Humanized hemato-lymphoid system mice

Abstract

O ver the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinicallypredictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment. Humanized hemato-lymphoid system mice

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

“…Over the past few years, this has prompted the development of new mouse strains encoding human cytokines and has also opened the door to a novel approach. By merging knowledge from biomaterials, tissue engineering, and cell-implantation fields, investigators have generated new models to mimic the native human hematopoietic microenvironment within s.c. 3D structures (4)(5). Using human mesenchymal stromal cells (hMSCs) as stromal cell support within bone-forming implants, researchers have studied normal (6)(7)(8)(9)(10) and malignant (11)(12)(13)(14)(15)(16) hematopoiesis.…”

A functional DC cross talk promotes human ILC homeostasis in humanized mice

“…3 Much progress has been made to improve overall human lymphoid and myeloid cell engraftment, and to enhance the development of HLArestricted T-and B-cell responses. In contrast, the in vivo development of human innate lymphoid effectors, including innate lymphoid cells (ILCs), natural killer (NK) T cells, mucosal-associated invariant T cells, and/or gdT cells, in HIS mice remains suboptimal.…”

Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice

“…Major advances in engrafting a human immune system in mice have been achieved using mice with genetic manipulations that lead to severe immunodeficiency and, consequently, minimal rejection of human hematopoietic stem cells (hHSCs) and their differentiated progeny. [4][5][6][7][8] One example of these recipients is the BALB/c-Rag2 null Il2rg null (BRG) strain that, when transplanted with hHSCs, develop human B cells, T cells, and, with varying frequencies, other human hematopoietic cell types. [9][10][11][12][13][14][15][16][17] This strain has been recently modified into BRGS with the introduction of the NOD-derived Sirpa allele (Sirpa NOD indicated that T cells are crucial to B-cell maturation in hu-mice, 16 other studies have suggested that the defects in B-cell maturation and antibody responses observed in hu-mice are caused by an inability of mouse B-cell-activating factor (mBAFF) to aid survival and antigen responses of human B cells.…”