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. 2015 Jul;22(4):302-8.
doi: 10.1097/MOH.0000000000000150.

Role of the Mammalian Target of Rapamycin Pathway in Lentiviral Vector Transduction of Hematopoietic Stem Cells

Free PMC article

Role of the Mammalian Target of Rapamycin Pathway in Lentiviral Vector Transduction of Hematopoietic Stem Cells

Cathy X Wang et al. Curr Opin Hematol. .
Free PMC article


Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.


The role of mTOR in HSC maintenance and transduction. Gray arrows denote upstream regulators of mTOR that are important for HSC maintenance (green: mTOR activators; red: mTOR inhibitors). Black arrows denote downstream effectors regulated by mTOR. mTOR is the active kinase subunit of two complexes: mTORC1 and mTORC2. mTORC1 regulates three processes implicated in HSC maintenance, shown in orange [26,29,30,31▪]. In addition to promoting HSC maintenance, mTOR inhibition also enhances lentiviral vector transduction of HSCs by enhancing one or more early steps of vector endocytosis, shown in blue, potentially via an mTORC2-mediated mechanism [8▪▪]. HSC, hematopoietic stem cell; mTOR, mammalian target of rapamycin.

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