scholarly journals Direct Reprogramming of Mouse Fibroblasts to Neural Stem Cells by Small Molecules

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-Chuang Han ◽  
Yoon Lim ◽  
Michael D. Duffieldl ◽  
Hua Li ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Small Molecules ◽  
Clinical Medicine ◽  
Viral Vector ◽  
Expression Patterns ◽  
Tumor Formation ◽  
Patient Specific ◽  
Mouse Fibroblasts

Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytesin vitroandin vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.

scholarly journals Reprogramming with Small Molecules instead of Exogenous Transcription Factors

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Tongxiang Lin ◽  
Shouhai Wu
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Small Molecules ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Mouse Embryonic Fibroblast ◽  
Patient Specific ◽  
Full Potential ◽  
Ipsc Generation ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) could be employed in the creation of patient-specific stem cells, which could subsequently be used in various basic and clinical applications. However, current iPSC methodologies present significant hidden risks with respect to genetic mutations and abnormal expression which are a barrier in realizing the full potential of iPSCs. A chemical approach is thought to be a promising strategy for safety and efficiency of iPSC generation. Many small molecules have been identified that can be used in place of exogenous transcription factors and significantly improve iPSC reprogramming efficiency and quality. Recent studies have shown that the use of small molecules results in the generation of chemically induced pluripotent stem cells from mouse embryonic fibroblast cells. These studies might lead to new areas of stem cell research and medical applications, not only human iPSC by chemicals alone, but also safe generation of somatic stem cells for cell based clinical trials and other researches. In this paper, we have reviewed the recent advances in small molecule approaches for the generation of iPSCs.

A combination of small molecules directly reprograms mouse fibroblasts into neural stem cells

2016 ◽  
Vol 476 (1) ◽  
pp. 42-48 ◽  
Author(s):  
Jie Zheng ◽  
Kyung-Ah Choi ◽  
Phil Jun Kang ◽  
Solji Hyeon ◽  
Suhyun Kwon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Small Molecules ◽  
Mouse Fibroblasts

scholarly journals mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1043 ◽  
Author(s):  
Phil Jun Kang ◽  
Daryeon Son ◽  
Tae Hee Ko ◽  
Wonjun Hong ◽  
Wonjin Yun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Urine ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Patient Specific ◽  
Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

scholarly journals Generation of Integration-free Induced Neural Stem Cells from Mouse Fibroblasts

2016 ◽  
Vol 291 (27) ◽  
pp. 14199-14212 ◽  
Author(s):  
Sung Min Kim ◽  
Jong-Wan Kim ◽  
Tae Hwan Kwak ◽  
Sang Woong Park ◽  
Kee-Pyo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Mouse Fibroblasts ◽  
Induced Neural Stem Cells

scholarly journals High Throughput Mechanobiological Screens Enable Mechanical Priming of Pluripotency in Mouse Fibroblasts

2018 ◽  
Author(s):  
Jason Lee ◽  
Miguel Ochoa ◽  
Pablo Maceda ◽  
Eun Yoon ◽  
Lara Samarneh ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput ◽  
Cultured Cells ◽  
Somatic Cells ◽  
Tumor Formation ◽  
Mechanical Forces ◽  
Mouse Fibroblasts ◽  
Cell Culture Systems ◽  
Ipsc Generation ◽  
Induced Pluripotent

Transgenic methods for direct reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) are effective in cell culture systems but ultimately limit the utility of iPSCs due to concerns of mutagenesis and tumor formation. Recent studies have suggested that some transgenes can be eliminated by using small molecules as an alternative to transgenic methods of iPSC generation. We developed a high throughput platform for applying complex dynamic mechanical forces to cultured cells. Using this system, we screened for optimized conditions to stimulate the activation of Oct-4 and other transcription factors to prime the development of pluripotency in mouse fibroblasts. Using high throughput mechanobiological screening assays, we identified small molecules that can synergistically enhance the priming of pluripotency of mouse fibroblasts in combination with mechanical loading. Taken together, our findings demonstrate the ability of mechanical forces to induce reprograming factors and support that biophysical conditioning can act cooperatively with small molecules to priming the induction pluripotency in somatic cells.

Direct conversion of mouse fibroblasts into induced neural stem cells

2014 ◽  
Vol 9 (4) ◽  
pp. 871-881 ◽  
Author(s):  
Sung Min Kim ◽  
Hannah Flaßkamp ◽  
Andreas Hermann ◽  
Marcos Jesús Araúzo-Bravo ◽  
Seung Chan Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Direct Conversion ◽  
Mouse Fibroblasts ◽  
Induced Neural Stem Cells
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