In vivo hematopoietic stem cell (HSC) gene therapy is an emerging and promising area of focus in the gene therapy field. Humanized mouse models are frequently used to evaluate novel HSC gene therapy approaches. Here, we comprehensively evaluated two mouse strains, NSG and NBSGW. We studied human HSC engraftment in the bone marrow (BM), mobilization of BM-engrafted HSCs into circulation, in vivo transduction using VSV-G-pseudotyped lentiviral vectors (VSV-G LVs), and the expression levels of surface receptors needed for transduction of viral vectors. Our findings reveal that the NBSGW strain exhibits superior engraftment of human long-term HSCs than the NSG strain. However, neither model resulted in a significan... More
In vivo hematopoietic stem cell (HSC) gene therapy is an emerging and promising area of focus in the gene therapy field. Humanized mouse models are frequently used to evaluate novel HSC gene therapy approaches. Here, we comprehensively evaluated two mouse strains, NSG and NBSGW. We studied human HSC engraftment in the bone marrow (BM), mobilization of BM-engrafted HSCs into circulation, in vivo transduction using VSV-G-pseudotyped lentiviral vectors (VSV-G LVs), and the expression levels of surface receptors needed for transduction of viral vectors. Our findings reveal that the NBSGW strain exhibits superior engraftment of human long-term HSCs than the NSG strain. However, neither model resulted in a significant increase in circulating human HSCs after mobilization. We show that time post humanization as well as human chimerism levels and platelet counts in the peripheral blood can be used as surrogates for human HSC engraftment in the BM. Furthermore, we observed low expression of the low-density lipoprotein receptor, a requirement for VSV-G LV transduction, in the human HSCs present in the murine BM. Our comprehensive characterization of humanized mouse models highlights the necessity of proper validation of the model and methods to study in vivo HSC gene therapy strategies.
