Schwann Cell-derived neuro-gliogenesis

SUMMARY
The enteric nervous system (ENS) is a complex network of neural crest-derived neurons and glia responsible
for regulating key intestinal functions including motility, sensation, and secretion. Unfortunately, the ENS is
frequently subject to injury leading to motor and other abnormalities. Often, this leads to debilitating disorders
with few available treatment options. Excitingly, there is now mounting evidence of postnatal ENS injury-induced
neurogenesis. Importantly, through work on adult animal models we have shown that Schwann cells (SC) can
enter the gut alongside the extrinsic nerves and then differentiate into specific neuronal and glial subtypes
(enteric neuro-gliogenesis). Thus, SC provide an unexpected source of cells to repopulate injured neurons and
enteric glia. Furthermore, we have found that microbiome manipulation is a powerful method to induce Schwann
cell-mediated enteric neuro-gliogenesis leading to functional recovery of the ENS and that this is mediated via
the serotonin 5HT4 pathway. However, many aspects of postnatal ENS neuro-gliogenesis are not fully
understood, including the functional impact of the neuro-gliogenesis from the SC, and the therapeutic potential
for 5HT4 manipulation in human disease aiming for an enhanced SC-induced neuro-glial regeneration.
Building on our published and preliminary results from mice and humans, our overarching hypothesis
is that SC migrating into the gut from the gut’s extrinsic innervation are an important source for postnatal
enteric neuro-gliogenesis, and that this ENS regenerative response is regulated by the microbiome via
5HT4. To test this novel hypothesis, we propose: Aim 1 will characterize postnatal SC-derived enteric neuro-
gliogenesis after microbiome eradication/re-establishment using inducible, fluorescently labeled mice. We will
also determine the functional effects of SC neuro-gliogenesis through extensive in vivo assays of motility and
permeability and ex vivo characterization of cellular function using calcium imaging. Additionally, we will
determine the functional effect of eliminating the SC entering the gut using a diphtheria toxin mouse model. In
Aim 2, we will use two knockout mouse lines: (1) P0CreER/tdT::Tph1-/- and (2) P0CreER/tdT::Tph2-/- to
determine the source of serotonin and the possible clinical applications of our findings by evaluating the SC
response to a 5HT4 agonist, prucalopride. We will also identify specific metabolomic and transcriptomic profiles
of the GI tract (mucosal and myenteric compartments). Finally in Aim 3, We will determine components of human
microbiome-host crosstalk regulating SC-derived enteric neuro-gliogenesis in patients with slow colonic
transit/dysmotility including the effect of 5HT4 agonists (i.e., prucalopride, tegaserod) on the ENS integrity/neuro-
glial regeneration and function and determine metagenomic profiles in our patient cohort. Last, we will perform
fecal transplants from these subjects into germ-free (GF) mice to evaluate ENS recovery. Results from this
proposal will be key for the continued progress in targeted regenerative therapy for the treatment of
congenital and acquired neuro-intestinal disease.

Grant Number: 5R01DK134561-03
NIH Institute/Center: NIH
Principal Investigator: Jaime Belkind-gerson