Innovations, challenges, and minimal information for standardization of humanized mice

Abstract

Mice xenotransplanted with human cells and/or expressing human gene products (also known as “humanized mice”) recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human‐specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community‐driven resource called “Minimal Information for Standardization of Humanized Mice” ( MISHUM ) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. Within MISHUM , we propose comprehensive guidelines for reporting critical information generated using humanized mice.

Use of Humanized Mouse Models to Investigate the Roles of Purinergic Signaling in Inflammation and Immunity

“…Moreover, the above studies of purinergic signaling in GVHD in Hu-PBMC-NSG mice serve as a proof-of-concept to consider studying the roles of purinergic signaling in inflammatory and immune processes in other humanized mouse models. In this regard, recent advances, such as the expression of transgenes for human growth factors and use of human progenitor cells, have facilitated the engraftment of human T cells and other human leukocytes in the absence of GVHD ( Stripecke et al, 2020 ). Other advances have assisted the study of human T cell responses in vivo .…”

“…In wanting to employ humanized mice, investigators also need to consider the ethical implications and constraints of using animals and human tissues, including the generation of human–mice chimeras and the source of human cells ( Devolder et al, 2020 ), with some humanized mouse models requiring human fetal liver tissue ( Shultz et al, 2019 ). Nevertheless, given the range of humanized mouse models emerging ( Stripecke et al, 2020 ), humanized mice provide new and exciting opportunities for the study of purinergic signaling in inflammation and immunity, as well as in other physiological and pathophysiological settings. For example, von Willebrand factor mutant mice, which support human but not murine platelet-induced thrombosis, have been used to study the P2Y 12 receptor antagonist clopidogrel in vivo ( Magallon et al, 2011 ).…”

“…Humanized mouse models also afford opportunities to develop personalized medicine relating to purinergic targets in disease, as illustrated by the use of human tumor xenografts (so called patient-derived xenograft or PDX models) in tailoring therapies for people with cancer ( Shultz et al, 2019 ). Finally, investigators are directed to recent standardized reporting guidelines concerning the use of humanized mice aimed at enhancing rigor and reproducibility ( Stripecke et al, 2020 ).…”

“…Humanized mice can be classified into two groups. The first involves the expression of specific human gene products within mice including cases in which a given mouse gene is replaced by the human ortholog ( Stripecke et al, 2020 ). Examples of mice incorporating transgenes of human purinergic molecules include the overexpression of human CD39 ( ENTPD1 ) ( Dwyer et al, 2004 ), as well as the substitution of the mouse gene with the corresponding human gene for the adenosine A 3 receptor ( ADORA3 ) ( Yamano et al, 2005 ), P2X7 receptor ( P2RX7 ) ( Metzger et al, 2017a ) or a Gln460Arg P2X7 receptor variant ( Metzger et al, 2017b ).…”

“…Examples of mice incorporating transgenes of human purinergic molecules include the overexpression of human CD39 ( ENTPD1 ) ( Dwyer et al, 2004 ), as well as the substitution of the mouse gene with the corresponding human gene for the adenosine A 3 receptor ( ADORA3 ) ( Yamano et al, 2005 ), P2X7 receptor ( P2RX7 ) ( Metzger et al, 2017a ) or a Gln460Arg P2X7 receptor variant ( Metzger et al, 2017b ). The second group of humanized mice, so called xenogeneic mouse models, involves the transfer of human cells into mice, which are typically immunodeficient ( Stripecke et al, 2020 ). It is this group which forms the focus of the remaining article.…”