Development of extrinsic innervation in the abdominal intestines of human embryos

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

Multipotent skin-derived precursors: adult neural crest-related precursors with therapeutic potential

We previously made the surprising finding that cultures of multipotent precursors can be grown from the dermis of neonatal and adult mammalian skin. These skin-derived precursors (SKPs) display multi-lineage differentiation potential, producing both neural and mesodermal progeny in vitro, and are an apparently novel precursor cell type that is distinct from other known precursors within the skin. In this review, we begin by placing these findings within the context of the rapidly evolving stem cell field. We then describe our recent efforts focused on understanding the developmental biology of SKPs, discussing the idea that SKPs are neural crest-related precursors that (i) migrate into the skin during embryogenesis, (ii) persist within a specific dermal niche, and (iii) play a key role in the normal physiology, and potentially pathology, of the skin. We conclude by highlighting some of the therapeutic implications and unresolved questions raised by these studies

Extrinsic innervation of the pelvic organs in the lesser pelvis of human embryos

Realistic models to understand the developmental appearance of the pelvic nervous system in mammals are scarce. We visualized the development of the inferior hypogastric plexus and its preganglionic connections in human embryos at 4–8 weeks post-fertilization, using Amira 3D reconstruction and Cinema 4D-remodelling software. We defined the embryonic lesser pelvis as the pelvic area caudal to both umbilical arteries and containing the hindgut. Neural crest cells (NCCs) appeared dorsolateral to the median sacral artery near vertebra S1 at ~5 weeks and had extended to vertebra S5 1 day later. Once para-arterial, NCCs either formed sympathetic ganglia or continued to migrate ventrally to the pre-arterial region, where they formed large bilateral inferior hypogastric ganglionic cell clusters (IHGCs). Unlike more cranial pre-aortic plexuses, both IHGCs did not merge because the 'pelvic pouch', a temporary caudal extension of the peritoneal cavity, interposed. Although NCCs in the sacral area started to migrate later, they reached their pre-arterial position simultaneously with the NCCs in the thoracolumbar regions. Accordingly, the superior hypogastric nerve, a caudal extension of the lumbar splanchnic nerves along the superior rectal artery, contacted the IHGCs only 1 day later than the lumbar splanchnic nerves contacted the inferior mesenteric ganglion. The superior hypogastric nerve subsequently splits to become the superior hypogastric plexus. The IHGCs had two additional sources of preganglionic innervation, of which the pelvic splanchnic nerves arrived at ~6.5 weeks and the sacral splanchnic nerves only at ~8 weeks. After all preganglionic connections had formed, separate parts of the inferior hypogastric plexus formed at the bladder neck and distal hindgut

Molecular analysis of neural crest migration

The neural crest (NC) cells have been called the ‘explorers of the embryos’ because they migrate all over the embryo where they differentiate into a variety of diverse kinds of cells. In this work, we analyse the role of different molecules controlling the migration of NC cells. First, we describe the strong similarity between the process of NC migration and metastasis in tumour cells. The epithelial–mesenchymal transition process that both kinds of cells undergo is controlled by the same molecular machinery, including cadherins, connexins, Snail and Twist genes and matrix metalloproteases. Second, we analysed the molecular signals that control the patterned migration of the cephalic and trunk NC cells. Most of the factors described so far, such as Eph/ephrins, semaphorins/neuropilins and Slit/Robo, are negative signals that prohibit the migration of NC cells into target areas of the embryo. Finally, we analyse how the direction of migration is controlled by regulation of cell polarity and how the planar cell polarity or non-canonical Wnt signalling is involved in this process