Accelerated Neuronal Differentiation Toward Motor Neuron Lineage from Human Embryonic Stem Cell Line (H9)

Abstract

Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a costeffective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron-treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are *1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening.

Ferritin nanoparticles for improved self-renewal and differentiation of human neural stem cells

“…Specifically, the high concentrations of iron, ferritin, and transferrin at birth indicate that a sufficient iron supply is closely related to normal neurological development [ 25 ]. Indeed, Lu et al demonstrated that elevated iron concentrations dramatically accelerated neuronal differentiation of ESCs through a transferrin-mediated mechanism [ 35 ]. Therefore, increasing iron concentration by incorporating iron-containing ferritin nanoparticles may also contribute to enhanced neuronal differentiation of NSCs and NPCs, but the exact mechanism requires further evaluation.…”

Dietary Micronutrients Promote Neuronal Differentiation by Modulating the Mitochondrial‐Nuclear Dialogue

“…In hESCs treated with 500 nM iron, expression of the neuronal marker HB9 is doubled and the number of mature and functional motor neurons is 1.5 times higher than control. This is potentially mediated by the transferrin‐ferritin intracellular iron transport and storage mechanism . Iron is crucial for mitochondrial respiration serving as a cofactor of cytochrome and Fe sulfur complexes during oxidative phosphorylation .…”

Advances in Stem Cell Research- A Ray of Hope in Better Diagnosis and Prognosis in Neurodegenerative Diseases

“…In this regard transplantation therapy is employed to restore and repair the damaged circuitry of the brain as well as to replenish the lost neuronal population (Thompson and Björklund, 2015). Successful commitment of stem cells toward the neuronal lineage is widely reported and myriad of protocols are available to achieve the same (Nikoletopoulou and Tavernarakis, 2012; Ferroni et al, 2013; Lu et al, 2015). …”