Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease
The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchan...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88051 |
| _version_ | 1797387149932232704 |
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| author | Subhash Kulkarni Monalee Saha Jared Slosberg Alpana Singh Sushma Nagaraj Laren Becker Chengxiu Zhang Alicia Bukowski Zhuolun Wang Guosheng Liu Jenna M Leser Mithra Kumar Shriya Bakhshi Matthew J Anderson Mark Lewandoski Elizabeth Vincent Loyal A Goff Pankaj Jay Pasricha |
| author_facet | Subhash Kulkarni Monalee Saha Jared Slosberg Alpana Singh Sushma Nagaraj Laren Becker Chengxiu Zhang Alicia Bukowski Zhuolun Wang Guosheng Liu Jenna M Leser Mithra Kumar Shriya Bakhshi Matthew J Anderson Mark Lewandoski Elizabeth Vincent Loyal A Goff Pankaj Jay Pasricha |
| author_sort | Subhash Kulkarni |
| collection | DOAJ |
| description | The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS. |
| first_indexed | 2024-03-08T22:19:43Z |
| format | Article |
| id | doaj.art-d74ff71d09fa45de82dc220b51c19e93 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T22:19:43Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d74ff71d09fa45de82dc220b51c19e932023-12-18T15:16:28ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.88051Age-associated changes in lineage composition of the enteric nervous system regulate gut health and diseaseSubhash Kulkarni0https://orcid.org/0000-0002-2298-0623Monalee Saha1Jared Slosberg2https://orcid.org/0000-0002-1803-2815Alpana Singh3https://orcid.org/0000-0001-6532-8654Sushma Nagaraj4https://orcid.org/0000-0001-5166-1309Laren Becker5Chengxiu Zhang6Alicia Bukowski7Zhuolun Wang8Guosheng Liu9Jenna M Leser10https://orcid.org/0000-0002-3037-0366Mithra Kumar11Shriya Bakhshi12Matthew J Anderson13https://orcid.org/0000-0001-9387-5743Mark Lewandoski14https://orcid.org/0000-0002-1066-3735Elizabeth Vincent15Loyal A Goff16https://orcid.org/0000-0003-2875-451XPankaj Jay Pasricha17https://orcid.org/0000-0002-8727-683XDivision of Gastroenterology, Dept of Medicine, Beth Israel Deaconess Medical Center, Boston, United States; Division of Medical Sciences, Harvard Medical School, Boston, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesDepartment of Genetic Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesDivision of Gastroenterology, Stanford University – School of Medicine, Stanford, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Neurogastroenterology, Department of Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesCenter for Cancer Research, National Cancer Institute, Frederick, United StatesCenter for Cancer Research, National Cancer Institute, Frederick, United StatesDepartment of Genetic Medicine, Johns Hopkins University – School of Medicine, Baltimore, United StatesDepartment of Neuroscience, Johns Hopkins University – School of Medicine, Baltimore, United States; Kavli Neurodiscovery Institute, Johns Hopkins University – School of Medicine, Baltimore, United StatesDepartment of Medicine, Mayo Clinic, Scottsdale, United StatesThe enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.https://elifesciences.org/articles/88051enteric nervous systemperipheral neurosciencemesodermneural crestagingmaturation |
| spellingShingle | Subhash Kulkarni Monalee Saha Jared Slosberg Alpana Singh Sushma Nagaraj Laren Becker Chengxiu Zhang Alicia Bukowski Zhuolun Wang Guosheng Liu Jenna M Leser Mithra Kumar Shriya Bakhshi Matthew J Anderson Mark Lewandoski Elizabeth Vincent Loyal A Goff Pankaj Jay Pasricha Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease eLife enteric nervous system peripheral neuroscience mesoderm neural crest aging maturation |
| title | Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| title_full | Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| title_fullStr | Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| title_full_unstemmed | Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| title_short | Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| title_sort | age associated changes in lineage composition of the enteric nervous system regulate gut health and disease |
| topic | enteric nervous system peripheral neuroscience mesoderm neural crest aging maturation |
| url | https://elifesciences.org/articles/88051 |
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