexed: 07/09/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.
Collapse
Affiliation(s)
- Neha Zutshi
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Bhopal C. Mohapatra
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Pinaki Mondal
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wei An
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Benjamin T. Goetz
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shuo Wang
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sicong Li
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Matthew D. Storck
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - David F. Mercer
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Adrian R. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sarah P. Thayer
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jennifer D. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chi Lin
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Vimla Band
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Hamid Band
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| |
Collapse
|
|
8
|
Abstract
Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan.
Collapse
Affiliation(s)
- Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
| |
Collapse
|
|
9
|
Sharp ZD, Strong R. Rapamycin, the only drug that has been consistently demonstrated to increase mammalian longevity. An update. Exp Gerontol 2023; 176:112166. [PMID: 37011714 PMCID: PMC10868408 DOI: 10.1016/j.exger.2023.112166] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023]
Affiliation(s)
- Zelton Dave Sharp
- Department of Molecular Medicine and Institute of Biotechnology, San Antonio, TX, United States of America; Barshop Institute for Longevity and Aging Studies, San Antonio, TX, United States of America; Mays Cancer Center, San Antonio, TX, United States of America.
| | - Randy Strong
- Barshop Institute for Longevity and Aging Studies, San Antonio, TX, United States of America; Department of Pharmacology, UT Health, San Antonio, TX, United States of America; Research Service of the South Texas Veterans Health Care System, San Antonio, TX 78229, United States of America.
| |
Collapse
|
|
10
|
Zutshi N, Mohapatra BC, Mondal P, An W, Goetz BT, Wang S, Li S, Storck MD, Mercer DF, Black AR, Thayer SP, Black JD, Lin C, Band V, Band H. Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.17.541154. [PMID: 37292716 PMCID: PMC10245689 DOI: 10.1101/2023.05.17.541154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Among the signaling pathways that control the stem cell self-renewal and maintenance vs. acquisition of differentiated cell fates, those mediated by receptor tyrosine kinase (RTK) activation are well established as key players. CBL family ubiquitin ligases are negative regulators of RTKs but their physiological roles in regulating stem cell behaviors are unclear. While hematopoietic Cbl/Cblb knockout (KO) leads to a myeloproliferative disease due to expansion and reduced quiescence of hematopoietic stem cells, mammary epithelial KO led to stunted mammary gland development due to mammary stem cell depletion. Here, we examined the impact of inducible Cbl/Cblb double-KO (iDKO) selectively in the Lgr5-defined intestinal stem cell (ISC) compartment. Cbl/Cblb iDKO led to rapid loss of the Lgr5 Hi ISC pool with a concomitant transient expansion of the Lgr5 Lo transit amplifying population. LacZ reporter-based lineage tracing showed increased ISC commitment to differentiation, with propensity towards enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro , Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single cell RNAseq analysis of organoids revealed Akt-mTOR pathway hyperactivation in iDKO ISCs and progeny cells, and pharmacological inhibition of the Akt-mTOR axis rescued the organoid maintenance and propagation defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.
Collapse
|
|
11
|
Ren J, Hu Z, Li Q, Gu S, Lan F, Wang X, Li J, Li J, Shao L, Yang N, Sun C. Temperature-induced embryonic diapause in chickens is mediated by PKC-NF-κB-IRF1 signaling. BMC Biol 2023; 21:52. [PMID: 36882743 PMCID: PMC9993608 DOI: 10.1186/s12915-023-01550-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Embryonic diapause (dormancy) is a state of temporary arrest of embryonic development that is triggered by unfavorable conditions and serves as an evolutionary strategy to ensure reproductive survival. Unlike maternally-controlled embryonic diapause in mammals, chicken embryonic diapause is critically dependent on the environmental temperature. However, the molecular control of diapause in avian species remains largely uncharacterized. In this study, we evaluated the dynamic transcriptomic and phosphoproteomic profiles of chicken embryos in pre-diapause, diapause, and reactivated states. RESULTS Our data demonstrated a characteristic gene expression pattern in effects on cell survival-associated and stress response signaling pathways. Unlike mammalian diapause, mTOR signaling is not responsible for chicken diapause. However, cold stress responsive genes, such as IRF1, were identified as key regulators of diapause. Further in vitro investigation showed that cold stress-induced transcription of IRF1 was dependent on the PKC-NF-κB signaling pathway, providing a mechanism for proliferation arrest during diapause. Consistently, in vivo overexpression of IRF1 in diapause embryos blocked reactivation after restoration of developmental temperatures. CONCLUSIONS We concluded that embryonic diapause in chicken is characterized by proliferation arrest, which is the same with other spices. However, chicken embryonic diapause is strictly correlated with the cold stress signal and mediated by PKC-NF-κB-IRF1 signaling, which distinguish chicken diapause from the mTOR based diapause in mammals.
Collapse
Affiliation(s)
- Junxiao Ren
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Zhengzheng Hu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Quanlin Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Shuang Gu
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Fangren Lan
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xiqiong Wang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Jianbo Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Junying Li
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Liwa Shao
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ning Yang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Congjiao Sun
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| |
Collapse
|
|
12
|
Guzel S, Gurpinar Y, Altunok TH, Yalcin A. Increased expression of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for growth of mouse embryonic stem cells that are undergoing differentiation. Cytotechnology 2023; 75:27-38. [PMID: 36713065 PMCID: PMC9880118 DOI: 10.1007/s10616-022-00557-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/01/2022] [Indexed: 11/11/2022] Open
Abstract
The unlimited proliferation capacity of embryonic stem cells (ESCs) coupled with their capability to differentiate into several cell types makes them an attractive candidate for studying the molecular mechanisms regulating self-renewal and transition from pluripotent state. Although the roles of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family (PFKFB1-4) in cell survival, proliferation, and differentiation in tumor cells have been studied, their role in mouse ESC (mESC) biology is currently unkown. In the current study, Pfkfb isoenzyme expressions were analyzed in R1 and J1 mESCs that were cultured in the presence and absence of leukemia inhibitory factor (LIF). We report that expression of the Pfkfb3 isoenzyme was markedly increased when mESCs were promoted to differentiate upon LIF removal. We then demonstrated that Pfkfb3 silencing induced the differentiation marker Brachyury suggesting that Pfkfb3 may be required for the regulation of mesodermal differentiation of mESCs. Furthermore, we show that the increase in Pfkfb3 expression is required for the growth of early differentiated mESCs. Although these results provide important insights into the early differentiation of mESCs with regard to Pfkfb expressions, further mechanistic studies will be needed for understanding the pathways and mechanisms involved in regulation of proliferation and early differentiation of mESCs through Pfkfb3.
Collapse
Affiliation(s)
- Saime Guzel
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Yunus Gurpinar
- Research Center for Translational Medicine, Koc University, 34010 Istanbul, Turkey
| | - Tugba Hazal Altunok
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Abdullah Yalcin
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| |
Collapse
|
|
13
|
Luo G, Wosinski P, Salazar-Noratto GE, Bensidhoum M, Bizios R, Marashi SA, Potier E, Sheng P, Petite H. Glucose Metabolism: Optimizing Regenerative Functionalities of Mesenchymal Stromal Cells Postimplantation. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:47-61. [PMID: 35754335 DOI: 10.1089/ten.teb.2022.0063] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Mesenchymal stromal cells (MSCs) are considered promising candidates for regenerative medicine applications. Their clinical performance postimplantation, however, has been disappointing. This lack of therapeutic efficacy is most likely due to suboptimal formulations of MSC-containing material constructs. Tissue engineers, therefore, have developed strategies addressing/incorporating optimized cell, microenvironmental, biochemical, and biophysical cues/stimuli to enhance MSC-containing construct performance. Such approaches have had limited success because they overlooked that maintenance of MSC viability after implantation for a sufficient time is necessary for MSCs to develop their regenerative functionalities fully. Following a brief overview of glucose metabolism and regulation in MSCs, the present literature review includes recent pertinent findings that challenge old paradigms and notions. We hereby report that glucose is the primary energy substrate for MSCs, provides precursors for biomass generation, and regulates MSC functions, including proliferation and immunosuppressive properties. More importantly, glucose metabolism is central in controlling in vitro MSC expansion, in vivo MSC viability, and MSC-mediated angiogenesis postimplantation when addressing MSC-based therapies. Meanwhile, in silico models are highlighted for predicting the glucose needs of MSCs in specific regenerative medicine settings, which will eventually enable tissue engineers to design viable and potent tissue constructs. This new knowledge should be incorporated into developing novel effective MSC-based therapies. Impact statement The clinical use of mesenchymal stromal cells (MSCs) has been unsatisfactory due to the inability of MSCs to survive and be functional after implantation for sufficient periods to mediate directly or indirectly a successful regenerative tissue response. The present review summarizes the endeavors in the past, but, most importantly, reports the latest findings that elucidate underlying mechanisms and identify glucose metabolism as the crucial parameter in MSC survival and the subsequent functions pertinent to new tissue formation of importance in tissue regeneration applications. These latest findings justify further basic research and the impetus for developing new strategies to improve the modalities and efficacy of MSC-based therapies.
Collapse
Affiliation(s)
- Guotian Luo
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Pauline Wosinski
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Giuliana E Salazar-Noratto
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Morad Bensidhoum
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Rena Bizios
- Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, Texas, USA
| | - Sayed-Amir Marashi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Esther Potier
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Puyi Sheng
- Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hervé Petite
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| |
Collapse
|
|
14
|
Lal MK, Sharma E, Tiwari RK, Devi R, Mishra UN, Thakur R, Gupta R, Dey A, Lal P, Kumar A, Altaf MA, Sahu DN, Kumar R, Singh B, Sahu SK. Nutrient-Mediated Perception and Signalling in Human Metabolism: A Perspective of Nutrigenomics. Int J Mol Sci 2022; 23:ijms231911305. [PMID: 36232603 PMCID: PMC9569568 DOI: 10.3390/ijms231911305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/03/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
The interaction between selective nutrients and linked genes involving a specific organ reveals the genetic make-up of an individual in response to a particular nutrient. The interaction of genes with food opens opportunities for the addition of bioactive compounds for specific populations comprising identical genotypes. The slight difference in the genetic blueprints of humans is advantageous in determining the effect of nutrients and their metabolism in the body. The basic knowledge of emerging nutrigenomics and nutrigenetics can be applied to optimize health, prevention, and treatment of diseases. In addition, nutrient-mediated pathways detecting the cellular concentration of nutrients such as sugars, amino acids, lipids, and metabolites are integrated and coordinated at the organismal level via hormone signals. This review deals with the interaction of nutrients with various aspects of nutrigenetics and nutrigenomics along with pathways involved in nutrient sensing and regulation, which can provide a detailed understanding of this new leading edge in nutrition research and its potential application to dietetic practice.
Collapse
Affiliation(s)
- Milan Kumar Lal
- Division of Crop Physiology, Biochemistry and Post-Harvest Technology, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Eshita Sharma
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar 143005, India
| | - Rahul Kumar Tiwari
- Division of Plant Protection, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Rajni Devi
- Department of Microbiology, Punjab Agricultural University, Ludhiana 141004, India
| | | | - Richa Thakur
- Division of Silviculture and Forest Management, Himalayan Forest Research Institute, Conifer Campus, Shimla 171001, India
| | - Rucku Gupta
- Department of horticulture, Sher-e-Kashmir University of Agricultural Science and Technology of Jammu, Jammu 181101, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India
| | - Priyanka Lal
- Department of Agricultural Economics and Extension, School of Agriculture, Lovely Professional University, Jalandhar GT Road (NH1), Phagwara 144402, India
| | - Awadhesh Kumar
- Division of Crop Physiology and Biochemistry, ICAR-National Rice Research Institute, Cuttack 754006, India
| | | | - Durgesh Nandini Sahu
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
| | - Ravinder Kumar
- Division of Plant Protection, ICAR-Central Potato Research Institute, Shimla 171001, India
| | - Brajesh Singh
- Division of Crop Physiology, Biochemistry and Post-Harvest Technology, ICAR-Central Potato Research Institute, Shimla 171001, India
- Correspondence: (B.S.); (S.K.S.)
| | - Sunil Kumar Sahu
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
- Correspondence: (B.S.); (S.K.S.)
| |
Collapse
|
|
15
|
Zhou C, Bai XY. Strategies for the induction of anti-inflammatory mesenchymal stem cells and their application in the treatment of immune-related nephropathy. Front Med (Lausanne) 2022; 9:891065. [PMID: 36059816 PMCID: PMC9437354 DOI: 10.3389/fmed.2022.891065] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have potent immunomodulatory functions. Animal studies and clinical trials have demonstrated that MSCs can inhibit immune/inflammatory response in tissues and have good therapeutic effects on a variety of immune-related diseases. However, MSCs currently used for treatment are a mixed, undefined, and heterogeneous cell population, resulting in inconsistent clinical treatment effects. MSCs have dual pro-inflammatory/anti-inflammatory regulatory functions in different environments. In different microenvironments, the immunomodulatory function of MSCs has plasticity; therefore, MSCs can transform into pro-inflammatory MSC1 or anti-inflammatory MSC2 phenotypes. There is an urgent need to elucidate the molecular mechanism that induces the phenotypic transition of MSCs to pro-inflammatory or anti-inflammatory MSCs and to develop technical strategies that can induce the transformation of MSCs to the anti-inflammatory MSC2 phenotype to provide a theoretical basis for the future clinical use of MSCs in the treatment of immune-related nephropathy. In this paper, we summarize the relevant strategies and mechanisms for inducing the transformation of MSCs into the anti-inflammatory MSC2 phenotype and enhancing the immunosuppressive function of MSCs.
Collapse
|
|
16
|
Parween S, Alawathugoda TT, Prabakaran AD, Dheen ST, Morse RH, Emerald BS, Ansari SA. Nutrient sensitive protein O-GlcNAcylation modulates the transcriptome through epigenetic mechanisms during embryonic neurogenesis. Life Sci Alliance 2022; 5:5/8/e202201385. [PMID: 35470239 PMCID: PMC9039347 DOI: 10.26508/lsa.202201385] [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: 01/24/2022] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 01/02/2023] Open
Abstract
Protein O-GlcNAcylation is a dynamic, nutrient-sensitive mono-glycosylation deposited on numerous nucleo-cytoplasmic and mitochondrial proteins, including transcription factors, epigenetic regulators, and histones. However, the role of protein O-GlcNAcylation on epigenome regulation in response to nutrient perturbations during development is not well understood. Herein we recapitulated early human embryonic neurogenesis in cell culture and found that pharmacological up-regulation of O-GlcNAc levels during human embryonic stem cells' neuronal differentiation leads to up-regulation of key neurogenic transcription factor genes. This transcriptional de-repression is associated with reduced H3K27me3 and increased H3K4me3 levels on the promoters of these genes, perturbing promoter bivalency possibly through increased EZH2-Thr311 phosphorylation. Elevated O-GlcNAc levels also lead to increased Pol II-Ser5 phosphorylation and affect H2BS112O-GlcNAc and H2BK120Ub1 on promoters. Using an in vivo rat model of maternal hyperglycemia, we show similarly elevated O-GlcNAc levels and epigenetic dysregulations in the developing embryo brains because of hyperglycemia, whereas pharmacological inhibition of O-GlcNAc transferase (OGT) restored these molecular changes. Together, our results demonstrate O-GlcNAc mediated sensitivity of chromatin to nutrient status, and indicate how metabolic perturbations could affect gene expression during neurodevelopment.
Collapse
Affiliation(s)
- Shama Parween
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Thilina T Alawathugoda
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ashok D Prabakaran
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - S Thameem Dheen
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Randall H Morse
- New York State Department of Health, Wadsworth Center, Albany, NY, USA
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.,Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Suraiya A Ansari
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates .,Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|
|
17
|
Preparation of Spheroids from Primary Pig Cells in a Mid-Scale Bioreactor Retaining Their Myogenic Potential. Cells 2022; 11:cells11091453. [PMID: 35563757 PMCID: PMC9103977 DOI: 10.3390/cells11091453] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 01/09/2023] Open
Abstract
Three-dimensional cell culture techniques mimic the in vivo cell environment more adequately than flat surfaces. Spheroids are multicellular aggregates and we aimed to produce scaffold-free spheroids of myogenic origin, called myospheres, using a mid-scale incubator and bioreactor hybrid. For the first time, we obtained spheroids from primary porcine muscle cells (PMCs) with this technology and compared their morphology and growth parameters, marker expression, and myogenic potential to C2C12-derived spheroids. Both cell types were able to form round-shaped spheroids in the bioreactor already after 24 h. The mean diameter of the C2C12 spheroids (44.6 µm) was larger than that of the PMCs (32.7 µm), and the maximum diameter exceeded 1 mm. C2C12 cells formed less aggregates than PMCs with a higher packing density (cell nuclei/mm2). After dissociation from the spheroids, C2C12 cells and PMCs started to proliferate again and were able to differentiate into the myogenic lineage, as shown by myotube formation and the expression of F-Actin, Desmin, MyoG, and Myosin. For C2C12, multinucleated syncytia and Myosin expression were observed in spheroids, pointing to accelerated myogenic differentiation. In conclusion, the mid-scale incubator and bioreactor system is suitable for spheroid formation and cultivation from primary muscle cells while preserving their myogenic potential.
Collapse
|
|
18
|
Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways. Cancers (Basel) 2022; 14:cancers14051311. [PMID: 35267619 PMCID: PMC8909278 DOI: 10.3390/cancers14051311] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/21/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary The oncogene MYC alters cellular metabolism. Medulloblastoma is the most common malignant pediatric brain tumor. MYC-amplified medulloblastoma has a poor prognosis, and the metabolism of MYC-amplified medulloblastoma is poorly understood. We performed comprehensive metabolic profiling of MYC-amplified medulloblastoma and found increased reliance on potentially targetable pathways. We also found that the metabolism of MYC-amplified cell lines differed from orthotopic brain tumors in vitro and in flank tumors, suggesting that analyses conducted in vitro or in flank tumors may miss key vulnerabilities. Abstract Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions—in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.
Collapse
|
|
19
|
Salmina AB, Malinovskaya NA, Morgun AV, Khilazheva ED, Uspenskaya YA, Illarioshkin SN. Reproducibility of developmental neuroplasticity in in vitro brain tissue models. Rev Neurosci 2022; 33:531-554. [PMID: 34983132 DOI: 10.1515/revneuro-2021-0137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/13/2021] [Indexed: 11/15/2022]
Abstract
The current prevalence of neurodevelopmental, neurodegenerative diseases, stroke and brain injury stimulates studies aimed to identify new molecular targets, to select the drug candidates, to complete the whole set of preclinical and clinical trials, and to implement new drugs into routine neurological practice. Establishment of protocols based on microfluidics, blood-brain barrier- or neurovascular unit-on-chip, and microphysiological systems allowed improving the barrier characteristics and analyzing the regulation of local microcirculation, angiogenesis, and neurogenesis. Reconstruction of key mechanisms of brain development and even some aspects of experience-driven brain plasticity would be helpful in the establishment of brain in vitro models with the highest degree of reliability. Activity, metabolic status and expression pattern of cells within the models can be effectively assessed with the protocols of system biology, cell imaging, and functional cell analysis. The next generation of in vitro models should demonstrate high scalability, 3D or 4D complexity, possibility to be combined with other tissues or cell types within the microphysiological systems, compatibility with bio-inks or extracellular matrix-like materials, achievement of adequate vascularization, patient-specific characteristics, and opportunity to provide high-content screening. In this review, we will focus on currently available and prospective brain tissue in vitro models suitable for experimental and preclinical studies with the special focus on models enabling 4D reconstruction of brain tissue for the assessment of brain development, brain plasticity, and drug kinetics.
Collapse
Affiliation(s)
- Alla B Salmina
- Laboratory of Experimental Brain Cytology, Research Center of Neurology, Volokolamskoe Highway 80, Moscow, 125367, Russia.,Research Institute of Molecular Medicine & Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, P. Zhelenzyaka str., 1, Krasnoyarsk 660022, Russia
| | - Natalia A Malinovskaya
- Research Institute of Molecular Medicine & Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, P. Zhelenzyaka str., 1, Krasnoyarsk 660022, Russia
| | - Andrey V Morgun
- Department of Ambulatory Pediatrics, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, P. Zheleznyaka str., 1, Krasnoyarsk 660022, Russia
| | - Elena D Khilazheva
- Research Institute of Molecular Medicine & Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, P. Zhelenzyaka str., 1, Krasnoyarsk 660022, Russia
| | - Yulia A Uspenskaya
- Research Institute of Molecular Medicine & Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, P. Zhelenzyaka str., 1, Krasnoyarsk 660022, Russia
| | - Sergey N Illarioshkin
- Department of Brain Studies, Research Center of Neurology, Volokolamskoe Highway, 80, Moscow 125367, Russia
| |
Collapse
|
|
20
|
Liu W, Chen G. Regulation of energy metabolism in human pluripotent stem cells. Cell Mol Life Sci 2021; 78:8097-8108. [PMID: 34773132 PMCID: PMC11071932 DOI: 10.1007/s00018-021-04016-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
All living organisms need energy to carry out their essential functions. The importance of energy metabolism is increasingly recognized in human pluripotent stem cells. Energy production is not only essential for cell survival and proliferation, but also critical for pluripotency and cell fate determination. Thus, energy metabolism is an important target in cellular regulation and stem cell applications. In this review, we will discuss key factors that influence energy metabolism and their association with stem cell functions.
Collapse
Affiliation(s)
- Weiwei Liu
- Faculty of Health Sciences, Centre of Reproduction, Development and Aging, University of Macau, Taipa, Macau SAR, China
- Bioimaging and Stem Cell Core Facility, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Guokai Chen
- Faculty of Health Sciences, Centre of Reproduction, Development and Aging, University of Macau, Taipa, Macau SAR, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
| |
Collapse
|
|
21
|
Campos J, Silva NA, Salgado AJ. Nutritional interventions for spinal cord injury: preclinical efficacy and molecular mechanisms. Nutr Rev 2021; 80:1206-1221. [PMID: 34472615 DOI: 10.1093/nutrit/nuab068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Spinal cord injury (SCI) is a debilitating condition that leads to motor, sensory, and autonomic impairments. Its intrinsic pathophysiological complexity has hindered the establishment of effective treatments for decades. Nutritional interventions (NIs) for SCI have been proposed as a route to circumvent some of the problems associated with this condition. Results obtained in animal models point to a more holistic effect, rather than to specific modulation, of several relevant SCI pathophysiological processes. Indeed, published data have shown NI improves energetic imbalance, oxidative damage, and inflammation, which are promoters of improved proteostasis and neurotrophic signaling, leading ultimately to neuroprotection and neuroplasticity. This review focuses on the most well-documented Nis. The mechanistic implications and their translational potential for SCI are discussed.
Collapse
Affiliation(s)
- Jonas Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno A Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| |
Collapse
|
|
22
|
Valente S, Ciavarella C, Hernández-Aguilera A, Salvador FA, Buzzi M, Joven J, Pasquinelli G. Phenotypic, morphological, and metabolic characterization of vascular-spheres from human vascular mesenchymal stem cells. Microsc Res Tech 2021; 85:447-459. [PMID: 34448515 PMCID: PMC9290655 DOI: 10.1002/jemt.23918] [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: 04/12/2021] [Revised: 07/15/2021] [Accepted: 07/31/2021] [Indexed: 01/01/2023]
Abstract
The ability to form spheroids under non‐adherent conditions is a well‐known property of human mesenchymal stem cells (hMSCs), in addition to stemness and multilineage differentiation features. In the present study, we tested the ability of hMSCs isolated from the vascular wall (hVW‐MSCs) to grow as spheres, and provide a characterization of this 3D model. hVW‐MSCs were isolated from femoral arteries through enzymatic digestion. Spheres were obtained using ultra‐low attachment and hanging drop methods. Immunophenotype and pluripotent genes (SOX‐2, OCT‐4, NANOG) were analyzed by immunocytochemistry and real‐time PCR, respectively. Spheres histological and ultrastructural architecture were examined. Cell viability and proliferative capacity were measured using LIVE/DEATH assay and ki‐67 proliferation marker. Metabolomic profile was obtained with liquid chromatography–mass spectrometry. In 2D, hVW‐MSCs were spindle‐shaped, expressed mesenchymal antigens, and displayed mesengenic potential. 3D cultures of hVW‐MSCs were CD44+, CD105low, CD90low, exhibited a low propensity to enter the cell cycle as indicated by low percentage of ki‐67 expression and accumulated intermediate metabolites pointing to slowed metabolism. The 3D model of hVW‐MSCs exhibits stemness, dormancy and slow metabolism, typically observed in stem cell niches. This culture strategy can represent an accurate model to investigate hMSCs features for future clinical applications in the vascular field.
Collapse
Affiliation(s)
- Sabrina Valente
- DIMES - Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Carmen Ciavarella
- DIMES - Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Anna Hernández-Aguilera
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Campus of International Excellence Southern Catalonia, Tarragona, Spain
| | - Fernández-Arroyo Salvador
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Campus of International Excellence Southern Catalonia, Tarragona, Spain
| | - Marina Buzzi
- Emilia Romagna Cord Blood Bank - Transfusion Service, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Jorge Joven
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Campus of International Excellence Southern Catalonia, Tarragona, Spain
| | - Gianandrea Pasquinelli
- DIMES - Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,Subcellular Nephro-Vascular Diagnostic Program, Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| |
Collapse
|
|
23
|
Physiological Functions of Threonine in Animals: Beyond Nutrition Metabolism. Nutrients 2021; 13:nu13082592. [PMID: 34444752 PMCID: PMC8399342 DOI: 10.3390/nu13082592] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 07/20/2021] [Accepted: 07/20/2021] [Indexed: 01/03/2023] Open
Abstract
Threonine (Thr), an essential amino acid for animals and the limiting amino acid in swine and poultry diets, which plays a vital role in the modulation of nutritional metabolism, macromolecular biosynthesis, and gut homeostasis. Current evidence supports that the supplementation of Thr leads to benefits in terms of energy metabolism. Threonine is not only an important component of gastrointestinal mucin, but also acts as a nutritional modulator that influences the intestinal immune system via complex signaling networks, particularly mitogen-activated protein kinase (MAPK) and the target of the rapamycin (TOR) signal pathway. Threonine is also recognized as an indispensable nutrient for cell growth and proliferation. Hence, optimization of Thr requirement may exert a favorable impact on the factors linked to health and diseases in animals. This review focuses on the latest reports of Thr in metabolic pathways and nutritional regulation, as well as the relationship between Thr and relevant physiological functions.
Collapse
|
|
24
|
Zurlinden TJ, Saili KS, Rush N, Kothiya P, Judson RS, Houck KA, Hunter ES, Baker NC, Palmer JA, Thomas RS, Knudsen TB. Profiling the ToxCast Library With a Pluripotent Human (H9) Stem Cell Line-Based Biomarker Assay for Developmental Toxicity. Toxicol Sci 2021; 174:189-209. [PMID: 32073639 DOI: 10.1093/toxsci/kfaa014] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The Stemina devTOX quickPredict platform is a human pluripotent stem cell-based assay that predicts the developmental toxicity potential based on changes in cellular metabolism following chemical exposure [Palmer, J. A., Smith, A. M., Egnash, L. A., Conard, K. R., West, P. R., Burrier, R. E., Donley, E. L. R., and Kirchner, F. R. (2013). Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening. Birth Defects Res. B Dev. Reprod. Toxicol. 98, 343-363]. Using this assay, we screened 1065 ToxCast phase I and II chemicals in single-concentration or concentration-response for the targeted biomarker (ratio of ornithine to cystine secreted or consumed from the media). The dataset from the Stemina (STM) assay is annotated in the ToxCast portfolio as STM. Major findings from the analysis of ToxCast_STM dataset include (1) 19% of 1065 chemicals yielded a prediction of developmental toxicity, (2) assay performance reached 79%-82% accuracy with high specificity (> 84%) but modest sensitivity (< 67%) when compared with in vivo animal models of human prenatal developmental toxicity, (3) sensitivity improved as more stringent weights of evidence requirements were applied to the animal studies, and (4) statistical analysis of the most potent chemical hits on specific biochemical targets in ToxCast revealed positive and negative associations with the STM response, providing insights into the mechanistic underpinnings of the targeted endpoint and its biological domain. The results of this study will be useful to improving our ability to predict in vivo developmental toxicants based on in vitro data and in silico models.
Collapse
Affiliation(s)
| | | | | | | | | | | | - E Sidney Hunter
- National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, North Carolina
| | | | | | | | | |
Collapse
|
|
25
|
Tiwari SK, Mandal S. Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila. Front Cell Dev Biol 2021; 9:606639. [PMID: 34012959 PMCID: PMC8128071 DOI: 10.3389/fcell.2021.606639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 04/06/2021] [Indexed: 01/09/2023] Open
Abstract
Over the years, Drosophila has served as a wonderful genetically tractable model system to unravel various facets of tissue-resident stem cells in their microenvironment. Studies in different stem and progenitor cell types of Drosophila have led to the discovery of cell-intrinsic and extrinsic factors crucial for stem cell state and fate. Though initially touted as the ATP generating machines for carrying various cellular processes, it is now increasingly becoming clear that mitochondrial processes alone can override the cellular program of stem cells. The last few years have witnessed a surge in our understanding of mitochondria's contribution to governing different stem cell properties in their subtissular niches in Drosophila. Through this review, we intend to sum up and highlight the outcome of these in vivo studies that implicate mitochondria as a central regulator of stem cell fate decisions; to find the commonalities and uniqueness associated with these regulatory mechanisms.
Collapse
Affiliation(s)
- Satish Kumar Tiwari
- Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, India
| | - Sudip Mandal
- Molecular Cell and Developmental Biology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, India
| |
Collapse
|
|
26
|
Ayhan S, Nemutlu E, Uçkan Çetinkaya D, Kır S, Özgül RK. Characterization of human bone marrow niches with metabolome and transcriptome profiling. J Cell Sci 2021; 134:jcs.250720. [PMID: 33526717 DOI: 10.1242/jcs.250720] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 01/13/2021] [Indexed: 12/28/2022] Open
Abstract
Bone marrow (BM) niches are special microenvironments that work in harmony with each other for the regulation and maintenance of hematopoiesis. Niche investigations have thus far been limited to various model organisms and animal studies; therefore, little is known about different niches in healthy humans. In this study, a special harvesting method for the collection of BM from two different anatomical regions in the iliac crest of humans was used to investigate the presence of different niches in BM. Additionally, metabolomic and transcriptomic profiles were compiled using comparative 'omics' technologies, and the main cellular pathways and corresponding transcripts and metabolites were identified. As a result, we found that the energy metabolism between the regions was different. This study provides basic broad data for regenerative medicine in terms of the design of the appropriate microenvironment for in vitro hematopoietic niche modeling, and identifies the normal reference values that can be compared in hematological disease.
Collapse
Affiliation(s)
- Selda Ayhan
- Center for Stem Cell Research and Development/PEDI-STEM and Department of Stem Cell Sciences, Health Sciences Institute, Hacettepe University, Sıhhıye, Ankara 06100, Turkey.,Department of Pediatric Metabolism, Institute of Child Health, Hacettepe University, Sıhhıye, Ankara 06100, Turkey
| | - Emirhan Nemutlu
- Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Sıhhıye, Ankara 06100, Turkey
| | - Duygu Uçkan Çetinkaya
- Center for Stem Cell Research and Development/PEDI-STEM and Department of Stem Cell Sciences, Health Sciences Institute, Hacettepe University, Sıhhıye, Ankara 06100, Turkey.,Department of Pediatrics, Division of Hematology, Hacettepe University, Sıhhıye, Ankara 06100, Turkey
| | - Sedef Kır
- Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Sıhhıye, Ankara 06100, Turkey
| | - Rıza Köksal Özgül
- Department of Pediatric Metabolism, Institute of Child Health, Hacettepe University, Sıhhıye, Ankara 06100, Turkey
| |
Collapse
|
|
27
|
Baghdadi M, Hinterding HM, Partridge L, Deelen J. From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing. Brief Funct Genomics 2021; 21:13-23. [PMID: 33690799 PMCID: PMC8789301 DOI: 10.1093/bfgp/elab005] [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: 11/30/2020] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 01/20/2023] Open
Abstract
Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer’s disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age.
Collapse
|
|
28
|
Pham HT, Ono M, Hara ES, Nguyen HTT, Dang AT, Do HT, Komori T, Tosa I, Hazehara-Kunitomo Y, Yoshioka Y, Oida Y, Akiyama K, Kuboki T. Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo. MATERIALS 2021; 14:ma14010208. [PMID: 33406724 PMCID: PMC7796421 DOI: 10.3390/ma14010208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 01/06/2023]
Abstract
Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.
Collapse
Affiliation(s)
- Hai Thanh Pham
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
- Faculty of Dentistry, Hai Phong University of Medical and Pharmacy, Haiphong 04211, Vietnam
| | - Mitsuaki Ono
- Department of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
- Correspondence: (M.O.); (E.S.H.); Tel.: +81-86-235-7127 (M.O.); +81-86-235-6667 (E.S.H.); Fax: +81-86-222-7768 (M.O.); +81-86-235-6669 (E.S.H.)
| | - Emilio Satoshi Hara
- Department of Biomaterials, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
- Correspondence: (M.O.); (E.S.H.); Tel.: +81-86-235-7127 (M.O.); +81-86-235-6667 (E.S.H.); Fax: +81-86-222-7768 (M.O.); +81-86-235-6669 (E.S.H.)
| | - Ha Thi Thu Nguyen
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
- Faculty of Dentistry, Hai Phong University of Medical and Pharmacy, Haiphong 04211, Vietnam
- Department of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
| | - Anh Tuan Dang
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
- Faculty of Dentistry, Hai Phong University of Medical and Pharmacy, Haiphong 04211, Vietnam
- Department of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
| | - Hang Thuy Do
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
- Faculty of Dentistry, Hai Phong University of Medical and Pharmacy, Haiphong 04211, Vietnam
- Department of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
| | - Taishi Komori
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| | - Ikue Tosa
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| | - Yuri Hazehara-Kunitomo
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
- Department of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
| | - Yuya Yoshioka
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| | - Yasutaka Oida
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| | - Kentaro Akiyama
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| | - Takuo Kuboki
- Department of Oral Rehabilitation and Regenerative Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; (H.T.P.); (H.T.T.N.); (A.T.D.); (H.T.D.); (T.K.); (I.T.); (Y.H.-K.); (Y.Y.); (Y.O.); (K.A.); (T.K.)
| |
Collapse
|
|
29
|
Robles-Flores M, Moreno-Londoño AP, Castañeda-Patlán MC. Signaling Pathways Involved in Nutrient Sensing Control in Cancer Stem Cells: An Overview. Front Endocrinol (Lausanne) 2021; 12:627745. [PMID: 33828530 PMCID: PMC8020906 DOI: 10.3389/fendo.2021.627745] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/18/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer cells characteristically have a high proliferation rate. Because tumor growth depends on energy-consuming anabolic processes, including biosynthesis of protein, lipid, and nucleotides, many tumor-associated conditions, including intermittent oxygen deficiency due to insufficient vascularization, oxidative stress, and nutrient deprivation, results from fast growth. To cope with these environmental stressors, cancer cells, including cancer stem cells, must adapt their metabolism to maintain cellular homeostasis. It is well- known that cancer stem cells (CSC) reprogram their metabolism to adapt to live in hypoxic niches. They usually change from oxidative phosphorylation to increased aerobic glycolysis even in the presence of oxygen. However, as opposed to most differentiated cancer cells relying on glycolysis, CSCs can be highly glycolytic or oxidative phosphorylation-dependent, displaying high metabolic plasticity. Although the influence of the metabolic and nutrient-sensing pathways on the maintenance of stemness has been recognized, the molecular mechanisms that link these pathways to stemness are not well known. Here in this review, we describe the most relevant signaling pathways involved in nutrient sensing and cancer cell survival. Among them, Adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway, mTOR pathway, and Hexosamine Biosynthetic Pathway (HBP) are critical sensors of cellular energy and nutrient status in cancer cells and interact in complex and dynamic ways.
Collapse
Affiliation(s)
- Martha Robles-Flores
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Angela P Moreno-Londoño
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - M Cristina Castañeda-Patlán
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| |
Collapse
|
|
30
|
Murakami K, Kurotaki D, Kawase W, Soma S, Fukuchi Y, Kunimoto H, Yoshimi R, Koide S, Oshima M, Hishiki T, Hayakawa N, Matsuura T, Oda M, Yanagisawa K, Kobayashi H, Haraguchi M, Atobe Y, Funakoshi K, Iwama A, Takubo K, Okamoto S, Tamura T, Nakajima H. OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy. Cell Rep 2021; 34:108579. [PMID: 33406421 DOI: 10.1016/j.celrep.2020.108579] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 07/04/2020] [Accepted: 12/09/2020] [Indexed: 01/07/2023] Open
Abstract
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
Collapse
Affiliation(s)
- Koichi Murakami
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Daisuke Kurotaki
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Wataru Kawase
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Shunsuke Soma
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yumi Fukuchi
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroyoshi Kunimoto
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Ryusuke Yoshimi
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Shuhei Koide
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8039, Japan
| | - Motohiko Oshima
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8039, Japan
| | - Takako Hishiki
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Noriyo Hayakawa
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomomi Matsuura
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Mayumi Oda
- Department of Systems Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kiichi Yanagisawa
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Hiroshi Kobayashi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Miho Haraguchi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Yoshitoshi Atobe
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Kengo Funakoshi
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Atsushi Iwama
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8039, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomohiko Tamura
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Hideaki Nakajima
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
| |
Collapse
|
|
31
|
Sheikh MA, Emerald BS, Ansari SA. Stem cell fate determination through protein O-GlcNAcylation. J Biol Chem 2021; 296:100035. [PMID: 33154167 PMCID: PMC7948975 DOI: 10.1074/jbc.rev120.014915] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022] Open
Abstract
Embryonic and adult stem cells possess the capability of self-renewal and lineage-specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell-type-specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications. UDP-GlcNAc is one such metabolite that acts as a substrate for enzymatic mono-glycosylation of various nuclear, cytosolic, and mitochondrial proteins on serine/threonine amino acid residues, a process termed protein O-GlcNAcylation. The levels of GlcNAc inside the cells depend on the nutrient availability, especially glucose. Thus, this metabolic sensor could modulate gene expression through O-GlcNAc modification of histones or other proteins in response to metabolic fluctuations. Herein, we review evidence demonstrating how stem cells couple metabolic inputs to gene regulatory pathways through O-GlcNAc-mediated epigenetic/transcriptional regulatory mechanisms to govern self-renewal and lineage-specific differentiation programs. This review will serve as a primer for researchers seeking to better understand how O-GlcNAc influences stemness and may catalyze the discovery of new stem-cell-based therapeutic approaches.
Collapse
Affiliation(s)
- Muhammad Abid Sheikh
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE; Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE; Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE.
| |
Collapse
|
|
32
|
Son JS, Chae SA, Wang H, Chen Y, Bravo Iniguez A, de Avila JM, Jiang Z, Zhu MJ, Du M. Maternal Inactivity Programs Skeletal Muscle Dysfunction in Offspring Mice by Attenuating Apelin Signaling and Mitochondrial Biogenesis. Cell Rep 2020; 33:108461. [PMID: 33264618 PMCID: PMC8137280 DOI: 10.1016/j.celrep.2020.108461] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 10/14/2020] [Accepted: 11/10/2020] [Indexed: 12/25/2022] Open
Abstract
Although maternal exercise (ME) becomes increasingly uncommon, the effects of ME on offspring muscle metabolic health remain largely undefined. Maternal mice are subject to daily exercise during pregnancy, which enhances mitochondrial biogenesis during fetal muscle development; this is correlated with higher mitochondrial content and oxidative muscle fibers in offspring muscle and improved endurance capacity. Apelin, an exerkine, is elevated due to ME, and maternal apelin administration mirrors the effect of ME on mitochondrial biogenesis in fetal muscle. Importantly, both ME and apelin induce DNA demethylation of the peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) promoter and enhance its expression and mitochondrial biogenesis in fetal muscle. Such changes in DNA methylation were maintained in offspring, with ME offspring muscle expressing higher levels of PGC-1α1/4 isoforms, explaining improved muscle function. In summary, ME enhances DNA demethylation of the Ppargc1a promoter in fetal muscle, which has positive programming effects on the exercise endurance capacity and protects offspring muscle against metabolic dysfunction. Son et al. demonstrate that maternal exercise facilitates fetal muscle development, which improves muscle function and exercise endurance in offspring. Maternal administration of apelin, an exerkine, mirrors the beneficial effects of maternal exercise on mitochondrial biogenesis and fetal muscle development. These findings suggest apelin and its receptor as potential drug targets for improving fetal muscle development of sedentary mothers.
Collapse
Affiliation(s)
- Jun Seok Son
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
| | - Song Ah Chae
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | - Hongyang Wang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
| | - Yanting Chen
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | | | - Jeanene M de Avila
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | - Zhihua Jiang
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA
| | - Min Du
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
| |
Collapse
|
|
33
|
Nicaise AM, Willis CM, Crocker SJ, Pluchino S. Stem Cells of the Aging Brain. Front Aging Neurosci 2020; 12:247. [PMID: 32848716 PMCID: PMC7426063 DOI: 10.3389/fnagi.2020.00247] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.
Collapse
Affiliation(s)
- Alexandra M Nicaise
- Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Cory M Willis
- Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Stephen J Crocker
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, United States
| | - Stefano Pluchino
- Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
34
|
Baulies A, Angelis N, Li VSW. Hallmarks of intestinal stem cells. Development 2020; 147:147/15/dev182675. [PMID: 32747330 DOI: 10.1242/dev.182675] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Intestinal stem cells (ISCs) are highly proliferative cells that fuel the continuous renewal of the intestinal epithelium. Understanding their regulatory mechanisms during tissue homeostasis is key to delineating their roles in development and regeneration, as well as diseases such as bowel cancer and inflammatory bowel disease. Previous studies of ISCs focused mainly on the position of these cells along the intestinal crypt and their capacity for multipotency. However, evidence increasingly suggests that ISCs also exist in distinct cellular states, which can be an acquired rather than a hardwired intrinsic property. In this Review, we summarise the recent findings into how ISC identity can be defined by proliferation state, signalling crosstalk, epigenetics and metabolism, and propose an update on the hallmarks of ISCs. We further discuss how these properties contribute to intestinal development and the dynamics of injury-induced regeneration.
Collapse
Affiliation(s)
- Anna Baulies
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Nikolaos Angelis
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Vivian S W Li
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| |
Collapse
|
|
35
|
Lu X, Chen HM, Qian XQ, Gui JF. Transcriptome analysis of grass carp (Ctenopharyngodon idella) between fast- and slow-growing fish. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2020; 35:100688. [PMID: 32454298 DOI: 10.1016/j.cbd.2020.100688] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 04/11/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022]
Abstract
Grass carp is one of the most important freshwater aquaculture species in China. However, the mechanisms underlying the growth of muscle tissue in the fish are unclear. High-throughput RNA-Seq was used to analyze the transcriptome of grass carp muscle tissue between fast- and slow-growing fish family groups. Twenty-four individuals each from 4 fast-growing families and 4 slow-growing families were used to reduce background noise. 71 up-regulated and 35 down-regulated genes were identified in the differentially expressed genes (DEGs). GO and KEGG enrichment analyses revealed the DEGs were involved in the GH/IGF axis, calcium metabolism, protein and glycogen synthesis, oxygen transport, cytoskeletal and myofibrillar components. IGFBP1 was up-regulated in big fish while GHR2 was down-regulated. Glutamic pyruvate transaminase 2, an indicator of liver tissue damage, was down-regulated in big grass carp, which indicates that the fish was better adapted to an artificially formulated diet. GAPDH, the rate-limiting enzyme in glycolytic flux was highly expressed in fast-growing grass carp, reflecting enhanced carbohydrate metabolism. Higher expression of ALAS2 and myoglobin 1 in big grass carp, related to oxygen transport might promote aerobic exercise along with food intake and muscle growth. Genes for cytoskeletal and myofibrillar components such as tropomyosin, meromyosin, and troponin I were also up-regulated in big grass carp. These results provide valuable information about the key genes for use as biomarkers of growth in selective breeding programs for grass carp and contribute to our understanding of the molecular mechanisms and regulative pathways regulating growth in fish.
Collapse
Affiliation(s)
- Xue Lu
- Key Laboratory of Utilization for Microbiological Resources in Breeding Industries, Ministry of Agriculture and Rural Affairs, Haid Central Research Institute, Animal Husbandry and Fisheries Research Center of Guangdong Haid Group Co., Ltd., Guangzhou 511400, China
| | - Hui-Min Chen
- Key Laboratory of Utilization for Microbiological Resources in Breeding Industries, Ministry of Agriculture and Rural Affairs, Haid Central Research Institute, Animal Husbandry and Fisheries Research Center of Guangdong Haid Group Co., Ltd., Guangzhou 511400, China
| | - Xue-Qiao Qian
- Key Laboratory of Utilization for Microbiological Resources in Breeding Industries, Ministry of Agriculture and Rural Affairs, Haid Central Research Institute, Animal Husbandry and Fisheries Research Center of Guangdong Haid Group Co., Ltd., Guangzhou 511400, China.
| | - Jian-Fang Gui
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Wuhan 430072, China
| |
Collapse
|
|
36
|
Somasundaram L, Levy S, Hussein AM, Ehnes DD, Mathieu J, Ruohola-Baker H. Epigenetic metabolites license stem cell states. Curr Top Dev Biol 2020; 138:209-240. [PMID: 32220298 DOI: 10.1016/bs.ctdb.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
It has become clear during recent years that stem cells undergo metabolic remodeling during their activation process. While these metabolic switches take place in pluripotency as well as adult stem cell populations, the rules that govern the switch are not clear. In this review, we summarize some of the transitions in adult and pluripotent cell types and will propose that the key function in this process is the generation of epigenetic metabolites that govern critical epigenetic modifications, and therefore stem cell states.
Collapse
Affiliation(s)
- Logeshwaran Somasundaram
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Shiri Levy
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Abdiasis M Hussein
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Devon D Ehnes
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Julie Mathieu
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States; Department of Comparative Medicine, University of Washington, Seattle, WA, United States
| | - Hannele Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States.
| |
Collapse
|
|
37
|
Succinate Supplement Elicited "Pseudohypoxia" Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells. Stem Cells Int 2020; 2020:2016809. [PMID: 32215014 PMCID: PMC7085835 DOI: 10.1155/2020/2016809] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/01/2020] [Accepted: 02/25/2020] [Indexed: 01/03/2023] Open
Abstract
Most mesenchymal stem cells reside in a niche of low oxygen tension. Iron-chelating agents such as CoCl2 and deferoxamine have been utilized to mimic hypoxia and promote cell growth. The purpose of the present study was to explore whether a supplement of succinate, a natural metabolite of the tricarboxylic acid (TCA) cycle, can mimic hypoxia condition to promote human periodontal ligament cells (hPDLCs). Culturing hPDLCs in hypoxia condition promoted cell proliferation, migration, and osteogenic differentiation; moreover, hypoxia shifted cell metabolism from oxidative phosphorylation to glycolysis with accumulation of succinate in the cytosol and its release into culture supernatants. The succinate supplement enhanced hPDLC proliferation, migration, and osteogenesis with decreased succinate dehydrogenase (SDH) expression and activity, as well as increased hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), suggesting metabolic reprogramming from oxidative phosphorylation to glycolysis in a normal oxygen condition. The succinate supplement in cell cultures promoted intracellular succinate accumulation while stabilizing hypoxia inducible factor-1α (HIF-1α), leading to a state of pseudohypoxia. Moreover, we demonstrate that hypoxia-induced proliferation was G-protein-coupled receptor 91- (GPR91-) dependent, while exogenous succinate-elicited proliferation involved the GPR91-dependent and GPR91-independent pathway. In conclusion, the succinate supplement altered cell metabolism in hPDLCs, induced a pseudohypoxia condition, and enhanced proliferation, migration, and osteogenesis of mesenchymal stem cells in vitro.
Collapse
|
|
38
|
TGF-ß1 Induces Changes in the Energy Metabolism of White Adipose Tissue-Derived Human Adult Mesenchymal Stem/Stromal Cells In Vitro. Metabolites 2020; 10:metabo10020059. [PMID: 32046088 PMCID: PMC7074410 DOI: 10.3390/metabo10020059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/27/2020] [Accepted: 02/05/2020] [Indexed: 12/19/2022] Open
Abstract
Adipose tissue plays an active role in the regulation of the body’s energy balance. Mesenchymal stem/stromal cells from adipose tissue (adMSC) are the precursor cells for repair and adipogenesis. Since the balance of the differentiation state of adipose tissue-resident cells is associated with the development of various diseases, the examination of the regulation of proliferation and differentiation of adMSC might provide new therapeutic targets. Transforming growth factor-β1 (TGF-ß1) is synthetized by many cell types and is involved in various biological processes. Here, we investigated the effects of different concentrations of TGF-ß1 (1–10 ng/mL) on adMSC proliferation, metabolic activity, and analyzed the gene expression data obtained from DNA microarrays by bioinformatics. TGF-ß1 induced the concentration- and time-dependent increase in the cell number of adMSC with simultaneously unchanged cell cycle distributions. The basal oxygen consumption rates did not change significantly after TGF-ß1 exposure. However, glycolytic activity was significantly increased. The gene expression analysis identified 3275 differentially expressed genes upon exposure to TGF-ß1. According to the pathway enrichment analyses, they also included genes associated with energy metabolism. Thus, it was shown that TGF-ß1 induces changes in the energy metabolism of adMSC. Whether these effects are of relevance in vivo and whether they contribute to pathogenesis should be addressed in further examinations.
Collapse
|
|
39
|
Yousuf Y, Datu A, Barnes B, Amini-Nik S, Jeschke MG. Metformin alleviates muscle wasting post-thermal injury by increasing Pax7-positive muscle progenitor cells. Stem Cell Res Ther 2020; 11:18. [PMID: 31915055 PMCID: PMC6950874 DOI: 10.1186/s13287-019-1480-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 10/14/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Profound skeletal muscle wasting and weakness is common after severe burn and persists for years after injury contributing to morbidity and mortality of burn patients. Currently, no ideal treatment exists to inhibit muscle catabolism. Metformin is an anti-diabetic agent that manages hyperglycemia but has also been shown to have a beneficial effect on stem cells after injury. We hypothesize that metformin administration will increase protein synthesis in the skeletal muscle by increasing the proliferation of muscle progenitor cells, thus mitigating muscle atrophy post-burn injury. METHODS To determine whether metformin can attenuate muscle catabolism following burn injury, we utilized a 30% total burn surface area (TBSA) full-thickness scald burn in mice and compared burn injuries with and without metformin treatment. We examined the gastrocnemius muscle at 7 and 14 days post-burn injury. RESULTS At 7 days, burn injury significantly reduced myofiber cross-sectional area (CSA) compared to sham, p < 0.05. Metformin treatment significantly attenuated muscle catabolism and preserved muscle CSA at the sham size. To investigate metformin's effect on satellite cells (muscle progenitors), we examined changes in Pax7, a transcription factor regulating the proliferation of muscle progenitors. Burned animals treated with metformin had a significant increase in Pax7 protein level and the number of Pax7-positive cells at 7 days post-burn, p < 0.05. Moreover, through BrdU proliferation assay, we show that metformin treatment increased the proliferation of satellite cells at 7 days post-burn injury, p < 0.05. CONCLUSION In summary, metformin's various metabolic effects and its modulation of stem cells make it an attractive alternative to mitigate burn-induced muscle wasting while also managing hyperglycemia.
Collapse
Affiliation(s)
- Yusef Yousuf
- Sunnybrook Research Institute, 2075 Bayview Ave., Rm. D704, Toronto, ON, M4N 3M5, Canada
| | - Andrea Datu
- Sunnybrook Research Institute, 2075 Bayview Ave., Rm. D704, Toronto, ON, M4N 3M5, Canada
| | - Ben Barnes
- Sunnybrook Research Institute, 2075 Bayview Ave., Rm. D704, Toronto, ON, M4N 3M5, Canada
| | - Saeid Amini-Nik
- Sunnybrook Research Institute, 2075 Bayview Ave., Rm. D704, Toronto, ON, M4N 3M5, Canada. .,Laboratory in Medicine and Pathobiology, University of Toronto, Toronto, Canada. .,Division of Plastic Surgery, Department of Surgery, University of Toronto, Toronto, Canada.
| | - Marc G Jeschke
- Sunnybrook Research Institute, 2075 Bayview Ave., Rm. D704, Toronto, ON, M4N 3M5, Canada. .,Division of Plastic Surgery, Department of Surgery, University of Toronto, Toronto, Canada. .,Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Canada. .,Department of Immunology, University of Toronto, Toronto, Canada.
| |
Collapse
|
|
40
|
Francescangeli F, De Angelis ML, Zeuner A. Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer. Nutrients 2019; 11:nu11122936. [PMID: 31816977 PMCID: PMC6950549 DOI: 10.3390/nu11122936] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/21/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Global CRC burden is expected to increase by 60% in the next decade, with low-income countries experiencing an escalation of CRC incidence and mortality in parallel to the adoption of western lifestyles. CRC incidence is also sharply increasing in individuals younger than 50 years, often presenting at advanced stages and with aggressive features. Both genetic and environmental factors have been recognized as major contributors for the development of CRC, the latter including diet-related conditions such as chronic inflammation and obesity. In particular, a diet rich in fat and sugars (Western-style diet, WSD) has been shown to induce multiple pathophysiological changes in the intestine linked to an increased risk of CRC. In this scenario, dietary factors have been recently shown to play novel unexpected roles in the regulation of intestinal stem cells (ISCs) and of the gut microbiota, which represent the two main biological systems responsible for intestinal homeostasis. Furthermore, diet is increasingly recognized to play a key role in the neoplastic transformation of ISCs and in the metabolic regulation of colorectal cancer stem cells. This review illustrates novel discoveries on the role of dietary components in regulating intestinal homeostasis and colorectal tumorigenesis. Particular focus is dedicated to new areas of research with potential clinical relevance including the effect of food components on ISCs and cancer stem cells (CSCs), the existence of CRC-specific microbial signatures and the alterations of intestinal homeostasis potentially involved in early-onset CRC. New insights on the role of dietary factors in intestinal regulation will provide new tools not only for the prevention and early diagnosis of CRC but also for improving the effectiveness of current CRC therapies.
Collapse
|
|
41
|
Vengayil V, Rashida Z, Laxman S. The E3 ubiquitin ligase Pib1 regulates effective gluconeogenic shutdown upon glucose availability. J Biol Chem 2019; 294:17209-17223. [PMID: 31604822 PMCID: PMC6873170 DOI: 10.1074/jbc.ra119.009822] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/27/2019] [Indexed: 12/31/2022] Open
Abstract
Cells use multiple mechanisms to regulate their metabolic states in response to changes in their nutrient environment. One example is the response of cells to glucose. In Saccharomyces cerevisiae growing in glucose-depleted medium, the re-availability of glucose leads to the down-regulation of gluconeogenesis and the activation of glycolysis, leading to "glucose repression." However, our knowledge of the mechanisms mediating the glucose-dependent down-regulation of the gluconeogenic transcription factors is limited. Using the major gluconeogenic transcription factor Rds2 as a candidate, we identify here a novel role for the E3 ubiquitin ligase Pib1 in regulating the stability and degradation of Rds2. Glucose addition to cells growing under glucose limitation results in a rapid ubiquitination of Rds2, followed by its proteasomal degradation. Through in vivo and in vitro experiments, we establish Pib1 as the ubiquitin E3 ligase that regulates Rds2 ubiquitination and stability. Notably, this Pib1-mediated Rds2 ubiquitination, followed by proteasomal degradation, is specific to the presence of glucose. This Pib1-mediated ubiquitination of Rds2 depends on the phosphorylation state of Rds2, suggesting a cross-talk between ubiquitination and phosphorylation to achieve a metabolic state change. Using stable isotope-based metabolic flux experiments, we find that the loss of Pib1 results in an imbalanced gluconeogenic state, regardless of glucose availability. Pib1 is required for complete glucose repression and enables cells to optimally grow in competitive environments when glucose again becomes available. Our results reveal the existence of a Pib1-mediated regulatory program that mediates glucose repression when glucose availability is restored.
Collapse
Affiliation(s)
- Vineeth Vengayil
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore 560065, India
- Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Zeenat Rashida
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore 560065, India
- Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sunil Laxman
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore 560065, India
| |
Collapse
|
|
42
|
McKeown CR, Cline HT. Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors. Development 2019; 146:146/20/dev178871. [PMID: 31649012 DOI: 10.1242/dev.178871] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 09/05/2019] [Indexed: 01/23/2023]
Abstract
Nutrient status affects brain development; however, the effects of nutrient availability on neural progenitor cell proliferation in vivo are poorly understood. Without food, Xenopus laevis tadpoles enter a period of stasis during which neural progenitor proliferation is drastically reduced, but resumes when food becomes available. Here, we investigate how neural progenitors halt cell division in response to nutrient restriction and subsequently re-enter the cell cycle upon feeding. We demonstrate that nutrient restriction causes neural progenitors to arrest in G2 of the cell cycle with increased DNA content, and that nutrient availability triggers progenitors to re-enter the cell cycle at M phase. Initiation of the nutrient restriction-induced G2 arrest is rapamycin insensitive, but cell cycle re-entry requires mTOR. Finally, we show that activation of insulin receptor signaling is sufficient to increase neural progenitor cell proliferation in the absence of food. A G2 arrest mechanism provides an adaptive strategy to control brain development in response to nutrient availability by triggering a synchronous burst of cell proliferation when nutrients become available. This may be a general cellular mechanism that allows developmental flexibility during times of limited resources.
Collapse
Affiliation(s)
| | - Hollis T Cline
- Department of Neuroscience, Scripps Research, La Jolla, CA 92037, USA
| |
Collapse
|
|
43
|
Hira VVV, Breznik B, Vittori M, Loncq de Jong A, Mlakar J, Oostra RJ, Khurshed M, Molenaar RJ, Lah T, Van Noorden CJF. Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies. J Histochem Cytochem 2019; 68:33-57. [PMID: 31566074 DOI: 10.1369/0022155419878416] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.
Collapse
Affiliation(s)
- Vashendriya V V Hira
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Miloš Vittori
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Annique Loncq de Jong
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Jernej Mlakar
- Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Roelof-Jan Oostra
- Department of Medical Biology, Section Clinical Anatomy and Embryology, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Mohammed Khurshed
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Remco J Molenaar
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Tamara Lah
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Cornelis J F Van Noorden
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
44
|
Serio RN, Lu C, Gross SS, Gudas LJ. Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation. Alcohol Clin Exp Res 2019; 43:1859-1871. [PMID: 31283017 PMCID: PMC6722009 DOI: 10.1111/acer.14146] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/26/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ethanol (EtOH) is a teratogen that causes severe birth defects, but the mechanisms by which EtOH affects stem cell differentiation are unclear. Our goal here is to examine the effects of EtOH and its metabolites, acetaldehyde (AcH) and acetate, on embryonic stem cell (ESC) differentiation. METHODS We designed ESC lines in which aldehyde dehydrogenase (ALDH2, NCBI#11669) and acyl-CoA synthetase short-chain family member 2 (ACSS2, NCBI#60525) were knocked out by CRISPR-Cas9 technology. We selected these genes because of their key roles in EtOH oxidation in order to dissect the effects of EtOH metabolism on differentiation. RESULTS By using kinetic assays, we confirmed that AcH is primarily oxidized by ALDH2 rather than ALDH1A2. We found increases in mRNAs of differentiation-associated genes (Hoxa1, Cyp26a1, and RARβ2) upon EtOH treatment of WT and Acss2-/- ESCs, but not Aldh2-/- ESCs. The absence of ALDH2 reduced mRNAs of some pluripotency factors (Nanog, Sox2, and Klf4). Treatment of WT ESCs with AcH or 4-hydroxynonenal (4-HNE), another substrate of ALDH2, increased differentiation-associated transcripts compared to levels in untreated cells. mRNAs of genes involved in retinoic acid (RA) synthesis (Stra6 and Rdh10) were also increased by EtOH, AcH, and 4-HNE treatment. Retinoic acid receptor-γ (RARγ) is required for both EtOH- and AcH-mediated increases in Hoxa1 and Stra6, demonstrating the critical role of RA:RARγ signaling in AcH-induced ESC differentiation. CONCLUSIONS ACSS2 knockouts showed no changes in differentiation phenotype, while pluripotency-related transcripts were decreased in ALDH2 knockout ESCs. We demonstrate that AcH increases differentiation-associated mRNAs in ESCs via RARγ.
Collapse
Affiliation(s)
- Ryan N Serio
- Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY
| | - Changyuan Lu
- Department of Pharmacology, Weill Cornell Medical College, New York, NY
| | - Steven S Gross
- Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY
- Department of Pharmacology, Weill Cornell Medical College, New York, NY
| | - Lorraine J Gudas
- Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, NY
- Department of Pharmacology, Weill Cornell Medical College, New York, NY
| |
Collapse
|
|
45
|
Armstrong DA, Chen Y, Dessaint JA, Aridgides DS, Channon JY, Mellinger DL, Christensen BC, Ashare A. DNA Methylation Changes in Regional Lung Macrophages Are Associated with Metabolic Differences. Immunohorizons 2019; 3:274-281. [PMID: 31356157 PMCID: PMC6686200 DOI: 10.4049/immunohorizons.1900042] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 06/05/2019] [Indexed: 12/21/2022] Open
Abstract
A number of pulmonary diseases occur with upper lobe predominance, including cystic fibrosis and smoking-related chronic obstructive pulmonary disease. In the healthy lung, several physiologic and metabolic factors exhibit disparity when comparing the upper lobe of the lung to lower lobe, including differences in oxygenation, ventilation, lymphatic flow, pH, and blood flow. In this study, we asked whether these regional differences in the lung are associated with DNA methylation changes in lung macrophages that could potentially lead to altered cell responsiveness upon subsequent environmental challenge. All analyses were performed using primary lung macrophages collected via bronchoalveolar lavage from healthy human subjects with normal pulmonary function. Epigenome-wide DNA methylation was examined via Infinium MethylationEPIC (850K) array and validated by targeted next-generation bisulfite sequencing. We observed 95 CpG loci with significant differential methylation in lung macrophages, comparing upper lobe to lower lobe (all false discovery rate < 0.05). Several of these genes, including CLIP4, HSH2D, NR4A1, SNX10, and TYK2, have been implicated as participants in inflammatory/immune-related biological processes. Functionally, we identified phenotypic differences in oxygen use, comparing upper versus lower lung macrophages. Our results support a hypothesis that epigenetic changes, specifically DNA methylation, at a multitude of gene loci in lung macrophages are associated with metabolic differences regionally in lung.
Collapse
Affiliation(s)
- David A Armstrong
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756;
| | - Youdinghuan Chen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.,Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756
| | - John A Dessaint
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756
| | - Daniel S Aridgides
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756
| | - Jacqueline Y Channon
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and
| | - Diane L Mellinger
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756
| | - Brock C Christensen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.,Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.,Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756
| | - Alix Ashare
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; .,Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and
| |
Collapse
|
|
46
|
Radu AG, Torch S, Fauvelle F, Pernet-Gallay K, Lucas A, Blervaque R, Delmas V, Schlattner U, Lafanechère L, Hainaut P, Tricaud N, Pingault V, Bondurand N, Bardeesy N, Larue L, Thibert C, Billaud M. LKB1 specifies neural crest cell fates through pyruvate-alanine cycling. SCIENCE ADVANCES 2019; 5:eaau5106. [PMID: 31328154 PMCID: PMC6636984 DOI: 10.1126/sciadv.aau5106] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 06/10/2019] [Indexed: 05/08/2023]
Abstract
Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.
Collapse
Affiliation(s)
- Anca G. Radu
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Sakina Torch
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Florence Fauvelle
- Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France
- Univ. Grenoble Alpes, INSERM, US17, MRI facility IRMaGe, 38000 Grenoble, France
| | - Karin Pernet-Gallay
- Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France
| | - Anthony Lucas
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Renaud Blervaque
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Véronique Delmas
- Institut Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347; INSERM U1021; Equipe Labellisée–Ligue Nationale Contre le Cancer, Orsay, France
| | - Uwe Schlattner
- Laboratory of Fundamental and Applied Bioenergetics, Univ Grenoble Alpes, 38185 Grenoble, France
- INSERM U1055, 38041 Grenoble France
| | - Laurence Lafanechère
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Pierre Hainaut
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Nicolas Tricaud
- INSERM U1051, Institut des Neurosciences de Montpellier (INM), Université de Montpellier, Montpellier, France
| | | | | | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Lionel Larue
- Institut Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347; INSERM U1021; Equipe Labellisée–Ligue Nationale Contre le Cancer, Orsay, France
| | - Chantal Thibert
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
- Corresponding author. (M.B.); (C.T.)
| | - Marc Billaud
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
- “Clinical and experimental model of lymphomagenesis” Univ Lyon, Université Claude Bernard Lyon1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon France
- Corresponding author. (M.B.); (C.T.)
| |
Collapse
|
|
47
|
Kfir SH, Barash I. Calorie restriction and rapamycin administration induce stem cell self-renewal and consequent development and production in the mammary gland. Exp Cell Res 2019; 382:111477. [PMID: 31242443 DOI: 10.1016/j.yexcr.2019.06.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 06/16/2019] [Accepted: 06/19/2019] [Indexed: 12/27/2022]
Abstract
Expansion of the mammary epithelial stem cell pool holds promise for consequent mammary gland development and production. Complementary analyses of bovine mammary implants maintained in de-epithelialized mouse mammary fat pad and endogenous mouse mammary gland were performed to elucidate the effect of calorie restriction (CR) on stem cell self-renewal. CR elevated propagation rate and non-adherent mammosphere generation in cultured bovine mammary cells. A corresponding decrease in progenitor-induced colony formation and differentiation marker expression was noted. In the mouse gland, CR enhanced the take rate of transplanted cells and outgrowths' fat pad occupancy. Downregulating mTOR activity by rapamycin administration reproduced CR's effects on stem cell self-renewal within a shorter period. Flow cytometry demonstrated a significant 1.5-fold increase in stem cell number and a corresponding decrease in luminal progenitor and differentiated cells. Consequent effects of rapamycin administration included enhanced ductlet generation in bovine implants and higher milk-protein gene expression in cultured mouse mammary cells. The stimulatory effect of CR on BST-1 expression in both bovine implants and mouse glands resembled that noted in the intestinal Paneth stem cell niche (Yilmaz et al., 2012). A putative niche may also exist in the mammary gland, conveying energy-status information to the insulated stem cells.
Collapse
Affiliation(s)
- Shenhav Hanna Kfir
- Institute of Animal Science, Agricultural Research Organization (ARO), The Volcani Center, Bet-Dagan, Israel; The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel
| | - Itamar Barash
- Institute of Animal Science, Agricultural Research Organization (ARO), The Volcani Center, Bet-Dagan, Israel.
| |
Collapse
|
|
48
|
Martano G, Borroni EM, Lopci E, Cattaneo MG, Mattioli M, Bachi A, Decimo I, Bifari F. Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions. Front Mol Neurosci 2019; 12:151. [PMID: 31249511 PMCID: PMC6584756 DOI: 10.3389/fnmol.2019.00151] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/28/2019] [Indexed: 01/01/2023] Open
Abstract
Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidence now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate (OCR) gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review article, we overview the methodologies currently available for the study of invitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single-cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype.
Collapse
Affiliation(s)
| | - Elena Monica Borroni
- Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Egesta Lopci
- Nuclear Medicine Unit, Humanitas Clinical and Research Hospital-IRCCS, Rozzano, Italy
| | - Maria Grazia Cattaneo
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Milena Mattioli
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Angela Bachi
- IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
| | - Ilaria Decimo
- Laboratory of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| |
Collapse
|
|
49
|
Mohammad K, Dakik P, Medkour Y, Mitrofanova D, Titorenko VI. Quiescence Entry, Maintenance, and Exit in Adult Stem Cells. Int J Mol Sci 2019; 20:ijms20092158. [PMID: 31052375 PMCID: PMC6539837 DOI: 10.3390/ijms20092158] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/24/2019] [Accepted: 04/28/2019] [Indexed: 12/13/2022] Open
Abstract
Cells of unicellular and multicellular eukaryotes can respond to certain environmental cues by arresting the cell cycle and entering a reversible state of quiescence. Quiescent cells do not divide, but can re-enter the cell cycle and resume proliferation if exposed to some signals from the environment. Quiescent cells in mammals and humans include adult stem cells. These cells exhibit improved stress resistance and enhanced survival ability. In response to certain extrinsic signals, adult stem cells can self-renew by dividing asymmetrically. Such asymmetric divisions not only allow the maintenance of a population of quiescent cells, but also yield daughter progenitor cells. A multistep process of the controlled proliferation of these progenitor cells leads to the formation of one or more types of fully differentiated cells. An age-related decline in the ability of adult stem cells to balance quiescence maintenance and regulated proliferation has been implicated in many aging-associated diseases. In this review, we describe many traits shared by different types of quiescent adult stem cells. We discuss how these traits contribute to the quiescence, self-renewal, and proliferation of adult stem cells. We examine the cell-intrinsic mechanisms that allow establishing and sustaining the characteristic traits of adult stem cells, thereby regulating quiescence entry, maintenance, and exit.
Collapse
Affiliation(s)
- Karamat Mohammad
- Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-13, Montreal, QC H4B 1R6, Canada.
| | - Paméla Dakik
- Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-13, Montreal, QC H4B 1R6, Canada.
| | - Younes Medkour
- Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-13, Montreal, QC H4B 1R6, Canada.
| | - Darya Mitrofanova
- Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-13, Montreal, QC H4B 1R6, Canada.
| | - Vladimir I Titorenko
- Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-13, Montreal, QC H4B 1R6, Canada.
| |
Collapse
|
|
50
|
Karakatsani A, Shah B, Ruiz de Almodovar C. Blood Vessels as Regulators of Neural Stem Cell Properties. Front Mol Neurosci 2019; 12:85. [PMID: 31031591 PMCID: PMC6473036 DOI: 10.3389/fnmol.2019.00085] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/20/2019] [Indexed: 01/07/2023] Open
Abstract
In the central nervous system (CNS), a precise communication between the vascular and neural compartments is essential for proper development and function. Recent studies demonstrate that certain neuronal populations secrete various molecular cues to regulate blood vessel growth and patterning in the spinal cord and brain during development. Interestingly, the vasculature is now emerging as a critical component that regulates stem cell niches during neocortical development, as well as during adulthood. In this review article, we will first provide an overview of blood vessel development and maintenance in embryonic and adult neurogenic niches. We will also summarize the current understanding of how blood vessel-derived signals influence the behavior of neural stem cells (NSCs) during early development as well as in adulthood, with a focus on their metabolism.
Collapse
Affiliation(s)
- Andromachi Karakatsani
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bhavin Shah
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carmen Ruiz de Almodovar
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|