Humanized Mouse Models for Type 1 Diabetes Including Pancreatic Islet Transplantation

Abstract

We comment here on the suitability of available mouse models for type 1 diabetes research including research on therapeutic pancreatic islet transplantation. The major emphasis will be laid on models that require minimal invasive procedures. Most biological processes are too complex for a complete recapitulation in a test tube. The study of innate or even adaptive immune responses involves a number of different cell types and organs making in vitro studies unreliable but also providing extreme challenges for the use of surrogate model organisms. Studying these processes directly in humans is impossible due to ethical and technical constraints. To resolve this problem small animal models such as mice or rats are frequently used to study mechanisms of complex diseases. This has brought much insight into hematopoiesis and immune cell function including type 1 diabetes (T1D); however, 65 million years of evolution introduced striking differences between mice and humans 1. In fact, none of the many suggested therapies arising from studies using mice 2 3 that have promised prevention or even reversion of T1D made it into the clinic yet 4 5 6. The reason for this are major species-specific differences between rodents and humans regarding the immune system and beta cells.

Liraglutide Compromises Pancreatic β Cell Function in a Humanized Mouse Model

“…Importantly, mice engrafted with human tissue, also known as humanized mice, hold great promise in improving our understanding of human diseases (Ito et al, 2012; Rahmig et al, 2015). Mice have also been used to study natural processes such as aging (Demetrius, 2006; Vanhooren and Libert, 2013).…”

Bone Marrow Stromal Stem Cells in Tissue Engineering and Regenerative Medicine

“…These more recently identified BMSSCs properties have led to an expansion of possible therapeutic applications, where a significant role is for them to enhance the intrinsic regenerative capacity of compromised tissues through modulation of the immune response, inflammation, and the concentration of growth factors in the local microenvironment [17]. In addition to therapeutic applications BMSSCs these cells can be used to study disease through the development of disease models [7][8][9]. The identification and characterization of various stem cell populations provide exciting opportunities to develop novel therapeutic strategies for tissue regeneration in the context of tissue engineering and regenerative medicine [1,10].…”

Enhanced differentiation of functional human T cells in NSGW41 mice with tissue-specific expression of human interleukin-7

“…4a). To study the activation of Treg cells in humanized NSGW41hIL7 mice, we transplanted porcine pancreatic islets into the portal vein of humanized NSGW41hIL7 mice 4 . 18 hours after xenotransplantation, Treg cells in the liver but not spleen displayed significantly increased expression of HLA-DR evidencing site-specific activation through the xenograft (Fig.…”

“…NSGW41 mice carry the hypomorph W41 allele in the Kit gene, harbor the NOD-specific variant of the Sirpa gene, are T-, B- and NK-cell deficient based on null mutations in Prkdc and Il2rg genes, and allow for human donor stem cell engraftment in the absence of preconditioning 2, 3 . NSGW41 mice that are stably engrafted with human hematopoietic stem cell display continuous human hematopoiesis with increased myeloid 2, 4 , megakaryocytic and erythroid output compared to irradiated NSG recipient mice 5, 6 .…”