Current opinion holds that pigment cells, melanocytes, are derived from neural crest cells produced at the dorsal neural tube and that migrate under the epidermis to populate all parts of the skin. Here, we identify growing nerves projecting throughout the body as a stem/progenitor niche containing Schwann cell precursors (SCPs) from which large numbers of skin melanocytes originate. SCPs arise as a result of lack of neuronal specification by Hmx1 homeobox gene function in the neural crest ventral migratory pathway. Schwann cell and melanocyte development share signaling molecules with both the glial and melanocyte cell fates intimately linked to nerve contact and regulated in an opposing manner by Neuregulin and soluble signals including insulin-like growth factor and platelet-derived growth factor. These results reveal SCPs as a cellular origin of melanocytes, and have broad implications on the molecular mechanisms regulating skin pigmentation during development, in health and pigmentation disorders.
Coherent network activity among assemblies of interconnected cells is essential for diverse functions in the adult brain. However, cellular networks before formations of chemical synapses are poorly understood. Here, embryonic stem cell-derived neural progenitors were found to form networks exhibiting synchronous calcium ion (Ca 2+ ) activity that stimulated cell proliferation. Immature neural cells established circuits that propagated electrical signals between neighboring cells, thereby activating voltage-gated Ca 2+ channels that triggered Ca 2+ oscillations. These network circuits were dependent on gap junctions, because blocking prevented electrotonic transmission both in vitro and in vivo. Inhibiting connexin 43 gap junctions abolished network activity, suppressed proliferation, and affected embryonic cortical layer formation. Cross-correlation analysis revealed highly correlated Ca 2+ activities in small-world networks that followed a scale-free topology. Graph theory predicts that such network designs are effective for biological systems. Taken together, these results demonstrate that immature cells in the developing brain organize in small-world networks that critically regulate neural progenitor proliferation.calcium signaling | neural networks | neural progenitor cells | spontaneous activity | stem cells
Control over progenitor proliferation and neurogenesis remains a key challenge for stem cell neurobiology and a prerequisite for successful stem cell replacement therapies for neurodegenerative diseases like Parkinson's disease (PD). Here, we examined the function of two nuclear receptors, liver X receptors (Lxralpha and beta) and their ligands, oxysterols, as regulators of cell division, ventral midbrain (VM) neurogenesis, and dopaminergic (DA) neuron development. Deletion of Lxrs reduced cell cycle progression and VM neurogenesis, resulting in decreased DA neurons at birth. Activation of Lxrs with oxysterol ligands increased the number of DA neurons in mouse embryonic stem cells (ESCs) and in wild-type but not Lxralphabeta(-/-) VM progenitor cultures. Likewise, oxysterol treatment of human ESCs (hESCs) during DA differentiation increased neurogenesis and the number of mature DA neurons, while reducing proliferating progenitors. Thus, Lxr ligands may improve current hESC replacement strategies for PD by selectively augmenting the generation of DA neurons.
Parkinson disease (PD)2 motor symptoms arise from the progressive degeneration of dopaminergic neurons (DAn). Experimental therapies, based on the cell replacement of the lost substantia nigra pars compacta (SNpc) DAn using human ventral mesencephalic (VM) fetal tissue provided proof of principle of a therapeutic effect of the transplants on a long term basis (1). However, in addition to ethical problems related to fetal tissue procurement, practical limitations were found, like the need for large amounts of VM tissue and the elevated cell death rate of the transplanted cells (2).As an alternative, human neural stem cells (hNSCs) derived from the developing and adult central nervous system were initially used, but they were inefficient for DAn generation (3). Another stem cell source, the embryonic stem cells, required long and difficult differentiation protocols as well as neuronal and DAn progenitor selection to obtain high amounts of DAn (4, 5). Previous transplantation studies established that the generation of functional SNpc DAn in vivo was highly dependent on the regional tissue origin, the VM being the optimal region (6), and that only DAn with SNpc properties (meaning adequate patterning, transcription factor, and differentiated protein profile) were able to reinervate the striatum and induce a therapeutic effect (7). Therefore, human fetal VM-derived cell strains were established (8, 9), but their use was hindered by a limited and unstable DA differentiation potential (10) (as it was previously described for rodent and human VM neurospheres (11, 12)) and DA-related oxidative stress (13).To the human cell lines of VM origin previously reported (8, 14), we have recently contributed a new immortalized human fetal VM NSC line (hVM1), which shows a great potential for the generation of SNpc DAn in vitro (15). In the present work, we have aimed at increasing our understanding of key factors involved in phenotypical stability, DAn generation, and functional maturation both in vitro and in vivo.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.