Rapamycin Enhances Long-Term Hematopoietic Reconstitution of Ex Vivo Expanded Mouse Hematopoietic Stem Cells by Inhibiting Senescence

Oct 5, 2013Transplantation

Rapamycin improves long-term blood stem cell recovery by preventing cell aging during growth outside the body

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Abstract

Inhibition of overactivated mTOR with rapamycin promoted long-term hematopoietic reconstitution of mouse bone marrow stem cells.

Mouse bone marrow stem cells showed a time-dependent activation of mTOR after expansion in specific growth conditions.
Overactivation of mTOR was linked to the induction of senescence in stem cells but not to cell death.
There was a significant decrease in the ability of stem cells to provide long-term hematopoietic support due to mTOR overactivation.
Rapamycin treatment increased both the expansion and long-term hematopoietic functionality of stem cells.
The enhanced long-term hematopoiesis is likely due to rapamycin's effects on increasing Bmi1 and decreasing p16, which help prevent senescence.

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BACKGROUND: The mammalian target of rapamycin (mTOR) is an important regulator of hematopoietic stem cell (HSC) self-renewal and its overactivation contributes to HSC premature exhaustion in part via induction of HSC senescence. Inhibition of mTOR with rapamycin has the potential to promote long-term hematopoiesis of ex vivo expanded HSCs to facilitate the clinical application of HSC transplantation for various hematologic diseases.

METHODS: A well-established ex vivo expansion system for mouse bone marrow HSCs was used to investigate whether inhibition of overactivated mTOR with rapamycin can promote long-term hematopoiesis of ex vivo expanded HSCs and to elucidate the mechanisms of action of rapamycin.

RESULTS: HSC-enriched mouse bone marrow LSK cells exhibited a time-dependent activation of mTOR after ex vivo expansion in a serum-free medium supplemented with stem cell factor, thrombopoietin, and Flt3 ligand. The overactivation of mTOR was associated with induction of senescence but not apoptosis in LSK cells and a significant reduction in the ability of HSCs to produce long-term hematopoietic reconstitution. Inhibition of overactivated mTOR with rapamycin promoted ex vivo expansion and long-term hematopoietic reconstitution of HSCs. The increase in long-term hematopoiesis of expanded HSCs is likely attributable in part to rapamycin-mediated up-regulation of Bmi1 and down-regulation of p16, which prevent HSCs from undergoing senescence during ex vivo expansion.

CONCLUSIONS: These findings suggest that mTOR plays an important role in the regulation of HSC self-renewal in vitro and inhibition of mTOR hyperactivation with rapamycin may represent a novel approach to promote ex vivo expansion and their long-term hematopoietic reconstitution of HSCs.

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Rapamycin Enhances Long-Term Hematopoietic Reconstitution of Ex Vivo Expanded Mouse Hematopoietic Stem Cells by Inhibiting Senescence

Abstract

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