Small Molecules for Neural Stem Cell Induction

Liu, Donghui; Manaph, Nimshitha Pavathuparambil Abdul; Al‐Hawwas, Mohammed; Zhou, Xin‐Fu; Liao, Hong

doi:10.1089/scd.2017.0282

Cited by 18 publications

(15 citation statements)

References 101 publications

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“…Then, we found that adding seven small molecules together would cause cell death, which was considered to be due to the possibility of simultaneous inhibition of some signaling pathways or excessive DMSO intake. To overcome this problem, we reviewed related researches and concluded that MET should be promoted in the early induction stage (Zhang et al, 2015; Zheng et al, 2016; Liu et al, 2018). TGF-β signaling plays an important role on modulation of EMT, a process by which an epithelial cell becomes a mesenchymal cell (Grunert et al, 2003), in normal human and mouse (Valcourt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…TGF-β signaling plays an important role on modulation of EMT, a process by which an epithelial cell becomes a mesenchymal cell (Grunert et al, 2003), in normal human and mouse (Valcourt et al, 2005). The generation of iNSCs from MEFs requires an increase in the MET process, through inhibition of TGF-β (Valcourt et al, 2005; Liu et al, 2018). The combination of the TGF-β inhibitor SB431542 and LDN193189 enhances the reprogramming efficiency of MET transition.…”

Section: Discussionmentioning

confidence: 99%

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Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling

Duan

Wen

et al. 2019

Front. Neurosci.

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Inducing somatic cells into neural stem cells (iNSCs) in specific ways provides a new cell therapy in a variety of neurological diseases. In the past, iNSCs were generated by transcription factors which increased the risk of mutagenesis, tumor formations, and immune reactions by viral transduction vectors. Therefore, in this study, different small molecules were used to induce mouse embryonic fibroblasts (MEFs) into iNSCs in different reprogramming stages, which showed high reprogramming efficiency without altering the genome. We demonstrated that the small molecules staged-induction neural stem cells (SMSINS) have the characteristics of neural stem cells (NSCs) in morphology, gene expression, self-renewal and differentiation potential. Furthermore, valproic acid (VPA), one of small molecules, was showed to enhance neural induction with highest efficiency compared with six other small molecules, which were also investigated in the present study. Moreover, our results suggested that activating the mammalian target of rapamycin (mTOR) signaling enhanced the induction efficiency and neuronal differentiation. Collectively, our findings indicated that using this induction program allowed us to obtain safe and efficient iNSCs which were free of genetic manipulation. The VPA-mediated mTOR signaling pathway may enhance reprogramming efficiency and neuronal differentiation. So we suggested that this program could be a new method of obtaining iNSCs for the treatment of neurological diseases by cell replacement therapy in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling

Duan

Wen

et al. 2019

Front. Neurosci.

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“…24 Conversely, the patterning cues for motor neurons involve neural induction to neuroepithelia with SMADi (LDN193189, SB413542) and a GSK3b inhibitor (CHIR99021) for a week before the addition of retinoic acid and purmorphamine to induce a motor neuron phenotype. 25 Liu et al 26 provide a comprehensive review of commonly used agents in NPC induction (e.g., SMADi LDN193189 and SB431542, transforming growth factor-b family inhibitors, GSK-3 b inhibitors, MAPK signaling pathway inhibitors, and Sonic hedgehog pathway agonists) and also provide insights on epigenetic modifiers that help accelerate iPSC reprogramming (i.e., valproic acid, ascorbic acid, and retinoic acid).…”

Section: Modeling Neurological Diseases With Ipscsmentioning

confidence: 99%

Neural Progenitor Cell Derivation Methodologies for Drug Discovery Applications

Porterfield

2020

ASSAY and Drug Development Technologies

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Inducible pluripotent stem cells (iPSCs) are being used to model brain disorders across the continuum of neurodevelopment, neurodegenerative, and neuropsychiatric disease allowing for the mechanistic unraveling of the neurological disease state. Subsequently, there is a diverse array of cell model systems that can be used for target validation, pharmacodynamic endpoint development, and high-throughput/content assay development and screening. However, to successfully model neurological disorders with iPSCs, the disease-relevant neuron must be first identified, and it is critical to have the appropriate neuronal progenitor cell derivation and neuron differentiation protocols available to produce desired neuronal phenotypes. Moreover, special considerations are necessary if adaptation to high-throughput/content assay systems is anticipated. Discussed here are the three-dimensional embryoid bodyneural rosette and two-dimensional monolayer methodologies to derive iPS neural progenitor cells and neurons with a specific focus on cortical neurons. Outlined are some of the commonalities, advantages, and disadvantages associated with both methodologies.

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“…Their effects have been specific and reversible [86]. Notable advantage of chemical formulations is that they are easy to handle and cost effective compared to transcription factor-mediated protocols [88]. Moreover, small molecules can aid the progression to feeder-free and serum-free protocols of stem cell culture [89].…”

Section: Small Molecules In Regenerative Medicinementioning

confidence: 99%

An overview on small molecule-induced differentiation of mesenchymal stem cells into beta cells for diabetic therapy

et al. 2019

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The field of regenerative medicine provides enormous opportunities for generating beta cells from different stem cell sources for cellular therapy. Even though insulin-secreting cells can be generated from a variety of stem cell types like pluripotent stem cells and embryonic stem cells, the ideal functional cells should be generated from patients' own cells and expanded to considerable levels by non-integrative culture techniques. In terms of the ease of isolation, plasticity, and clinical translation to generate autologous cells, mesenchymal stem cell stands superior. Furthermore, small molecules offer a great advantage in terms of generating functional beta cells from stem cells. Research suggests that most of the mesenchymal stem cell-based protocols to generate pancreatic beta cells have small molecules in their cocktail. However, most of the protocols generate cells that mimic the characteristics of human beta cells, thereby generating "beta cell-like cells" as opposed to mature beta cells. Diabetic therapy becomes feasible only when there are robust, functional, and safe cells for replacing the damaged or lost beta cells. In this review, we discuss the current protocols used to generate beta cells from mesenchymal cells, with emphasis on small molecule-mediated conversion into insulin-producing beta cell-like cells. Our data and the data presented from the references within this review would suggest that although mesenchymal stem cells are an attractive cell type for cell therapy they are not readily converted into functional mature beta cells.

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Small Molecules for Neural Stem Cell Induction

Cited by 18 publications

References 101 publications

Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling

Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling

Neural Progenitor Cell Derivation Methodologies for Drug Discovery Applications

An overview on small molecule-induced differentiation of mesenchymal stem cells into beta cells for diabetic therapy

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