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Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration.

ABSTRACT: The signals that control the regenerative ability of hematopoietic stem cells (HSCs) in response to damage are unknown. Here, we demonstrate that downstream activation of the Hedgehog (Hh) signaling pathway induces cycling and expansion of primitive bone marrow hematopoietic cells under homeostatic conditions and during acute regeneration. However, this effect is at the expense of HSC function, because continued Hh activation during regeneration represses expression of specific cell cycle regulators, leading to HSC exhaustion. In vivo treatment with an inhibitor of the Hh pathway rescues these transcriptional and functional defects in HSCs. Our study establishes Hh signaling as a regulator of the HSC cell cycle machinery that balances hematopoietic homeostasis and regeneration in vivo.

SUBMITTER: Trowbridge JJ

PROVIDER: S-EPMC1599924 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration.

Trowbridge Jennifer J JJ Scott Matthew P MP Bhatia Mickie M

Proceedings of the National Academy of Sciences of the United States of America 20060912 38

The signals that control the regenerative ability of hematopoietic stem cells (HSCs) in response to damage are unknown. Here, we demonstrate that downstream activation of the Hedgehog (Hh) signaling pathway induces cycling and expansion of primitive bone marrow hematopoietic cells under homeostatic conditions and during acute regeneration. However, this effect is at the expense of HSC function, because continued Hh activation during regeneration represses expression of specific cell cycle regula ...[more]

PMID: 16968775

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