Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury

Abstract

The enteric nervous system (ENS) in mammals forms from neural crest cells during embryogenesis and early postnatal life. Nevertheless, multipotent progenitors of the ENS can be identified in the adult intestine using clonal cultures and in vivo transplantation assays. The identity of these neurogenic precursors in the adult gut and their relationship to the embryonic progenitors of the ENS are currently unknown. Using genetic fate mapping, we here demonstrate that mouse neural crest cells marked by SRY box-containing gene 10 (Sox10) generate the neuronal and glial lineages of enteric ganglia. Most neurons originated from progenitors residing in the gut during mid-gestation. Afterward, enteric neurogenesis was reduced, and it ceased between 1 and 3 months of postnatal life. Sox10-expressing cells present in the myenteric plexus of adult mice expressed glial markers, and we found no evidence that these cells participated in neurogenesis under steady-state conditions. However, they retained neurogenic potential, as they were capable of generating neurons with characteristics of enteric neurons in culture. Furthermore, enteric glia gave rise to neurons in vivo in response to chemical injury to the enteric ganglia. Our results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain limited neurogenic potential, which can be activated by tissue dissociation or injury.

ET3 Promotes the Glial Phenotype in Enteric Neural Progenitors When Used in Parallel or after GDNF Stimulus

“…In the postnatal gut persistent bipotential progenitors can generate glial cells or neurons depending on certain physiological or pathological requirements (15)(16)(17). GDNF plays an important role in proliferation but also during cell differentiation, while ET3 stimulates the proliferative properties of GDNF but blocks its differentiating ability maintaining a constant pool of progenitors.…”

“…This population was initially supposed to be only capable of generating glia in vivo. Now it has been shown to be susceptible to regenerate neuronal loss caused by an insult though this replacement does not occur constitutively [16,17]. Nonetheless, it has been shown that intestinal neurogenesis occurs, and this is possibly at least in part to signaling through 5-HT4 receptors [18].…”

Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease

“…This is consistent with findings from previous reports (Natarajan et al 1999;Lindley et al 2008;Metzger et al 2009;Hotta et al 2013) and again raised a question how to bridge the gap between limited migratory capacity of grafted cells and reasonably long distance for them to travel covering the aganglionic gut segments. Recently, several investigators from leading laboratories have shown that neurogenesis occurs in ENS of adult rodents ex vivo (Becker et al 2013) and in vivo (Liu et al 2009;Joseph et al 2011;Laranjeira et al 2011). Liu et al (2009) signaling and the more recent study utilizing genetic fate mapping has shown that Sox10-expressing common precursors contribute to neurogenesis in response to ENS injury (Laranjeira et al 2011).…”

Toward a better understanding of enteric gliogenesis

“…Indeed, they have been shown to possess a neurogenic potential in vitro and in vivo even though they are restricted to a glial fate in their native environment. 11,12 Furthermore, enteric glia are also capable of performing the functions of oligodendrocytes and astrocytes when transplanted into the CNS. 13 Harnessing the plastic capabilities of enteric glia thus holds great promise for the development of cell-based therapies for many diseases but the conditions and factors involved remain to be identified.…”