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Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells



Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells



Current Opinion in Hematology 22(4): 302-308



A major goal in repopulating hematopoietic stem cell (HSC) gene therapies is achieving high-efficacy gene transfer, while maintaining robust HSC engraftment and differentiation in vivo. Recent studies have documented that rapamycin treatment of HSC during lentiviral vector transduction enhances gene transfer to human and mouse HSCs and maintains engraftment capacity. In this review, we place into context the role of mammalian target of rapamycin (mTOR) pathways in HSC quiescence and function, endocytic regulation, and lentiviral gene delivery. Lentiviral vector transduction of human and mouse HSCs is considerably enhanced by rapamycin treatment. Furthermore, rapamycin preserves long-term engraftment of human and mouse HSCs. Investigations of cellular mechanisms that contribute to increased transduction in HSCs uncover a role for mTOR inhibition-dependent activation of endocytosis. Rapamycin enhances lentiviral vector transduction of HSCs through regulation of endocytic activity via mTOR inhibition. An important attribute of rapamycin treatment during transduction is the preservation of HSC function, allowing reconstitution of long-term hematopoiesis in vivo in murine models.

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Accession: 058791381

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PMID: 26049750

DOI: 10.1097/MOH.0000000000000150


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