Transcription Factors in Regulatory and Protein Subnetworks during Generation of Neural Stem Cells and Neurons from Direct Reprogramming of Non-fibroblastic Cell Sources

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy.

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

Stem Cells International ◽

10.1155/2016/4304916 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 23

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.

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Die Kunst des Neuronenschmiedens: Direkte Reprogrammierung somatischer Zellen in induzierte neuronale Zellen

e-Neuroforum ◽

10.1515/nf-2013-0204 ◽

2013 ◽

Vol 19 (2) ◽

Author(s):

Marisa Karow ◽

Benedikt Berninger

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neuronal Cells ◽

Somatic Cells ◽

Cell Types ◽

Direct Conversion ◽

Cellular Reprogramming ◽

Direct Reprogramming ◽

Brain Pericytes

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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PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

PPAR Research ◽

10.1155/2007/48242 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

A. Cimini ◽

L. Cristiano ◽

E. Benedetti ◽

B. D'Angelo ◽

M. P. Cerù

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Proliferation ◽

Transcription Factors ◽

Neural Stem Cells ◽

Osteoblast Differentiation ◽

Adult Mouse ◽

Cell Type ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation

PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC). To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

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Neural Transcription Factors: from Embryos to Neural Stem Cells

Molecules and Cells ◽

10.14348/molcells.2014.0227 ◽

2014 ◽

Vol 37 (10) ◽

pp. 705-712 ◽

Cited By ~ 20

Author(s):

Hyun-Kyung Lee ◽

Hyun-Shik Lee ◽

Sally A. Moody

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Neural Stem Cells

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STEM-25. HDAC1 IS ESSENTIAL FOR GLIOMA STEM CELL SURVIVAL

Neuro-Oncology ◽

10.1093/neuonc/noz175.998 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi239-vi239

Author(s):

Costanza Lo Cascio ◽

James McNamara ◽

Ernesto Luna Melendez ◽

Shwetal Mehta

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Neural Stem Cells ◽

Malignant Glioma ◽

Radiation Treatment ◽

High Grade Glioma ◽

Dependent Manner ◽

Minimal Impact ◽

Histone Deacetylase 1

Abstract OLIG2 is a central nervous system-specific transcription factor that is expressed in almost all diffuse gliomas. It is also one of the key core transcription factors that can reprogram differentiated glioma cells to highly tumorigenic glioma stem-like cells (GSCs). We have previously shown that expression of OLIG2 is critical for glioma growth both in a genetically relevant mouse model as well as in patient-derived xenograft models. Our work suggests that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high-grade glioma; however, transcription factors are generally very difficult to target because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our laboratory has shown that OLIG2 functions are regulated through interactions with distinct co-regulator proteins in normal neural stem cells. However, there are currently no reports on interactors that promote the proto-oncogenic functions of OLIG2 in malignant glioma. In this study, we employed two independent proteomics screens identify tumor-specific, druggable OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function in glioma. These screens led to the identification of a novel OLIG2 partner protein: Histone Deacetylase 1 (HDAC1). We confirmed that this interaction occurs in both murine and human glioma models. Although HDACs are ubiquitously expressed and are known to be functionally redundant, we show that ablation of HDAC1 alone significantly decreases the stemness and proliferation capacity of patient-derived GSCs in a p53-dependent manner, while having a minimal impact on normal human neural stem cells and astrocytes. Furthermore, we demonstrate that knockdown of HDAC1, in combination with ionizing radiation treatment, significantly alters the growth pattern of intracranial tumors in vivo. We demonstrate that HDAC1 function is critical for GSC growth and provide a strong rationale for targeting the OLIG2-HDAC1 interaction in malignant glioma.

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