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High levels of Id1 expression define B1 type adult neural stem cells.

ABSTRACT: Defining the molecular identity of stem cells may be critical for formulating a rational strategy for the therapeutic intervention of stem cell dysfunction. We find that high expression of Id1, a dominant-negative helix-loop-helix transcriptional regulator, identifies a rare population of GFAP(+) astrocytes with stem cell attributes among the subventricular astrocytes in the adult brain. The rare, long-lived, and relatively quiescent Id1(high) astrocytes with morphology characteristic of B1 type astrocytes self-renew and generate migratory neuroblasts that differentiate into olfactory bulb interneurons. Cultured Id1(high) neural stem cells can self-renew asymmetrically and generate a stem and a differentiated cell expressing progressively lower levels of Id1, revealing an Id1 gradient in unperturbed cells of subventricular neurogenic lineages. Moreover, Id genes are necessary to confer self-renewal capacity, a characteristic of stem cell identity. We suggest that high expression of a single transcriptional regulator, Id1, molecularly defines the long-sought-after B1 type adult neural stem cells.

SUBMITTER: Nam HS

PROVIDER: S-EPMC2775820 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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High levels of Id1 expression define B1 type adult neural stem cells.

Nam Hyung-song HS Benezra Robert R

Cell stem cell 20091101 5

Defining the molecular identity of stem cells may be critical for formulating a rational strategy for the therapeutic intervention of stem cell dysfunction. We find that high expression of Id1, a dominant-negative helix-loop-helix transcriptional regulator, identifies a rare population of GFAP(+) astrocytes with stem cell attributes among the subventricular astrocytes in the adult brain. The rare, long-lived, and relatively quiescent Id1(high) astrocytes with morphology characteristic of B1 type ...[more]

PMID: 19896442

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Project description:BackgroundCD44 is a molecular marker associated with cancer stem cell populations and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting glioma cells high in CD44.MethodsGlioma-initiating cell lines were derived from fresh surgical glioblastoma samples. Expression of tissue transglutaminase 2 (TGM2) was attenuated through lentivirus-mediated short hairpin RNA knockdown. MTT assay [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] was used to evaluate the growth inhibition induced by TGM2 inhibitor. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling was used to evaluate cell apoptosis following TGM2 inhibition. CD44(+) glioma stem cells were sorted by flow cytometry. A nude mice orthotopic xenograft model was used to evaluate the in vivo effect of TGM2 inhibitor.ResultsTGM2 was highly expressed in CD44-high glioblastoma tissues and tumor-derived glioma-initiating cell lines. TGM2 knockdown impaired cell proliferation and induced apoptosis in CD44-high glioma-initiating cell lines. Further studies indicated that expression of inhibitor of DNA binding 1 protein (ID1) is regulated by TGM2 and might be an important mediator for TGM2-regulated cell proliferation in CD44-high glioma-initiating cell lines. TGM2 inhibitor reduces ID1 expression, suppresses cell proliferation, and induces apoptosis in CD44-high glioma-initiating cell lines. Furthermore, TGM2 is highly expressed in CD44(+) glioma stem cells, while pharmacological inhibition of TGM2 activity preferentially eliminates CD44(+) glioma stem cells. Consistently, TGM2 inhibitor treatment reduced ID1 expression and induced apoptosis in our orthotopic mice xenograft model, which can be translated into prolonged median survival in tumor-bearing mice.ConclusionsTGM2 regulates ID1 expression in glioma-initiating cell lines high in CD44. Targeting TGM2 could be an effective strategy to treat gliomas with high CD44 expression.

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High levels of Id1 expression define B1 type adult neural stem cells.

Publications

High levels of Id1 expression define B1 type adult neural stem cells.

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