scholarly journals Efficient and Rapid generation of neural stem cells by direct conversion Fibroblasts with A Single microRNA

2021 ◽  
Author(s):  
yuesi wang ◽  
Yuanyuan Li ◽  
Jing Sun ◽  
Tingting Xu ◽  
Xiaobin Weng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
High Efficiency ◽  
Disease Modeling ◽  
System Development ◽  
Direct Conversion ◽  
Tumor Formation ◽  
Low Efficiency

Neural stem cells (NSCs) have great potential in the application of neurodegenerative disease therapy, drug screening and disease modeling. NSC can be generated by reprogramming from terminally differentiated cells with transcription factors or small molecules. However, current methods for producing NSCs involve the danger of integrating foreign genes into the genome and the problem of low efficiency. Here, we report an efficient method to generate NSCs from human skin-derived fibroblasts with microRNA (mir-302a) in 2-3 days. The induced NSCs (iNSCs) have more than 90% of purity. Their morphology is similar to regular NSCs, expressing key markers including Nestin, Pax6 and Sox2, and can be expanded for more than 20 passages in vitro. They can also differentiate into functional neuron progeny, astrocytes and oligodendrocytes as well. Those cells can elicit action potential, can be xeno-transplanted into the brain of immune-deficient mice, and can survive and differentiate in vivo without tumor formation. This study shows that a single part of pluripotency-inducing mir-302 cluster can drive fibroblasts reprogramming, providing a general platform for high-efficiency generation of individual-specific human NSCs for studies of neuron system development and regenerative cell therapy.

scholarly journals Development of next-generation tumor-homing induced neural stem cells to enhance treatment of metastatic cancers

2021 ◽  
Vol 7 (24) ◽  
pp. eabf1526
Author(s):  
Wulin Jiang ◽  
Yuchen Yang ◽  
Alison R. Mercer-Smith ◽  
Alain Valdivia ◽  
Juli R. Bago ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Tumor Therapy ◽  
Drug Carriers ◽  
Leptomeningeal Carcinomatosis ◽  
Tumor Burden ◽  
Tumor Formation ◽  
Tumor Homing

Engineered tumor-homing neural stem cells (NSCs) have shown promise in treating cancer. Recently, we transdifferentiated skin fibroblasts into human-induced NSCs (hiNSC) as personalized NSC drug carriers. Here, using a SOX2 and spheroidal culture-based reprogramming strategy, we generated a new hiNSC variant, hiNeuroS, that was genetically distinct from fibroblasts and first-generation hiNSCs and had significantly enhanced tumor-homing and antitumor properties. In vitro, hiNeuroSs demonstrated superior migration to human triple-negative breast cancer (TNBC) cells and in vivo rapidly homed to TNBC tumor foci following intracerebroventricular (ICV) infusion. In TNBC parenchymal metastasis models, ICV infusion of hiNeuroSs secreting the proapoptotic agent TRAIL (hiNeuroS-TRAIL) significantly reduced tumor burden and extended median survival. In models of TNBC leptomeningeal carcinomatosis, ICV dosing of hiNeuroS-TRAIL therapy significantly delayed the onset of tumor formation and extended survival when administered as a prophylactic treatment, as well as reduced tumor volume while prolonging survival when delivered as established tumor therapy.

scholarly journals EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii88-ii88
Author(s):  
Alison Mercer-Smith ◽  
Wulin Jiang ◽  
Alain Valdivia ◽  
Juli Bago ◽  
Scott Floyd ◽  
...  
Keyword(s):  
Stem Cells ◽  
Brain Metastases ◽  
Neural Stem Cells ◽  
Adjuvant Treatment ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Homing ◽  
Induced Neural Stem Cells

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.

scholarly journals Immunosuppressants Affect Human Neural Stem Cells In Vitro but Not in an In Vivo Model of Spinal Cord Injury

2013 ◽  
Vol 2 (10) ◽  
pp. 731-744 ◽  
Author(s):  
Christopher J. Sontag ◽  
Hal X. Nguyen ◽  
Noriko Kamei ◽  
Nobuko Uchida ◽  
Aileen J. Anderson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Neural Stem Cells ◽  
In Vivo Model ◽  
Human Neural Stem Cells ◽  
Cord Injury

CBIO-13. THOC1 DRIVES GBM AGGRESSION THROUGH MODULATION OF R-LOOPS AND GENOMIC STABILITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi29-vi30
Author(s):  
Shreya Budhiraja ◽  
Shivani Baisiwala ◽  
Khizar Nandoliya ◽  
Li Chen ◽  
Crismita Dmello ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Neural Stem Cells ◽  
Histone Deacetylase ◽  
Genomic Stability ◽  
Loop Formation ◽  
Driver Genes ◽  
A Genome

Abstract Glioblastoma (GBM) is the most aggressive and common type of adult malignant brain tumor, with a median survival of only 21 months. To identify which genes drive its highly aggressive phenotype, we performed a genome-wide CRISPR-Cas9 knockout screen. Results showed substantial enrichment of ~160 novel essential oncogenic driver genes and pathways, including a previously unstudied gene THOC1—involved in RNA processing—that showed significant elevations in expression at RNA and protein levels (p< 0.05) in GBM, as well as a significant survival benefit in patient datasets when downregulated (p< 0.05). Knocking out THOC1 resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines and extended survival compared to the controls (p< 0.01) in vivo. Overexpression of THOC1 in neural stem cells resulted in transformation to a cancerous phenotype, as evidenced by sphere formation in a soft agar assay (p< 0.01) and in vivo tumor engraftment assays. Further investigation of THOC1 through immunoprecipitation in neural stem cells and multiple GBM lines showed significant interaction in GBM with histone deacetylase complex SIN3A, involved in recruiting major histone deacetylases in order to close the DNA and prevent the accumulation of R-loops, RNA:DNA hybrids that pose a threat to genomic stability. Additional investigation revealed that THOC1-knockdowns in vitro induced R-loop formation and DNA damage, while THOC1-overexpression in vitro resulted in an untenable decrease in R-loops and DNA damage, suggesting that the THOC1-SIN3A axis is elevated in GBM in order to prevent the accumulation of genotoxic R-loops. Additionally, histone deacetylase activity was shown to be elevated in THOC1-overexpression conditions and reduced in THOC1-knockdown conditions, confirming that the THOC1-SIN3A axis functions to prevent R-loop accumulation through the epigenetic regulation. In summary, our whole-genome CRISPR-Cas9 knockout screen has identified a promising therapeutic target for GBM—a disease desperately in need of therapeutic innovations.

MicroRNAs: Crucial Players in the Differentiation of Human Pluripotent and Multipotent Stem Cells into Functional Hepatocyte-Like Cells

2021 ◽  
Vol 16 ◽  
Author(s):  
Hao Xu ◽  
Liying Wu ◽  
Guojia Yuan ◽  
Xiaolu Liang ◽  
Xiaoguang Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Disease ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Critical Role ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
The Body

: Hepatic disease negatively impacts liver function and metabolism. Primary human hepatocytes are the gold standard for the prediction and successful treatment of liver disease. However, the sources of hepatocytes for drug toxicity testing and disease modeling are limited. To overcome this issue, pluripotent stem cells (PSCs) have emerged as an alternative strategy for liver disease therapy. Human PSCs, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can self-renew and give rise to all cells of the body. Human PSCs are attractive cell sources for regenerative medicine, tissue engineering, drug discovery, and developmental studies. Several recent studies have shown that mesenchymal stem cells (MSCs) can also differentiate (or trans-differentiate) into hepatocytes. Differentiation of human PSCs and MSCs into functional hepatocyte-like cells (HLCs) opens new strategies to study genetic diseases, hepatotoxicity, infection of hepatotropic viruses, and analyze hepatic biology. Numerous in vitro and in vivo differentiation protocols have been established to obtain human PSCs/MSCs-derived HLCs and mimic their characteristics. It was recently discovered that microRNAs (miRNAs) play a critical role in controlling the ectopic expression of transcription factors and governing the hepatocyte differentiation of human PSCs and MSCs. In this review, we focused on the role of miRNAs in the differentiation of human PSCs and MSCs into hepatocytes.

Superparamagnetic iron oxide labeling of neural stem cells and 4.7T MRI tracking in vivo and in vitro

2007 ◽  
Vol 27 (1) ◽  
pp. 107-110 ◽  
Author(s):  
Wenzhen Zhu ◽  
Xiang Li ◽  
Zhouping Tang ◽  
Suiqiang Zhu ◽  
Jianpin Qi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Iron Oxide ◽  
Neural Stem Cells ◽  
Superparamagnetic Iron Oxide

The synthetic NCAM mimetic peptide FGL mobilizes neural stem cells in vitro and in vivo

2014 ◽  
Vol 10 (4) ◽  
pp. 539-547 ◽  
Author(s):  
Rebecca Klein ◽  
Stefan Blaschke ◽  
Bernd Neumaier ◽  
Heike Endepols ◽  
Rudolf Graf ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Mimetic Peptide

Abstract 4759: Integrated in vitro and in vivo screening of tumor and normal neural stem cells identifies potential new treatments of ependymoma

2011 ◽  
Author(s):  
Jennifer M. Atkinson ◽  
Anang A. Shelat ◽  
Tanya A. Kranenburg ◽  
Angel M. Carcaboso ◽  
Alexander Arnold ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
In Vivo Screening ◽  
New Treatments

scholarly journals HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways

2019 ◽  
Vol 28 (12) ◽  
pp. 1686-1699 ◽  
Author(s):  
Chongfeng Chen ◽  
Yujia Yang ◽  
Yue Yao
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Signaling Pathways ◽  
System Development ◽  
Nervous System Development ◽  
Bmp Signaling ◽  
Nuclear Proteins ◽  
Therapeutic Effects ◽  
Morphogenetic Protein

Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of Wnt3a, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of Wnt3a, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.

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