Development of extrinsic innervation in the abdominal intestines of human embryos

Abstract

Compared to the intrinsic enteric nervous system (ENS), development of the extrinsic ENS is poorly documented, even though its presence is easily detectable with histological techniques. We visualised its development in human embryos and foetuses of 4–9.5 weeks post‐fertilisation using Amira 3D‐reconstruction and Cinema 4D‐remodelling software. The extrinsic ENS originated from small, basophilic neural crest cells (NCCs) that migrated to the para‐aortic region and then continued ventrally to the pre‐aortic region, where they formed autonomic pre‐aortic plexuses. From here, nerve fibres extended along the ventral abdominal arteries and finally connected to the intrinsic system. Schwann cell precursors (SCPs), a subgroup of NCCs that migrate on nerve fibres, showed region‐specific differences in differentiation. SCPs developed into scattered chromaffin cells of the adrenal medulla dorsolateral to the coeliac artery (CA) and into more tightly packed chromaffin cells of the para‐aortic bodies ventrolateral to the inferior mesenteric artery (IMA), with reciprocal topographic gradients between both fates. The extrinsic ENS first extended along the CA and then along the superior mesenteric artery (SMA) and IMA 5 days later. Apart from the branch to the caecum, extrinsic nerves did not extend along SMA branches in the herniated parts of the midgut until the gut loops had returned in the abdominal cavity, suggesting a permissive role of the intraperitoneal environment. Accordingly, extrinsic innervation had not yet reached the distal (colonic) loop of the midgut at 9.5 weeks development. Based on intrinsic ENS‐dependent architectural remodelling of the gut layers, extrinsic innervation followed intrinsic innervation 3–4 Carnegie stages later.

Development of the sympathetic trunks in human embryos

“…In the next few days (CS14‐late; ~35 days), the number of ganglionic cells increases greatly (Figure 1a). In the lower cervical and upper thoracic region these scattered ganglionic cells form longitudinal columns between the entrance of a spinal nerve into the dermomyotome laterally and the aorta medially (Figure 2a and f), while others are found more ventrally to the pre‐aortic region (not shown, but described at length in our earlier studies (Kruepunga et al, 2020a; Kruepunga et al, 2020b). The sympathetic trunk at CS14 consists of ganglionic cells only (blue dots in Figure 1a and blue arrows in Figure 2f), although nerve fibres from spinal nerves are already extending medially towards the forming columns of ganglionic cells to form the so‐called “communicating branches” ( cf .…”

“…The splanchnic nerves start to extend ventrally as scattered ganglionic cells at CS15‐late (37 days), but have reached the pre‐aortic ganglia at this stage only at the level of the coeliac trunk. We have described the spatiotemporal development of the splanchnic nerves in our studies on the autonomic innervation of the abdominal and pelvic intestines (Kruepunga et al, 2020a; Kruepunga et al, 2020b).…”

“…The peripheral autonomic nervous system derives mostly from neural crest cells (NCCs) that arise concomitantly with neurulation in a cranio‐caudal gradient at the junction of the neural tube and skin (Pla & Monsoro‐Burq, 2018; Theveneau & Mayor, 2012). In human embryos NCCs appear in a cranio‐caudal sequence between CS10 and CS15 [29–36 days of development (Kruepunga et al, 2020a; O'Rahilly & Müller, 2007)]. After delamination, these NCCs migrate ventrally to form, among others, dorsal root ganglia, sympathetic ganglia and pre‐aortic nerve plexuses (Theveneau & Mayor, 2012; Vega‐Lopez et al, 2017).…”

“…In our studies of the extrinsic innervation in the abdomen and lesser pelvis (Kruepunga et al, 2020a; Kruepunga et al, 2020b), we identified neural crest‐derived ganglionic cells by their intense staining properties and topography ( cf . also (Lutz, 1968)).…”

Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota

“…Neurons of dorsal root and nodose ganglia along with intrinsic primary afferent neurons (Dogiel Type II neurons) of the ENS provide sensory functions to gut structures and relay information concerning gut homeostasis to the CNS [43,57]. Ganglionic neurons of the ANS found in the superior and inferior mesenteric ganglia, celiac, middle and inferior cervical ganglia provide direct PNS innervation to visceral organs although those that specifically innervate structures of the gut are largely found in the celiac, superior and inferior mesenteric ganglia [59] (Figure 1). Direct, local control of gut function is mediated almost entirely by the ENS or the gut-brain which is made up of neural networks or plexuses and include the submucosal and myenteric plexuses [59].…”