Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

Abstract

The human skin is a major barrier for host defense against many human pathogens, with several pathogens directly targeting the skin for replication and disease. The skin is also the primary route of infection for a myriad of vector-borne diseases; thus cutaneous immune cells play a major role in modulating transmission for such infectious diseases. Several human pathogens that target the skin as a major route of infection are unable to infect traditional rodent models or recapitulate the pathogenesis in humans. It is well established that differences exist in human skin and immune cell biology compared to rodent models. Therefore, rodent (mouse and rat) models that incorporate human skin and immune cells would addressed the above discussed technical gap, and enable in vivo mechanistic studies of human host-skin pathogen interactions, and support the development of novel therapeutics. Here, we introduce the novel human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rg null (NSG) mouse and Sprague-Dawley-Rag2 tm2hera Il2rg tm1hera (SRG) rat models, coengrafted with full-thickness human fetal skin, autologous fetal lymphoid tissues, and fetal liverderived hematopoietic stem cells. hSIS-humanized rodents support the development of adult-like, fullthickness human skin and human lymphoid tissues, and support human immune cell development.Furthermore, the engrafted human skin supports Methicillin-resistant Staphylococcus aureus infection, demonstrating the utility of these humanized rodent models in studying human disease.

Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

“…These studies primarily attempt to generate humanized rat models of various pathological conditions and tissue damage without using BC methods. With the emergence of new humanized rat models, the future of functional human-rat interspecies chimerism holds excellent promise, while the permissiveness of non-cancerous, normal human epithelial chimerism needs to be addressed well (Agarwal et al, 2020).…”

Progress in Vocal Fold Regenerative Biomaterials: An Immunological Perspective

“…[162] With the advances of genetic engineering such as CRISPR-Cas9, various laboratories have begun to genomically humanize rodents that may better represent, for instance, the reaction of the human immune system to viral infection and wound injury. [163][164][165][166][167] At the same time, recent innovations in science, technology, and ethics have intensified the debate around animal models and whether they represent the most efficient preclinical testing model. [168,169] Biomedical research continues to be challenged by complex, multifactorial diseases such as cancer, cardiovascular diseases, infectious diseases, and neurodegenerative disorders that require flexible, clinically relevant experimental models to explore the biology of, and potential therapies for, such conditions.…”