Julie Norville’s Post

Amazing humanized mouse model developed by a UTSA research team: THX model. It has been highlighted in several News as the first model with the "full human immune system". Why? 1. An important limitation of humanized mouse models is the failure to mount mature antibody responses and the lack of GCs. After the engraftment of cord blood huCD34+ cells in NSGW41 mice,17β-estradiol (E2), the most potent and physiologically abundant estrogen, was administrated. In THX mice, E2 is critical in promoting the development of LNs and GCs, supporting differentiation of huTECs, huTFH cells and huGC B cells, increasing B2:B1 cell ratio and generating huMBCs. E2 conditioning was also important for the appearance of huIgM, huIgD, huIgG and huIgA in BALF and feces, as well as the high baseline levels of huIgD, huIgG and huIgA in non-intentionally immunized THX mice. Additionally, E2 supported differentiation of huMZ B cells, which contribute antibodies that provide the first-line of defense against blood-borne microbial pathogens. 2. Humanized mice generally lack thymic huMHCs, resulting in huT cells selected on mouse MHC. In THX model some mature antibody responses seemed to be T cell-dependent, indicating its CD4+ T cells were educated on huTECs or other human cells expressing MHC class II, such as human B cells and human DCs, also present in THX mouse thymus. How could THX mice populate their thymus with huTECs, which supposedly emerge from non-hematopoietic CD34− progenitors? The authors explained: "Epithelial cells can differentiate from CD34+ stem cells, including cord blood CD34+ cells, possibly giving rise to huTECs. Interestingly, TECs express ERα and ERβ, consistent with an E2 role in promoting their differentiation". 3. One of the shortcomings of humanized mice is poor development of human myeloid cells, particularly neutrophils. THX mice reconstituted human neutrophils, to almost one-fourth of spleen huCD45+ cells, a proportion comparable to neutrophils in spleen of humans. Neutrophils express both ERα and ERβ, and estrogen has been shown to increase neutrophils in women’s peripheral blood and in mouse blood, BM and spleen. Moreover, human platelets in THX mice accounted for approximately one-third of total platelets, possibly also as a result of direct E2 impact on megakaryocytes, which express ERα and ERβ and whose maturation is boosted by estrogen. https://lnkd.in/edScTZHZ