Mouse models and human islet transplantation sites for intravital imaging

Abstract

Human islet transplantations into rodent models are an essential tool to aid in the development and testing of islet and cellular-based therapies for diabetes prevention and treatment. Through the ability to evaluate human islets in an in vivo setting, these studies allow for experimental approaches to answer questions surrounding normal and disease pathophysiology that cannot be answered using other in vitro and in vivo techniques alone. Intravital microscopy enables imaging of tissues in living organisms with dynamic temporal resolution and can be employed to measure biological processes in transplanted human islets revealing how experimental variables can influence engraftment, and transplant survival and function. A key consideration in experimental design for transplant imaging is the surgical placement site, which is guided by the presence of vasculature to aid in functional engraftment of the islets and promote their survival. Here, we review transplantation sites and mouse models used to study beta cell biology in vivo using intravital microscopy and we highlight fundamental observations made possible using this methodology.

LRH-1/NR5A2 Activation Rewires Immunometabolism Blunting Inflammatory Immune Cell Progression in Individuals with Type 1 Diabetes and Enhances Human Islet Function in Mice

“…Most studies have primarily concentrated on non-fully mature DCs, evaluating the effects of compounds like 1α,25- Dihydroxyvitamin D3 on DCs maturation and activation, but none have investigated their potential to transform fully mature DCs isolated from individuals with T1DM into a tolerogenic phenotype 70,71 . Similarly, most human islet transplantation survival and functional studies have been carried out in immunodeficient mice in order to prevent rejection 72 . Consequently, our findings hold significant implications for human studies, as reversing the disease will require resolution of the chronic pro-inflammatory/autoimmune attack predominantly steered by islet self-antigen activated macrophages and dendritic cells, which play a central role in the induction of T-cell expansion and subsequent β-cell destruction 73 .…”

“…Similarly, most human islet transplantation survival and functional studies have been carried out in immunodeficient mice to prevent rejection (69). Herein, we selected the STZ-treated C57/BL6J mouse model with the specific intention of expanding on our previous findings on BL001 tolerizing a pro-inflammatory environment, key for the sustained engraftment and long-term functionality of human islets (21).…”

“…Most studies have primarily concentrated on non-fully mature DCs, evaluating the effects of compounds such as 1α,25-Dihydroxyvitamin D3 on DCs maturation and activation, but none have investigated their potential to transform fully mature DCs isolated from individuals with T1DM into a tolerogenic phenotype 72,73 . Similarly, most human islet transplantation survival and functional studies have been carried out in immunodeficient mice to prevent rejection 74 . Herein, we selected the STZ-treated C57/BL6j mouse model with the specific intention of expanding on our previous findings on BL001 tolerizing a pro-inflammatory environment, key for the sustained engraftment and long-term functionality of human islets 21 .…”

Bidirectional Relationship between Glycemic Control and COVID-19 and Perspectives of Islet Organoid Models of SARS-CoV-2 Infection

“…Glycemic control and islet cell damage in SARS-CoV-2-infected islet organoids could then be assessed both in vitro and in vivo, which would help us to further understand the mechanism of infection and define a road map for new therapeutics ( Figure 1 ). The intravital imaging and microscopic techniques of islet organoids also allow the exploration of dynamic changes after transplantation into mouse models [ 99 ].…”

Microfluidic vascular formation model for assessing angiogenic capacities of single islets

“…The angiogenic capacity of pancreatic islets has been explored using animal models (Speier et al, 2008; Wagner et al, 2022), which have revealed specific angiogenic secretions from the islets, such as vascular growth factor A (VEGF‐A) (Brissova et al, 2006; Xiong et al, 2020), the significant contribution of the donor's endothelium to the formation of a vascular network after transplantation (Brissova et al, 2004; Linn et al, 2003; Nyqvist et al, 2005), and the effects of immunosuppressive drugs on vascular formation (Nishimura et al, 2013). However, analyzing individual islets for their molecular functions in animal models is technically difficult, making it challenging to unveil the detailed mechanisms of vascular formation induced by islets.…”