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Zhang XY, Li C, Lin J, Zhou Y, Shi RZ, Wang ZY, Jiang HB, Wang YY. Intestinal obstruction caused by early stage primary ileum adenocarcinoma: A case report and review of literature. World J Gastrointest Oncol 2025; 17:104919. [DOI: 10.4251/wjgo.v17.i4.104919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/06/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Ileum adenocarcinoma (IA), a type of small bowel adenocarcinoma, is a rather uncommon factor associated with obstruction in small bowel. Owing to its location and indefinite clinical symptoms, the diagnosis of IA is difficult, and survival is usually poor. With respect to the rarity of this disease, very few studies have reported such cases to provide a reference for treatment.
CASE SUMMARY In this manuscript, a case of a 48-year-old man presented with chronic right lower abdominal pain and distention, queasiness and emesis. A computed tomography scan revealed intestinal wall thickening and an intestinal obstruction in the terminal ileum. He was diagnosed with inflammatory bowel disease. However, his symptoms were not relieved after conservative treatment. The patient subsequently underwent exploratory laparotomy, and a tumour in the ileum measuring approximately 2.0 cm × 2.0 cm that was located 20 cm from the ileocolic valve was discovered incidentally and was operatively resected along with the enlarged lymph nodes. Pathological examination revealed a stage IIA (T3N0M0) ulcerative IA. Along with imaging examinations, a diagnosis of primary IA with no lymph or distant metastases was considered. The patient was discharged and recovered well as of the writing of this manuscript.
CONCLUSION IA should be considered as a differential diagnosis in cases of intestinal obstruction, and the recommended method for local disease treatment is surgery.
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Affiliation(s)
- Xiao-Yue Zhang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Chao Li
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Jie Lin
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yan Zhou
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Rui-Zhe Shi
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Zhong-Yu Wang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hai-Bo Jiang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yuan-Yuan Wang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Hazart D, Moulzir M, Delhomme B, Oheim M, Ricard C. Imaging the enteric nervous system. Front Neuroanat 2025; 19:1532900. [PMID: 40145027 PMCID: PMC11937143 DOI: 10.3389/fnana.2025.1532900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025] Open
Abstract
The enteric nervous system (ENS) has garnered increasing scientific interest due to its pivotal role in digestive processes and its involvement in various gastrointestinal and central nervous system (CNS) disorders, including Crohn's disease, Parkinson's disease, and autism. Despite its significance, the ENS remains relatively underexplored by neurobiologists, primarily because its structure and function are less understood compared to the CNS. This review examines both pioneering methodologies that initially revealed the intricate layered structure of the ENS and recent advancements in studying its three-dimensional (3-D) organization, both in fixed samples and at a functional level, ex-vivo or in-vivo. Traditionally, imaging the ENS relied on histological techniques involving sequential tissue sectioning, staining, and microscopic imaging of single sections. However, this method has limitations representing the full complexity of the ENS's 3-D meshwork, which led to the development of more intact preparations, such as whole-mount preparation, as well as the use of volume imaging techniques. Advancements in 3-D imaging, particularly methods like spinning-disk confocal, 2-photon, and light-sheet microscopies, combined with tissue-clearing techniques, have revolutionized our understanding of the ENS's fine structure. These approaches offer detailed views of its cellular architecture, including interactions among various cell types, blood vessels, and lymphatic vessels. They have also enhanced our comprehension of ENS-related pathologies, such as inflammatory bowel disease, Hirschsprung's disease (HSCR), and the ENS's involvement in neurodegenerative disorders like Parkinson's (PD) and Alzheimer's diseases (AD). More recently, 2-photon or confocal in-vivo imaging, combined with transgenic approaches for calcium imaging, or confocal laser endomicroscopy, have opened new avenues for functional studies of the ENS. These methods enable real-time observation of enteric neuronal and glial activity and their interactions. While routinely used in CNS studies, their application to understanding local circuits and signals in the ENS is relatively recent and presents unique challenges, such as accommodating peristaltic movements. Advancements in 3-D in-vivo functional imaging are expected to significantly deepen our understanding of the ENS and its roles in gastrointestinal and neurological diseases, potentially leading to improved diagnostic and therapeutic strategies.
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Affiliation(s)
- Doriane Hazart
- Université Paris Cité, CNRS, Saints-Pères Paris Institute for the Neurosciences, Paris, France
- Doctoral School Brain, Cognition and Behaviour – ED3C - ED 158, Paris, France
| | - Marwa Moulzir
- Université Paris Cité, CNRS, Saints-Pères Paris Institute for the Neurosciences, Paris, France
| | - Brigitte Delhomme
- Université Paris Cité, CNRS, Saints-Pères Paris Institute for the Neurosciences, Paris, France
| | - Martin Oheim
- Université Paris Cité, CNRS, Saints-Pères Paris Institute for the Neurosciences, Paris, France
| | - Clément Ricard
- Université Paris Cité, CNRS, Saints-Pères Paris Institute for the Neurosciences, Paris, France
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Abankwah JK, Wang Y, Wang J, Ogbe SE, Pozzo LD, Chu X, Bian Y. Gut aging: A wane from the normal to repercussion and gerotherapeutic strategies. Heliyon 2024; 10:e37883. [PMID: 39381110 PMCID: PMC11456882 DOI: 10.1016/j.heliyon.2024.e37883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/01/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
Globally, age-related diseases represent a significant public health concern among the elderly population. In aging, healthy organs and tissues undergo structural and functional changes that put the aged adults at risk of diseases. Some of the age-related diseases include cancer, atherosclerosis, brain disorders, muscle atrophy (sarcopenia), gastrointestinal (GIT) disorders, etc. In organs, a decline in stem cell function is the starting point of many conditions and is extremely important in GIT disorder development. Many studies have established that aging affects stem cells and their surrounding supportive niche components. Although there is a significant advancement in treating intestinal aging, the rising elderly population coupled with a higher occurrence of chronic gut ailments necessitates more effective therapeutic approaches to preserve gut health. Notable therapeutic strategies such as Western medicine, traditional Chinese medicine, and other health-promotion interventions have been reported in several studies to hold promise in mitigating age-related gut disorders. This review highlights findings across various facets of gut aging with a focus on aging-associated changes of intestinal stem cells and their niche components, thus a deviation from the normal to repercussion, as well as essential therapeutic strategies to mitigate intestinal aging.
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Affiliation(s)
- Joseph K. Abankwah
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ying Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jida Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Susan Enechojo Ogbe
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Lisa Dal Pozzo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - XiaoQian Chu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - YuHong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
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4
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Choi J, Augenlicht LH. Intestinal stem cells: guardians of homeostasis in health and aging amid environmental challenges. Exp Mol Med 2024; 56:495-500. [PMID: 38424189 PMCID: PMC10985084 DOI: 10.1038/s12276-024-01179-1] [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: 11/14/2023] [Accepted: 12/11/2023] [Indexed: 03/02/2024] Open
Abstract
The intestinal epithelium is the first line of defense and acts as an interface between the vast microbial world within the gastrointestinal tract and the body's internal milieu. The intestinal epithelium not only facilitates nutrient absorption but also plays a key role in defending against pathogens and regulating the immune system. Central to maintaining a healthy epithelium are intestinal stem cells (ISCs), which are essential for replenishing the intestinal epithelium throughout an individual's lifespan. Recent research has unveiled the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. In this review, we delve into the most recent advances in ISC research, with a focus on the roles of ISCs in maintaining mucosal homeostasis and how ISC functionality is influenced by the niche environment. In this review, we explored the regulatory mechanisms that govern ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in the face of various challenges. Understanding the intricate regulation of ISCs and the impact of aging and environmental factors is crucial for advancing our knowledge and developing translational approaches. Future studies should investigate the interactive effects of different risk factors on intestinal function and develop strategies for improving the regenerative capacity of the gut.
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Affiliation(s)
- Jiahn Choi
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Leonard H Augenlicht
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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5
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Hopton RE, Jahahn NJ, Zemper AE. Lrig1 drives cryptogenesis and restrains proliferation during colon development. Am J Physiol Gastrointest Liver Physiol 2023; 325:G570-G581. [PMID: 37873577 PMCID: PMC11192189 DOI: 10.1152/ajpgi.00094.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 10/04/2023] [Accepted: 10/13/2023] [Indexed: 10/25/2023]
Abstract
Growth and specification of the mouse intestine occurs in utero and concludes after birth. Although numerous studies have examined this developmental process in the small intestine, far less is known about the cellular and molecular cues required for colon development. In this study, we examine the morphological events leading to crypt formation, epithelial cell differentiation, proliferation, and the emergence and expression of a stem and progenitor cell marker Lrig1. Through multicolor lineage tracing, we show Lrig1-expressing cells are present at birth and behave as stem cells to establish clonal crypts within 3 wk of life. In addition, we use an inducible knockout mouse to eliminate Lrig1 and show Lrig1 restrains proliferation within a critical developmental time window, without impacting colonic epithelial cell differentiation. Our study illustrates morphological changes during crypt development and the importance of Lrig1 in the developing colon.NEW & NOTEWORTHY Our studies define the importance of studying Lrig1 in colon development. We address a critical gap in the intestinal development literature and provide new information about the molecular cues that guide colon development. Using a novel, inducible knockout of Lrig1, we show Lrig1 is required for appropriate colon epithelial growth and illustrate the importance of Lrig1-expressing cells in the establishment of colonic crypts.
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Affiliation(s)
- Rachel E Hopton
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States
- Department of Biology, University of Oregon, Eugene, Oregon, United States
| | - Nicholas J Jahahn
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States
- Department of Biology, University of Oregon, Eugene, Oregon, United States
| | - Anne E Zemper
- Department of Biology, University of Oregon, Eugene, Oregon, United States
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6
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Meng G, Monaghan TM, Duggal NA, Tighe P, Peerani F. Microbial-Immune Crosstalk in Elderly-Onset Inflammatory Bowel Disease: Unchartered Territory. J Crohns Colitis 2023; 17:1309-1325. [PMID: 36806917 DOI: 10.1093/ecco-jcc/jjad025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Indexed: 02/23/2023]
Abstract
Elderly-onset inflammatory bowel disease [IBD] patients exhibit a distinct natural history compared to younger IBD patients, with unique disease phenotypes, differential responses to therapy, and increased surgical morbidity and mortality. Despite the foreseeable high demand for personalized medicine and specialized IBD care in the elderly, current paradigms of IBD management fail to capture the required nuances of care for elderly-onset IBD patients. Our review postulates the roles of systemic and mucosal immunosenescence, inflammageing and a dysbiotic microbial ecosystem in the pathophysiology of elderly-onset IBD. Ultimately, a better understanding of elderly-onset IBD can lead to improved patient outcomes and the tailoring of future preventative and treatment strategies.
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Affiliation(s)
- Guanmin Meng
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Tanya M Monaghan
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Niharika A Duggal
- MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Paddy Tighe
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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7
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Choi J, Zhang X, Li W, Houston M, Peregrina K, Dubin R, Ye K, Augenlicht L. Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis. Mol Cancer Res 2023; 21:808-824. [PMID: 37097719 PMCID: PMC10390890 DOI: 10.1158/1541-7786.mcr-22-1000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/27/2023] [Accepted: 04/21/2023] [Indexed: 04/26/2023]
Abstract
New Western-style diet 1 (NWD1), a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency, and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and single-cell RNA sequencing, single-cell Assay for Transposase-Accessible Chromatin using sequencing, functional genomics, and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically downregulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, protumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also protumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5-positive and -negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. IMPLICATIONS Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
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Affiliation(s)
- Jiahn Choi
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Xusheng Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Wenge Li
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Michele Houston
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Karina Peregrina
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Robert Dubin
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Kenny Ye
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Leonard Augenlicht
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
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8
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Hopton RE, Jahahn NJ, Zemper AE. The Role of Lrig1 in the Development of the Colonic Epithelium. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.02.539114. [PMID: 37205411 PMCID: PMC10187246 DOI: 10.1101/2023.05.02.539114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Growth and specification of the mouse intestine occurs in utero and concludes after birth. While numerous studies have examined this developmental process in the small intestine, far less is known about the cellular and molecular cues required for colon development. In this study, we examine the morphological events leading to crypt formation, epithelial cell differentiation, areas of proliferation, and the emergence and expression of a stem and progenitor cell marker Lrig1. Through multicolor lineage tracing, we show Lrig1 expressing cells are present at birth and behave as stem cells to establish clonal crypts within three weeks after birth. In addition, we use an inducible knockout mouse to eliminate Lrig1 during colon development and show loss of Lrig1 restrains proliferation within a critical developmental time window, without impacting colonic epithelial cell differentiation. Our study illustrates the morphological changes that occur during crypt development and the importance of Lrig1 in the developing colon.
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9
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Honda M, Kadohisa M, Yoshii D, Komohara Y, Hibi T. Intravital imaging of immune responses in intestinal inflammation. Inflamm Regen 2023; 43:9. [PMID: 36737792 PMCID: PMC9896837 DOI: 10.1186/s41232-023-00262-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
To date, many kinds of immune cells have been identified, but their precise roles in intestinal immunity remain unclear. Understanding the in vivo behavior of these immune cells and their function in gastrointestinal inflammation, including colitis, inflammatory bowel disease, ischemia-reperfusion injury, and neutrophil extracellular traps, is critical for gastrointestinal research to proceed to the next step. Additionally, understanding the immune responses involved in gastrointestinal tumors and tissue repair is becoming increasingly important for the elucidation of disease mechanisms that have been unknown. In recent years, the application of intravital microscopy in gastrointestinal research has provided novel insights into the mechanisms of intestine-specific events including innate and adaptive immunities. In this review, we focus on the emerging role of intravital imaging in gastrointestinal research and describe how to observe the intestines and immune cells using intravital microscopy. Additionally, we outline novel findings obtained by this new technique.
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Affiliation(s)
- Masaki Honda
- grid.274841.c0000 0001 0660 6749Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556 Japan
| | - Masashi Kadohisa
- grid.274841.c0000 0001 0660 6749Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556 Japan
| | - Daiki Yoshii
- grid.411152.20000 0004 0407 1295Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan
| | - Yoshihiro Komohara
- grid.274841.c0000 0001 0660 6749Department of Cell Pathology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Taizo Hibi
- grid.274841.c0000 0001 0660 6749Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556 Japan
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10
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Donath S, Angerstein L, Gentemann L, Müller D, Seidler AE, Jesinghaus C, Bleich A, Heisterkamp A, Buettner M, Kalies S. Investigation of Colonic Regeneration via Precise Damage Application Using Femtosecond Laser-Based Nanosurgery. Cells 2022; 11:1143. [PMID: 35406708 PMCID: PMC8998079 DOI: 10.3390/cells11071143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 11/23/2022] Open
Abstract
Organoids represent the cellular composition of natural tissue. So called colonoids, organoids derived from colon tissue, are a good model for understanding regeneration. However, next to the cellular composition, the surrounding matrix, the cell-cell interactions, and environmental factors have to be considered. This requires new approaches for the manipulation of a colonoid. Of key interest is the precise application of localized damage and the following cellular reaction. We have established multiphoton imaging in combination with femtosecond laser-based cellular nanosurgery in colonoids to ablate single cells in the colonoids' crypts, the proliferative zones, and the differentiated zones. We observed that half of the colonoids recovered within six hours after manipulation. An invagination of the damaged cell and closing of the structure was observed. In about a third of the cases of targeted crypt damage, it caused a stop in crypt proliferation. In the majority of colonoids ablated in the crypt, the damage led to an increase in Wnt signalling, indicated via a fluorescent lentiviral biosensor. qRT-PCR analysis showed increased expression of various proliferation and Wnt-associated genes in response to damage. Our new model of probing colonoid regeneration paves the way to better understand organoid dynamics on a single cell level.
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Affiliation(s)
- Sören Donath
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - Leon Angerstein
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - Lara Gentemann
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - Dominik Müller
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
- REBIRTH Research Center for Translational Regenerative Medicine, 30625 Hannover, Germany
| | - Anna E. Seidler
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - Christian Jesinghaus
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - André Bleich
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
- REBIRTH Research Center for Translational Regenerative Medicine, 30625 Hannover, Germany
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Alexander Heisterkamp
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
| | - Manuela Buettner
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
- REBIRTH Research Center for Translational Regenerative Medicine, 30625 Hannover, Germany
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Stefan Kalies
- Institute of Quantum Optics, Leibniz University Hannover, 30167 Hannover, Germany; (L.A.); (L.G.); (D.M.); (A.E.S.); (C.J.); (A.H.); (S.K.)
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), 30625 Hannover, Germany; (A.B.); (M.B.)
- REBIRTH Research Center for Translational Regenerative Medicine, 30625 Hannover, Germany
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11
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Donaldson DS, Shih BB, Mabbott NA. Aging-Related Impairments to M Cells in Peyer's Patches Coincide With Disturbances to Paneth Cells. Front Immunol 2021; 12:761949. [PMID: 34938288 PMCID: PMC8687451 DOI: 10.3389/fimmu.2021.761949] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/17/2021] [Indexed: 11/26/2022] Open
Abstract
The decline in mucosal immunity during aging increases susceptibility, morbidity and mortality to infections acquired via the gastrointestinal and respiratory tracts in the elderly. We previously showed that this immunosenescence includes a reduction in the functional maturation of M cells in the follicle-associated epithelia (FAE) covering the Peyer’s patches, diminishing the ability to sample of antigens and pathogens from the gut lumen. Here, co-expression analysis of mRNA-seq data sets revealed a general down-regulation of most FAE- and M cell-related genes in Peyer’s patches from aged mice, including key transcription factors known to be essential for M cell differentiation. Conversely, expression of ACE2, the cellular receptor for SARS-Cov-2 virus, was increased in the aged FAE. This raises the possibility that the susceptibility of aged Peyer’s patches to infection with the SARS-Cov-2 virus is increased. Expression of key Paneth cell-related genes was also reduced in the ileum of aged mice, consistent with the adverse effects of aging on their function. However, the increased expression of these genes in the villous epithelium of aged mice suggested a disturbed distribution of Paneth cells in the aged intestine. Aging effects on Paneth cells negatively impact on the regenerative ability of the gut epithelium and could indirectly impede M cell differentiation. Thus, restoring Paneth cell function may represent a novel means to improve M cell differentiation in the aging intestine and increase mucosal vaccination efficacy in the elderly.
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Affiliation(s)
- David S Donaldson
- The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, United Kingdom
| | - Barbara B Shih
- The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, United Kingdom
| | - Neil A Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, United Kingdom
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Tallapragada NP, Cambra HM, Wald T, Keough Jalbert S, Abraham DM, Klein OD, Klein AM. Inflation-collapse dynamics drive patterning and morphogenesis in intestinal organoids. Cell Stem Cell 2021; 28:1516-1532.e14. [PMID: 33915079 DOI: 10.1016/j.stem.2021.04.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 12/29/2020] [Accepted: 04/01/2021] [Indexed: 02/07/2023]
Abstract
How stem cells self-organize to form structured tissues is an unsolved problem. Intestinal organoids offer a model of self-organization as they generate stem cell zones (SCZs) of typical size even without a spatially structured environment. Here we examine processes governing the size of SCZs. We improve the viability and homogeneity of intestinal organoid cultures to enable long-term time-lapse imaging of multiple organoids in parallel. We find that SCZs are shaped by fission events under strong control of ion channel-mediated inflation and mechanosensitive Piezo-family channels. Fission occurs through stereotyped modes of dynamic behavior that differ in their coordination of budding and differentiation. Imaging and single-cell transcriptomics show that inflation drives acute stem cell differentiation and induces a stretch-responsive cell state characterized by large transcriptional changes, including upregulation of Piezo1. Our results reveal an intrinsic capacity of the intestinal epithelium to self-organize by modulating and then responding to its mechanical state.
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Affiliation(s)
- Naren P Tallapragada
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Hailey M Cambra
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Tomas Wald
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Samantha Keough Jalbert
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Diana M Abraham
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Allon M Klein
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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13
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Signaling Network Centered on mTORC1 Dominates Mammalian Intestinal Stem Cell Ageing. Stem Cell Rev Rep 2020; 17:842-849. [PMID: 33201440 DOI: 10.1007/s12015-020-10073-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/19/2022]
Abstract
The intestine integrates the function of digestion, absorption, and barrier, which is easily damaged by the external factors upon ageing. The intestinal stem cells (ISCs) exist at the intestinal crypt base and play an indispensable role in intestinal homeostasis and regeneration. The intestine ageing contributes to malabsorption and other associated illnesses, which were considered to be related to ISCs. Here, we summarize the current research progress of mammalian ISCs ageing and pay more attention to the central regulatory role of the mTORC1 signaling pathway in regulating mammalian ISCs ageing, and its related AMPK, FOXO, Wnt signaling pathways. Furthermore, we also discuss the interventions aimed at mTORC1 and its associated signaling pathways, which may provide potential strategies for rejuvenating aged ISCs and the therapy of age-related intestinal diseases. Graphical abstract Many signaling pathways are altered in the ageing ISCs, thereby inducing the decrease of ISC self-renewal, differentiation, and regeneration, an increasing of oxidative stress may contribute to damage to the ISCs. Interventions such as calorie restriction, fasting and so on can effectively alleviate these adverse effects.
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14
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Walrath T, Dyamenahalli KU, Hulsebus HJ, McCullough RL, Idrovo JP, Boe DM, McMahan RH, Kovacs EJ. Age-related changes in intestinal immunity and the microbiome. J Leukoc Biol 2020; 109:1045-1061. [PMID: 33020981 DOI: 10.1002/jlb.3ri0620-405rr] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/11/2020] [Accepted: 09/13/2020] [Indexed: 12/19/2022] Open
Abstract
The gastrointestinal (GI) tract is a vitally important site for the adsorption of nutrients as well as the education of immune cells. Homeostasis of the gut is maintained by the interplay of the intestinal epithelium, immune cells, luminal Ags, and the intestinal microbiota. The well-being of the gut is intrinsically linked to the overall health of the host, and perturbations to this homeostasis can have severe impacts on local and systemic health. One factor that causes disruptions in gut homeostasis is age, and recent research has elucidated how critical systems within the gut are altered during the aging process. Intestinal stem cell proliferation, epithelial barrier function, the gut microbiota, and the composition of innate and adaptive immune responses are all altered in advanced age. The aging population continues to expand worldwide, a phenomenon referred to as the "Silver Tsunami," and every effort must be made to understand how best to prevent and treat age-related maladies. Here, recent research about changes observed in the intestinal epithelium, the intestinal immune system, the microbiota, and how the aging gut interacts with and influences other organs such as the liver, lung, and brain are reviewed. Better understanding of these age-related changes and their impact on multi-organ interactions will aid the development of therapies to increase the quality of life for all aged individuals.
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Affiliation(s)
- Travis Walrath
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Kiran U Dyamenahalli
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Holly J Hulsebus
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Rebecca L McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.,GI and Liver Innate Immune Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Juan-Pablo Idrovo
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Devin M Boe
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA.,Medical Scientist Training Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Rachel H McMahan
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Elizabeth J Kovacs
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA.,Medical Scientist Training Program, University of Colorado Denver, Aurora, Colorado, USA.,GI and Liver Innate Immune Program, University of Colorado Denver, Aurora, Colorado, USA
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15
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The role of stem cell niche in intestinal aging. Mech Ageing Dev 2020; 191:111330. [DOI: 10.1016/j.mad.2020.111330] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/16/2022]
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16
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Fumagalli A, Bruens L, Scheele CLGJ, van Rheenen J. Capturing Stem Cell Behavior Using Intravital and Live Cell Microscopy. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a035949. [PMID: 31767651 DOI: 10.1101/cshperspect.a035949] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Stem cells maintain tissue homeostasis by driving cellular turnover and regeneration upon damage. They reside within specialized niches that provide the signals required for stem cell maintenance. Stem cells have been identified in many tissues and cancer types, but their behavior within the niche and their reaction to microenvironmental signals were inferred from limited static observations. Recent advances in live imaging techniques, such as live cell imaging and intravital microscopy, have allowed the visualization of stem cell behavior and dynamics over time in their (near) native environment. Through these recent technological advances, it is now evident that stem cells are much more dynamic than previously anticipated, resulting in a model in which stemness is a state that can be gained or lost over time. In this review, we will highlight how live imaging and intravital microscopy have unraveled previously unanticipated stem cell dynamics and plasticity during development, homeostasis, regeneration, and tumor formation.
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Affiliation(s)
- Arianna Fumagalli
- Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066CX, Netherlands
| | - Lotte Bruens
- Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066CX, Netherlands
| | - Colinda L G J Scheele
- Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066CX, Netherlands
| | - Jacco van Rheenen
- Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066CX, Netherlands
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17
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Serowoky MA, Arata CE, Crump JG, Mariani FV. Skeletal stem cells: insights into maintaining and regenerating the skeleton. Development 2020; 147:147/5/dev179325. [PMID: 32161063 DOI: 10.1242/dev.179325] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Skeletal stem cells (SSCs) generate the progenitors needed for growth, maintenance and repair of the skeleton. Historically, SSCs have been defined as bone marrow-derived cells with inconsistent characteristics. However, recent in vivo tracking experiments have revealed the presence of SSCs not only within the bone marrow but also within the periosteum and growth plate reserve zone. These studies show that SSCs are highly heterogeneous with regard to lineage potential. It has also been revealed that, during digit tip regeneration and in some non-mammalian vertebrates, the dedifferentiation of osteoblasts may contribute to skeletal regeneration. Here, we examine how these research findings have furthered our understanding of the diversity and plasticity of SSCs that mediate skeletal maintenance and repair.
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Affiliation(s)
- Maxwell A Serowoky
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Claire E Arata
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - J Gage Crump
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Francesca V Mariani
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Abstract
Intravital microscopy is a powerful technique to observe dynamic processes with single-cell resolution in live animals. No intravital window has been developed for imaging the colon due to its anatomic location and motility, although the colon is a key organ where the majority of microbiota reside and common diseases such as inflammatory bowel disease, functional gastrointestinal disorders, and colon cancer occur. Here we describe an intravital murine colonic window with a stabilizing ferromagnetic scaffold for chronic imaging, minimizing motion artifacts while maximizing long-term survival by preventing colonic obstruction. Using this setup, we image fluorescently-labeled stem cells, bacteria, and immune cells in live animal colons. Furthermore, we image nerve activity via calcium imaging in real time to demonstrate that electrical sacral nerve stimulation can activate colonic enteric neurons. The simple implantable apparatus enables visualization of live processes in the colon, which will open the window to a broad range of studies. Performing intravital imaging of the colon in mouse models is challenging due to the colon’s anatomic location and motility. Here, the authors develop a murine colonic window for intravital chronic imaging that maximises long-term animal survival and minimises motion artefacts.
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Abstract
Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function.
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Affiliation(s)
- Heinrich Jasper
- Immunology Discovery, Genentech, Inc., South San Francisco, California 94080, USA;
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20
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Branca JJ, Gulisano M, Nicoletti C. Intestinal epithelial barrier functions in ageing. Ageing Res Rev 2019; 54:100938. [PMID: 31369869 DOI: 10.1016/j.arr.2019.100938] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/19/2019] [Accepted: 07/24/2019] [Indexed: 12/11/2022]
Abstract
The intestinal epithelial barrier protects the mucosa of the gastrointestinal (GI)-tract and plays a key role in maintaining the host homeostasis. It encompasses several elements that include the intestinal epithelium and biochemical and immunological products, such as the mucus layer, antimicrobial peptides (AMPs) and secretory immunologlobulin A (sIgA). These components are interlinked with the large microbial community inhabiting the gut to form a highly sophisticated biological system that plays an important role on many aspects of human health both locally and systemically. Like any other organ and tissue, the intestinal epithelial barrier is affected by the ageing process. New insights have surfaced showing that critical functions, including intestinal stem cell regeneration and regulation of the intestinal crypt homeostasis, barrier integrity, production of regulatory cytokines, and epithelial innate immunity to pathogenic antigens change across life. Here we review the age-associated changes of the various components of the intestinal epithelial barrier and we highlight the necessity to elucidate further the mechanisms underlying these changes. Expanding our knowledge in this area is a goal of high medical relevance and it will help to define intervention strategies to ameliorate the quality of life of the ever-expanding elderly population.
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21
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DNA damage in aging, the stem cell perspective. Hum Genet 2019; 139:309-331. [PMID: 31324975 DOI: 10.1007/s00439-019-02047-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/05/2019] [Indexed: 02/07/2023]
Abstract
DNA damage is one of the most consistent cellular process proposed to contribute to aging. The maintenance of genomic and epigenomic integrity is critical for proper function of cells and tissues throughout life, and this homeostasis is under constant strain from both extrinsic and intrinsic insults. Considering the relationship between lifespan and genotoxic burden, it is plausible that the longest-lived cellular populations would face an accumulation of DNA damage over time. Tissue-specific stem cells are multipotent populations residing in localized niches and are responsible for maintaining all lineages of their resident tissue/system throughout life. However, many of these stem cells are impacted by genotoxic stress. Several factors may dictate the specific stem cell population response to DNA damage, including the niche location, life history, and fate decisions after damage accrual. This leads to differential handling of DNA damage in different stem cell compartments. Given the importance of adult stem cells in preserving normal tissue function during an individual's lifetime, DNA damage sensitivity and accumulation in these compartments could have crucial implications for aging. Despite this, more support for direct functional effects driven by accumulated DNA damage in adult stem cell compartments is needed. This review will present current evidence for the accumulation and potential influence of DNA damage in adult tissue-specific stem cells and propose inquiry directions that could benefit individual healthspan.
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22
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Moura J, Madureira P, Leal EC, Fonseca AC, Carvalho E. Immune aging in diabetes and its implications in wound healing. Clin Immunol 2019; 200:43-54. [PMID: 30735729 PMCID: PMC7322932 DOI: 10.1016/j.clim.2019.02.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/04/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
Abstract
Immune systems have evolved to recognize and eliminate pathogens and damaged cells. In humans, it is estimated to recognize 109 epitopes and natural selection ensures that clonally expanded cells replace unstimulated cells and overall immune cell numbers remain stationary. But, with age, it faces continuous repertoire restriction and concomitant accumulation of primed cells. Changes shaping the aging immune system have bitter consequences because, as inflammatory responses gain intensity and duration, tissue-damaging immunity and inflammatory disease arise. During inflammation, the glycolytic flux cannot cope with increasing ATP demands, limiting the immune response's extent. In diabetes, higher glucose availability stretches the glycolytic limit, dysregulating proteostasis and increasing T-cell expansion. Long-term hyperglycemia exerts an accumulating effect, leading to higher inflammatory cytokine levels and increased cytotoxic mediator secretion upon infection, a phenomenon known as diabetic chronic inflammation. Here we review the etiology of diabetic chronic inflammation and its consequences on wound healing.
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Affiliation(s)
- J Moura
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, University of Porto, Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
| | - P Madureira
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal; IBMC - Instituto de Biologia Celular e Molecular, University of Porto, Porto, Portugal; Immunethep, Biocant Park, Cantanhede, Portugal
| | - E C Leal
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - A C Fonseca
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - E Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Instituto de Investigação Interdisciplinar, University of Coimbra, Coimbra, Portugal; Department of Geriatrics, University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, AR, United States
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