Humanized Mouse Models for Evaluation of PSC Immunogenicity

Abstract

New human pluripotent stem cell (hPSC)‐derived therapies are advancing to clinical trials at an increasingly rapid pace. In addition to ensuring that the therapies function properly, there is a critical need to investigate the human immune response to these cell products. A robust allogeneic (or autologous) immune response could swiftly eliminate an otherwise promising cell therapy, even in immunosuppressed patients. In coming years, researchers in the regenerative medicine field will need to utilize a number of in vitro and in vivo assays and models to evaluate and better understand hPSC immunogenicity. Humanized mouse models—mice engrafted with functional human immune cell types—are an important research tool for investigating the mechanisms of the adaptive immune response to hPSC therapies. This article provides an overview of humanized mouse models relevant to the study of hPSC immunogenicity and explores central considerations for investigators seeking to utilize these powerful models in their research. © 2020 Wiley Periodicals LLC.

Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Pluripotent Stem Cells

“…Other additive hypoimmune editing approaches may be needed, such as a promising CD64 overexpression strategy recently described by Gravina et al 51 Relatedly, better in vitro and in vivo models of human antibody-mediated rejection are needed to adequately interrogate these types of research questions. Humanized mouse models are quite useful for T cell-mediated rejection and natural killer cell-mediated allorejection studies, [64][65][66][67] but the most commonly used humanized mice are suboptimal for antibody-mediated rejection studies due to B cell immaturity and impeded class switching in de novo antibodies. 68 Our group and others are working on new iterations of humanized mouse models that incorporate more robust T cell, natural killer cell, and innate immune cell repertoires in order to improve their utility for transplantation immunology-focused research studies, and creation of tractable models harboring antigen-specific IgG antibody pools is an area of intense focus.…”

Stem cell-derived pancreatic beta cells for the study and treatment of diabetes

“…Mice containing aspects of the human immune system, also known as 'humanized mice,' offer an amenable pre-clinical model of the human immune response and have been used for a variety of transplantation immunology studies [88][89][90][91]. There are number of humanized models available [92], but most advanced for transplant of hPSCs or their derivatives are those models which incorporate human hematopoietic stem cells (HSC) and thymic fragments into immune deficient mice to facilitate human T cell developmental in the animals.…”

Genetic Engineering of Immune Evasive Stem Cell-Derived Islets

“…There is a critical need for assessing the in vivo immune response to PSC-based therapies prior to clinical trials. Human immune system (HIS) humanized mice offer a tractable pre-clinical in vivo model of the human immune response and have been used for a variety of transplantation immunology studies (92)(93)(94)(95). There are a variety of HIS models available (96), but most useful for PSC transplant immunology studies are those models which incorporate both the infusion of human hematopoietic stem/progenitor cells (HSPCs) as well as thymic fragments into immune-deficient mouse strains to provide T cell developmental cues in the animals.…”