Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling

Bianchi, Fabio; Malboubi, Majid; Li, Yichen; George, Julian H.; Jérusalem, Antoine; Szele, Francis G.; Thompson, Mark S.; Ye, Hua

doi:10.1016/j.scr.2018.09.006

Cited by 71 publications

(62 citation statements)

References 53 publications

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“…The differentiation period is usually around 4 weeks when the NPC induction stage is included; however, the differentiation efficiency varied slightly depending on the cell source used or the markers used for identification. The proportions of Islet 1+ and HB9+ cells, considered to be indicators of MN differentiation, were 23.68% and 11.74%, respectively, of T-MSC-MNCs in this study and 70–90% and 35–46% for the iPS-MNCs generated in the other studies [18,26,27]. These results indicate that T-MSC can be differentiated into MNs, although their differentiation efficiency is lower than that of iPSC.…”

Section: Discussioncontrasting

confidence: 39%

“…This method of differentiating T-MSCs into T-MSC-MNCs via NPCs seems to be a factor in the successful generation of functional MNCs. A previous study showed that iPSCs could also be differentiated into MNs, but did not demonstrate increased acetylcholine secretion or formation of NMJs [26]. A comparison of the differentiation methods used in our study with previously reported methods suggests that most of the factors added to the differentiation culture, e.g., retinoic acid (RA) and sonic hedgehog (Shh), are common to the methods, although some additional factors are added.…”

Section: Discussionmentioning

confidence: 62%

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Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation

Park

Kim

Myung

et al. 2019

IJMS

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Human tonsil-derived mesenchymal stem cells (T-MSCs) are newly identified MSCs and present typical features of MSCs, including having the differentiation capacity into the three germ layers and excellent proliferation capacity. They are easily sourced and are useful for stem cell therapy in various disease states. We previously reported that T-MSCs could be differentiated into skeletal myocytes and Schwann-like cells; therefore, they are a promising candidate for cell therapies for neuromuscular disease. Motor neurons (MNs), which regulate spontaneous behavior, are affected by a wide range of MN diseases (MNDs) for which there are no effective remedies. We investigated the differentiation potential of MN-like cells derived from T-MSCs (T-MSC-MNCs) for application to therapy of MNDs. After the process of MN differentiation, the expression of MN-related markers, including Islet 1, HB9/HLXB9 (HB9), and choline acetyltransferase (ChAT), was increased when compared with undifferentiated T-MSCs. The secretion of acetylcholine to the conditioned medium was significantly increased after MN differentiation. We cocultured T-MSC-MNCs and human skeletal muscle cells, and confirmed the presence of the acetylcholine receptor clusters, which demonstrated the formation of neuromuscular junctions. The potential functional improvements afforded by these T-MSC-MNCs could be useful in the treatment of MNDs caused by genetic mutation, viral infection, or environmental problems.

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Section: Discussioncontrasting

confidence: 39%

Section: Discussionmentioning

confidence: 62%

Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation

Park

Kim

Myung

et al. 2019

IJMS

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“…This method can accurately and sensitively quantify the nerve conduction function (Murayama, Sasaki, & Shibahara, 2015). NCV can reflect the degree of impairment in the nerve myelin sheath (Bianchi et al, 2018). In this study, the NCVs of groups A and C were better than that of group B, whereas there was no statistically significant difference between groups A and C, which suggests that promoting vascularization can obviously increase the tissue‐engineered nerve conduction velocity of peripheral nerves.…”

Section: Discussionmentioning

confidence: 99%

Repairing peripheral nerve defects with revascularized tissue‐engineered nerve based on a vascular endothelial growth factor‐heparin sustained release system

Zhao

et al. 2020

J Tissue Eng Regen Med

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To enhance the angiogenic capacity of tissue-engineered peripheral nerves, we have constructed revascularized tissue-engineered nerves based on a vascular endothelial growth factor (VEGF)-heparin sustained release system. However, the effects of the repair of large peripheral nerve defects are not known. In this study, we used the above revascularized tissue-engineered nerve to repair large nerve defects in rats. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, wet weight ratio of bilateral gastrocnemius muscle, histological evaluation, and quantitative realtime polymerase chain reaction (PCR) analysis. The results showed that the tissueengineered peripheral nerve based on a VEGF-heparin sustained release system can achieve early vascularization and restore blood supply in the nerve graft area. The realization of early vascularization in the area of the nerve defect greatly promotes the speed of nerve regeneration and reconstruction in the area of the nerve defect, which greatly advances the process of nerve repair and reconstruction and accelerates the restoration of the normal morphological structure and function of peripheral nerves.

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“…In terms of motor neurons for skeletal muscle engineering, several studies have reported the induction of motor neurons from iPSCs, as reviewed elsewhere 183 . For example, a recent protocol involved promoting Wnt signaling, inhibiting Notch signaling, adding retinoic acid, activating hedgehog signaling, and subsequent exposure to ascorbic acid, CNTF, BDNF, NT-3, and GDNF 221 . Differentiated motor neurons after 21 days expressed the neuronal markers β-tubulin III and microtubule-associated protein 2 (MAP2) and the motor neuron markers choline acetyltransferase (ChAT) and homeobox HB9, with 73% showing HB9.…”

Section: Challenges and Advancements Towards Fabricating Innervated Tmentioning

confidence: 99%

Innervation: the missing link for biofabricated tissues and organs

et al. 2020

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Innervation plays a pivotal role as a driver of tissue and organ development as well as a means for their functional control and modulation. Therefore, innervation should be carefully considered throughout the process of biofabrication of engineered tissues and organs. Unfortunately, innervation has generally been overlooked in most non-neural tissue engineering applications, in part due to the intrinsic complexity of building organs containing heterogeneous native cell types and structures. To achieve proper innervation of engineered tissues and organs, specific host axon populations typically need to be precisely driven to appropriate location(s) within the construct, often over long distances. As such, neural tissue engineering and/or axon guidance strategies should be a necessary adjunct to most organogenesis endeavors across multiple tissue and organ systems. To address this challenge, our team is actively building axon-based "living scaffolds" that may physically wire in during organ development in bioreactors and/or serve as a substrate to effectively drive targeted long-distance growth and integration of host axons after implantation. This article reviews the neuroanatomy and the role of innervation in the functional regulation of cardiac, skeletal, and smooth muscle tissue and highlights potential strategies to promote innervation of biofabricated engineered muscles, as well as the use of "living scaffolds" in this endeavor for both in vitro and in vivo applications. We assert that innervation should be included as a necessary component for tissue and organ biofabrication, and that strategies to orchestrate host axonal integration are advantageous to ensure proper function, tolerance, assimilation, and bio-regulation with the recipient post-implant.

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Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling

Cited by 71 publications

References 53 publications

Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation

Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation

Repairing peripheral nerve defects with revascularized tissue‐engineered nerve based on a vascular endothelial growth factor‐heparin sustained release system

Innervation: the missing link for biofabricated tissues and organs

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