summary: Previously, scientists believed that development of the enteric nervous system (ENS) stops before birth. However, recent findings have overturned this, showing that ENS development continues postnatally in mice and humans.
This study reveals that the mesoderm is the surprising origin of a significant number of postnatal gut neurons. This finding has profound implications for our understanding of ENS maturation, aging, and disease.
- The ENS, or gut nervous system, produces the same neurotransmitters as the brain and plays an important role in digestion, immunity, and brain-gut communication.
- BIDMC researchers documented the emergence and expansion of new populations of gut neurons that derive from the mesoderm, the same lineage that gives rise to muscle and heart cells.
- This newly discovered lineage of neurons presents a potential new drug target that can be manipulated to treat age-related digestive problems.
Follow your gut. I lose my appetite. Brave move.
While we may think of the gut as a simple digestive organ, these familiar phrases reflect the central role it plays in a much broader range of essential functions.
The entire gastrointestinal tract is lined with the enteric nervous system (ENS), a vast network of millions of neurons and glial cells. These two major cell types are also found in the central nervous system.
Often referred to as the second brain, the ENS produces the same neurotransmitters and was born long before the brain’s central nervous system evolved.
The function of the ENS is vital to life and goes far beyond digestion, as it regulates immunity, gut secretion, and enables complex two-way communication between the gut and brain.
This is why a happy gut and a happy brain coexist, and why digestive problems lead to changes in mood and behavior.
from mid 20’sth For centuries, scientists have believed that the ENS originates from the prenatal neural crest and remains unchanged after birth.
In a paper published in a journal e-lifeResearchers at the Beth Israel Deaconess Medical Center (BIDMC) present an entirely new paradigm to explain the developmental pathways that continue postnatal development of the ENS in mouse and human tissue samples.
This finding marked the first time that evidence for the non-ectodermal and mesodermal origin of a large number of postnatal intestinal neurons has led to decades of scientific research into neuroscience and the basic biology of the ENS. It defies the myth.
This finding indicates that these neurons are associated with ENS maturation and aging in health and disease.
“These results show for the first time that the mesoderm is an important source of neurons in the body’s second largest nervous system,” said Subhash, BIDMC staff scientist and assistant professor of medicine. Dr. Kulkarni said. Harvard Medical School.
“How we mature and how we age is central to understanding health and disease in a rapidly aging population. It is a natural result of maturation and aging.In addition, we would expect this strain to have a clear vulnerability to disease.”
Kulkarni et al. used transgenic mouse models, high-resolution microscopy, and genetic analysis to analyze ENS neuron populations in adult mouse and human tissues. Using mouse models, the researchers found that early postnatal ENS cells were derived from the expected neural crest lineage, but that pattern changed rapidly as the animals matured.
Kulkarni and colleagues documented the arrival and continued expansion of new populations of intestinal neurons derived from the mesoderm, the same lineage that gives rise to muscle and heart cells.
This newly discovered population of mesodermal-derived neurons expands with age, forming one-third of the whole-gut neurons in adolescent mice, half of the whole-gut neurons in adult mice, and eventually forming the original It outnumbered the neural crest-derived enteric neuron population. in aged mice.
By assessing the molecular characteristics of these neurons, the research team identified new cellular markers used to identify populations of mesodermal-derived neurons in human intestinal tissue.
These markers also provide pharmacological targets, which researchers have used not only to manipulate the proportion of mesoderm neurons in adolescent mice, but also to cure the age-related decline in intestinal motility in aged mice. was also used to reduce the predominance rate in the gut of
“We can now work to understand how these findings can be applied to the human system to provide disease-modifying therapies to older patients with gastrointestinal disorders. added Kulkarni.
“By subverting one of neuroscience’s greatest dogmas, we are stepping into uncharted territory while at the same time understanding the basic, translational, and clinical biology of this hidden neuron. I got a big opportunity.
“The newly discovered lineage of neurons presents us with new drug targets that may help a large number of patients.”
Co-authors include Monalee Saha, Jared Slosberg, Alpana Singh, Sushma Nagaraj, Chengxiu Zhang, Alicia Bukowski, Zhuolun Wang, Guosheng Liu, Jenna Leser, Mithra Kumar, Shriya Bakhshi, Elizabeth Vincent, and Loyal A. Goff of Johns Hopkins University. It is included. Medicine; Laren Becker, Stanford University School of Medicine. Matthew Anderson and Mark Lewandski of the National Cancer Institute Cancer Research Center. and Pankaj Jay Pasricha of Mayo Clinic.
Microscopy was performed using an Olympus FV 3000rs (purchased with NIH-NIDDK S10 OD025244 grant) at the Ross Imaging Core at the Hopkins-Conte Digestive Disease Center at Johns Hopkins University (P30DK089502).
10X Genomics Chromium processing of scRNAseq was performed in the GRCF core and sequencing was performed in the Johns Hopkins University CIDR core.
Funding: This study was supported by a grant from the Ludwig Foundation, a grant from the NIA (R01AG066768), a pilot award from the Hopkins Gastroenterology Basic and Translational Research Core Center grant (P30DK089502), and a grant from the Diacomp initiative through the University of Augusta. Supported by the Pilot Award. the Johns Hopkins Catalyst Award; Maryland genetics, epidemiology, and medical residency programs sponsored by the Burroughs Wellcome Foundation. Hopkins Conte Gastroenterology Center at Johns Hopkins University (P30DK089502). NIDDK (R01DK080920); Maryland Stem Cell Research Foundation (MSCRF130005), and grants from the AMOS family.
About this neuroscience research news
author: Chloe Meck
contact: Chloe Meck – BIDMC
image: Image credited to Neuroscience News
Original research: open access.
“Age-related changes in enteric nervous system phylogeny regulate gut health and diseaseSubhash Kulkarni et al. e-life
Age-related changes in enteric nervous system phylogeny regulate gut health and disease
The enteric nervous system (ENS), a collection of nerve cells contained in the intestinal wall, is of fundamental importance to gastrointestinal and systemic health. According to a common paradigm, ENSs arise from progenitor cells that migrate from the neural crest and remain largely unchanged thereafter.
Here we show that the lineage organization of mature ENSs changes over time, with the canonical lineage of neural crest-derived neurons diminishing and being replaced by a newly identified lineage of mesoderm-derived neurons. Single-cell transcriptomics and immunochemical approaches establish distinct expression profiles in mesoderm-derived neurons.
The dynamic balance between the proportions of these two different lineages of neurons in the postnatal gut depends on the availability of their respective trophic signals (GDNF-RET and HGF-MET). With increasing age, mesodermal-derived neurons became the dominant form of neurons in the ENS, and this change is associated with profound functional effects on gut motility and can be reversed by GDNF supplementation. .
Transcriptomic analysis of human intestinal tissue shows that GDNF-RET signaling is reduced in patients with intestinal motility disorders, which is associated with a decrease in neural crest-derived neuronal markers and an associated increase in mesoderm-derived neuron-specific transcriptional patterns. has been shown to be related to
Therefore, it is likely that normal intestinal function in the adult gastrointestinal tract requires an optimal balance between these two distinct lineages within the ENS.