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Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain

Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain

Objective

The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
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Principal Investigator

Patrik Ernfors (Prof.)

Host institution

KAROLINSKA INSTITUTET

Address

Nobels Vag 5
17177 Stockholm

Sweden

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 492 593

Principal Investigator

Patrik Ernfors (Prof.)

Administrative Contact

Jill Blomstrand (Ms.)

Beneficiaries (1)

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KAROLINSKA INSTITUTET

Sweden

EU Contribution

€ 2 492 593

Project information

Grant agreement ID: 232675

Status

Closed project

  • Start date

    1 March 2009

  • End date

    28 February 2014

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 492 593

  • EU contribution

    € 2 492 593

Hosted by:

KAROLINSKA INSTITUTET

Sweden