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How To Unlock Blocked Differentiation In ESCs.

BIRMINGHAM, Ala., November 15, 2017 -- Scientists here have partly solved a long-unanswered basic question about stem cells: Why are pluripotent stem cells that have mutations to block the production of microRNAs unable to differentiate?

One very active area of biology is cells that mimic these fountainhead embryonic stem cells, cells that are called induced pluripotent stem cells (iPSCs).

Future progress with iPSCs needs a much greater understanding of the basic biology of pluripotency and differentiation.

The most important step in using stem cells in therapy is differentiation from iPSCs. Scientists need to be able to differentiate the iPSCs into a disease-relevant cell type at high efficiency and high purity.

Researchers have found a key that allows those microRNA-deficient pluripotent stem cells to differentiate into neural cells, including subtypes with markers for dopaminergic, glutamatergic and GABAergic neurons.

Scientists for many years did not know why these cells did not differentiate. The answer for neural cell differentiation in the microRNA-deficient cells turned out to be simple: a single microRNA or a single protein.

The study shows that a microRNA-302 mimic, delivered by a specially constructed lentivirus, was sufficient to enable neural differentiation of mouse embryonic stem cells that lacked Dgcr8, a vital gene for the processing of the more than 2,000 microRNAs in cells.

They examined gene expression profiles in the differentiated cells and saw changes in many gene sets regulated by p53, also known as tumor suppressor p53.

This tumor suppressor has been called "the guardian of the genome" because of its many roles in preventing DNA damage and cancer.

They showed that microRNA-302 acted to reduce p53 expression in the microRNA-deficient embryonic stem cells by binding to the 3' untranslated region of p53 mRNA.

They further showed that direct inhibition of p53 with the simian virus large T antigen or short hairpin RNA, or even deleting the p53 gene itself, allowed embryonic stem cells or iPSCs to proceed to neural differentiation without the need for microRNA-302.

Thus, the differentiation barrier that prevents the neuronal lineage specification from microRNA-deficient stem cells is expression of p53.

The keys to unlock the paths cells to other cell lineage specifications from microRNA-deficient embryonic stem are still unknown, however.

Citation: Zhong Liu et al., "Elevated p53 Activities Restrict Differentiation Potential of MicroRNA-Deficient Pluripotent Stem Cells," Stem Cell Reports, 2017; 9 (5): 1604 DOI: 10.1016/j.stemcr.2017.10.006


Contact: Rui Zhao,

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Title Annotation:Basic Research
Author:Zhao, Rui
Publication:Stem Cell Research News
Date:Nov 20, 2017
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