ISX-9

Inducer of neural differentiation

ISX-9

Inducer of neural differentiation

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Inducer of neural differentiation
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Overview

ISX-9 is a small molecule inducer of adult neural stem cell differentiation both in vitro and in vivo (Schneider et al.). It has been shown to act through a calcium-activated signaling pathway dependent on myocyte-enhancer factor 2 (MEF2)-dependent gene expression (Schneider et al.; Petrik et al.).

REPROGRAMMING
· Direct lineage reprogramming of fibroblasts to mature neurons, in combination with CHIR99021, Forskolin , SB431542, and I-BET151 (Li et al.).

DIFFERENTIATION
· Induces neuronal differentiation in the HCN hippocampal neural stem/progenitor cell line from adult rat, in whole brain or subventricular zone neural progenitor cells from adult mice, and in P19 embryonic carcinoma cells (Schneider et al.).
· Improves hippocampal neurogenesis and function in mice (Petrik et al.).
· Stimulates cardiac muscle gene expression and cell cycle activity in adult mouse myocardium (Russell et al.).
· Blocks tumor cell proliferation and induces neuronal gene expression in malignant astrocytes (Zhang et al.).
· Improves β-cell function, increases expression of transcription factors that enhance β-cell differentiation and increases intracellular insulin content in primary human islet cultures (Dioum et al.).
Cell Type
Cancer Cells and Cell Lines, Cardiomyocytes, PSC-Derived, Neural Stem and Progenitor Cells, Neurons, Pancreatic Cells
Species
Human, Mouse, Non-Human Primate, Other, Rat
Application
Differentiation, Reprogramming
Area of Interest
Cancer, Epithelial Cell Biology, Neuroscience, Stem Cell Biology
CAS Number
832115-62-5
Chemical Formula
C₁₁H₁₀N₂O₂S
Purity
≥ 95%

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Product Name
ISX-9
Catalog #
73202
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
ISX-9
Catalog #
73202
Lot #
All
Language
English

Applications

This product is designed for use in the following research area(s) as part of the highlighted workflow stage(s). Explore these workflows to learn more about the other products we offer to support each research area.

Resources and Publications

Educational Materials (1)

Publications (6)

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Li X et al. Cell stem cell 2015 AUG

Abstract

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to textgreater90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a proof of principle" for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation�
Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. Petrik D et al. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2012

Abstract

Adult neurogenesis occurs throughout life in the mammalian hippocampus and is essential for memory and mood control. There is significant interest in identifying ways to promote neurogenesis and ensure maintenance of these hippocampal functions. Previous work with a synthetic small molecule, isoxazole 9 (Isx-9), highlighted its neuronal-differentiating properties in vitro. However, the ability of Isx-9 to drive neurogenesis in vivo or improve hippocampal function was unknown. Here we show that Isx-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. Isx-9 also improves hippocampal function, enhancing memory in the Morris water maze. Notably, Isx-9 enhances neurogenesis and memory without detectable increases in cellular or animal activity or vascularization. Molecular exploration of Isx-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte-enhancer family of proteins (Mef2). Indeed, transgenic-mediated inducible knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically from neural stem cells and their progeny confirmed Mef2's requirement for Isx-9-induced increase in hippocampal neurogenesis. Thus, Isx-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2, revealing a novel cell-intrinsic molecular pathway regulating adult neurogenesis.
Targeting native adult heart progenitors with cardiogenic small molecules. Russell JL et al. ACS chemical biology 2012

Abstract

Targeting native progenitors with small molecule pharmaceuticals that direct cell fate decisions is an attractive approach for regenerative medicine. Here, we show that 3,5-disubstituted isoxazoles (Isx), stem cell-modulator small molecules originally recovered in a P19 embryonal carcinoma cell-based screen, directed cardiac muscle gene expression in vivo in target tissues of adult transgenic reporter mice. Isx also stimulated adult mouse myocardial cell cycle activity. Narrowing our focus onto one target cardiac-resident progenitor population, Isx directed muscle transcriptional programs in vivo in multipotent Notch-activated epicardium-derived cells (NECs), generating Notch-activated adult cardiomyocyte-like precursors. Myocardial infarction (MI) preemptively differentiated NECs toward fibroblast lineages, overriding Isx's cardiogenic influence in this cell population. Isx dysregulated gene expression in vivo in Notch-activated repair fibroblasts, driving distinctive (pro-angiogenesis) gene programs, but failed to mitigate fibrosis or avert ventricular functional decline after MI. In NECs in vitro, Isx directed partial muscle differentiation, which included biosynthesis and assembly of sarcomeric α-actinin premyofibrils, beaded structures pathognomonic of early developing cardiomyocytes. Thus, although Isx small molecules have promising in vivo efficacy at the level of cardiac muscle gene expression in native multipotent progenitors and are first in class in this regard, a greater understanding of the dynamic interplay between fibrosis and cardiogenic small molecule signals will be required to pharmacologically enable regenerative repair of the heart.