Humanized mice, also known as ‘Hu’ mice, are generated through transplantation of human cells, tissues, or organs. But, there’s a hitch. The mouse immune system often forcefully rejects these foreign elements. So, to tackle this, we usually use different strains of immunodeficient mice. We transplant various human tissues and cells into these mice, which is how we craft our humanized mouse models.

Humanized mice have three main types: genetically humanized mice, human-organ mice, and human immune system mice.

Genetically humanized mice are those where certain mouse genes are replaced with human genes, gene sequences or regulatory components. Mice can express either complete human proteins or chimeric proteins that include specific human structural domains.

In humanized organ mouse models, mice carry specific human organs. Two main types of human immune cells used to establish a functional human immune system. It includes peripheral blood mononuclear cells (PBMCs) and CD34+ hematopoietic stem cells (HSCs), which establish three models:

(A) Hu-PBL-SCID model: using peripheral blood mononuclear cells (PBMC);

(B) Hu-SRC-SCID model: using hematopoietic stem cells (HSC);

(C) BLT model: transplanting human fetal tissue, thymus, or liver into immunodeficient mice[10].

PBMCs: Hu-PBL Model

The simplest and most economical method of humanization is the implantation of human leukocytes into immunodeficient mice, termed Hu-PBL. Besides, this method was first described in 1988 using CB17-scid mice. This model is ideal for studying human T cell functions in vivo, but due to the presence of lethal graft-versus-host disease (GVHD), the experimental window is relatively short, usually within 4-8 weeks.

CD34+ Stem Cells: Hu-CD34+ and BLT Models

Another humanization method involves injecting human CD34+HSCs into newborn or immunodeficient mice. This approach requires sublethal gamma irradiation on host mice to deplete mouse HSCs and promote human HSC engraftment.

This model supports the implantation of a complete human immune system. Although B cells, T cells, myeloid cells, and antigen-presenting cells (APCs) exist in peripheral hematopoietic tissues, the content of granulocytes, platelets, and red blood cells produced in the bone marrow is very low in the blood. We can establish the BLT model through the subrenal capsule transplantation of human fetal liver and thymus and intravenous injection of autologous fetal liver HSCs.

Moreover, in most labs, BLT model mice experience a consumptive GVHD-like syndrome, which limits the experimental time window.


[1] De La Rochere P, et al. Trends Immunol. 2018 Sep;39(9):748-763.