Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

AbstractThe art of forging neurons: direct reprogramming of somatic cells into induced neuronal cells.Cellular reprogramming has shed new light on the plasticity of terminally differentiated cells and discloses novel strategies for cell-based therapies for neurological disorders. With accumulating knowledge of the programs underlying the genesis of the distinct neural cell types, especially with the identification of relevant transcription factors and microRNAs, reprogramming of somatic cells of different origins into induced neuronal cells or neural stem cells has been successfully achieved. Starting with the general concept of reprogramming we discuss here three different paradigms: 1) direct conversion of CNS-foreign cells such as skin fibroblasts into induced neuronal cells or neural stem cells; 2) transdifferentiation of CNS resident cells such as astrocytes and brain pericytes into induced neuronal cells; 3) reprogramming of one neuronal subtype into another. The latter has already been successfully achieved in vivo during early brain development, providing strong impulse for the attempt to succeed in direct reprogramming in situ for future brain repair.

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Predicting involvement of polycomb repressive complex 2 in direct conversion of mouse fibroblasts into induced neural stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-015-0045-x ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 7

Author(s):

Moein Yaqubi ◽

Abdulshakour Mohammadnia ◽

Hossein Fallahi

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Direct Conversion ◽

Polycomb Repressive Complex ◽

Mouse Fibroblasts ◽

Polycomb Repressive Complex 2 ◽

Induced Neural Stem Cells

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Reprogramming of somatic cells to induced neural stem cells

Methods ◽

10.1016/j.ymeth.2017.09.007 ◽

2018 ◽

Vol 133 ◽

pp. 21-28 ◽

Cited By ~ 8

Author(s):

Ebrahim Shahbazi ◽

Fahimeh Mirakhori ◽

Vahid Ezzatizadeh ◽

Hossein Baharvand

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Somatic Cells ◽

Induced Neural Stem Cells

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The art of forging neurons: direct reprogramming of somatic cells into induced neuronal cells

e-Neuroforum ◽

10.1007/s13295-013-0041-5 ◽

2013 ◽

Vol 19 (2) ◽

Author(s):

M. Karow ◽

B. Berninger

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neuronal Cells ◽

Somatic Cells ◽

Cell Types ◽

Direct Conversion ◽

Cellular Reprogramming ◽

Direct Reprogramming ◽

Brain Pericytes

AbstractCellular reprogramming has shed new light on the plasticity of terminally differentiated cells and unearthed novel strategies for cell-based therapies to treat neurological disorders. With accumulating knowledge of the programs underlying the genesis of the distinct neural cell types, particularly the identification of crucial transcription factors and microRNAs, reprogramming of somatic cells of different origins into induced neuronal cells or neural stem cells has been successfully achieved. Starting with the general concept of reprogramming, we discuss three different paradigms: (1) direct conversion of central nervous system (CNS) foreign cells such as skin fibroblasts into induced neuronal cells or neural stem cells; (2) transdifferentiation of CNS resident cells such as astrocytes and brain pericytes into induced neuronal cells; (3) reprogramming of one neuronal subtype into another. The latter has already been successfully achieved in vivo during early brain development, providing a strong impulse to attempt direct reprogramming in situ for future brain repair.

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Rapid and Efficient Direct Conversion of Human Adult Somatic Cells into Neural Stem Cells by HMGA2/let-7b

Cell Reports ◽

10.1016/j.celrep.2014.12.038 ◽

2015 ◽

Vol 10 (3) ◽

pp. 441-452 ◽

Cited By ~ 66

Author(s):

Kyung-Rok Yu ◽

Ji-Hee Shin ◽

Jae-Jun Kim ◽

Myung Guen Koog ◽

Jin Young Lee ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Somatic Cells ◽

Direct Conversion ◽

Human Adult

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Robust and Reproducible Generation of Induced Neural Stem Cells from Human Somatic Cells by Defined Factors

International Journal of Stem Cells ◽

10.15283/ijsc19097 ◽

2020 ◽

Vol 13 (1) ◽

pp. 80-92

Author(s):

Tae Hwan Kwak ◽

Sai Hali ◽

Sungmin Kim ◽

Jonghun Kim ◽

Hyeonwoo La ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Somatic Cells ◽

Induced Neural Stem Cells

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Direct Conversion of Human Umbilical Cord Blood into Induced Neural Stem Cells with SOX2 and HMGA2

International Journal of Stem Cells ◽

10.15283/ijsc17025 ◽

2017 ◽

Vol 10 (2) ◽

pp. 227-234 ◽

Cited By ~ 7

Author(s):

Jae-Jun Kim ◽

Ji-Hee Shin ◽

Kyung-Rok Yu ◽

Byung-Chul Lee ◽

Insung Kang ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Direct Conversion ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord ◽

Induced Neural Stem Cells

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.361 ◽

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.

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