Intestinal motility is regulated by the Enteric Nervous System (ENS), which resides entirely within the gut wall and comprises the largest collection of neurons and glial cells outside of the brain. Previously, we have provided evidence that post-natal development and adult maintenance of the ENS are controlled by distinct fetal-juvenile Sox10-expressing and adult Nestin-expressing Enteric Neural Stem Cells (ENSC). With maturation, the Sox10-expressing cells lose their neurogenic potential in healthy gut but regain it after specific types of injuries, suggesting that certain juvenile protective factors (JPFs) that allow for Sox10+ cells to generate neurons in juvenile gut are lost in adults, but are re-introduced upon injury in adults. The continual genesis of neurons throughout life suggests that a consistent loss of neurons during the juvenile or adult life is due to significant insufficiencies in the neurogenic capacity of ENSC active at that time. Aging is associated with significant loss of enteric neurons and associated chronic intestinal dysmotility, suggesting that an insufficiency in neurogenic capacity of adult ENSC is responsible for such disorders and that the key to crafting a long-term cure for the elderly patients rests in finding novel strategies to increase or supplement existing adult neurogenesis to normalize ENS structure and function. If latent neurogenic capacity of adult Sox10+ cells can be modulated by JPFs, we hypothesize that identifying, recruiting, and re-introducing JPFs into the aging gut would restart neurogenesis from the newly re-invigorated Sox10+ ENSC and that this strategy holds promise for providing lasting relief to elderly suffering from chronic intestinal dysmotility by supplementing insufficient adult Nestin+ derived enteric neurogenesis. Here, we provide significant preliminary data that identifies some putative extrinsic and intrinsic JPFs and test their effect on ENSC behavior and in this proposal, we aim to use next-generation sequencing, large-scale single-cell measurements, integrative cross-platform analyses, and cutting-edge computational tools to identify diverse putative JPFs, describe the regulatory networks through which they act, and functionally validate their ability to modulate neurogenic capacity using our novel biological insight to correct ENS structure and function in animal models of aging.
Post-natal maturation in mammals is associated with significant changes in diet and microbiota, requiring corresponding changes in digestive behaviors which are heavily regulated by the neurons of the Enteric Nervous System (ENS). To accommodate these changes and to maintain the structural and functional integrity of the ENS, enteric neurons are continually replenished by dedicated and distinct juvenile and adult Enteric Neural Stem Cells (ENSC) by processes that become less robust with aging leading to neuronal insufficiencies and associated intestinal dysmotilities. In this study, we will identify and test key Juvenile Protective Factors (JPFs) that regulate and enable neurogenesis in juvenile ENSC, which may be re-introduced as potential therapies in the aging gut to supplement insufficient neuron production and improve aging-associated intestinal dysfunction.
