Key Takeaways & Executive Findings
- •• NOGW mice with c-kit mutation enable efficient human hematopoietic engraftment with reduced CD34+ cell numbers and without irradiation. • NOGW-EXL mice support enhanced multilineage reconstitution, particularly granulocytes and platelets/megakaryocytes, in non-irradiated recipients. • NOGW mice demonstrate superior long-term hematopoietic stem cell potential in serial transplantation assays. • The NOGW-EXL humanized mouse model offers a versatile platform for studying human hematology and immunology with broader accessibility.
Abstract
Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34+ HSCs and total-body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). In this study, we examined the ability of NOGW mice to reconstitute human hematopoietic cells. Irradiated NOGW mice exhibited high engraftment levels of human CD45+ cells in the peripheral blood, even when only 5,000–10,000 CD34+ HSCs were transferred. Efficient engraftment of human CD45+ cells was also observed in non-irradiated NOGW mice transferred with 20,000–40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34+CD38− or CD34+CD38+ cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45+ and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34+ cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread applications owing to their high versatility.
1. Introduction
Reconstitution of the human hematologic environment in severely immunodeficient mice plays a pivotal role in advancing the field of humanized mouse research, which is valuable for investigations pertaining to human hematology and immunology. Significant challenges in this field include achieving a high engraftment capacity and multilineage differentiation of human hematopoietic cells within humanized mice in order to create models that accurately mimic human hematopoietic processes.
NOD-scid IL-2rgnull (NOG and NSG) mice possess a mutated Prkdc gene (severe combined immunodeficiency; scid) and lack the interleukin (IL)-2 receptor subunit gamma (IL-2rg), making them useful recipients for transferring CD34+ human hematopoietic stem cells (HSCs) [1, 2]. The high engraftment rates observed in NOG and NSG mice are attributed to the deficiency of T cells, B cells, and natural killer (NK) cells as well as to the enhanced engraftment of human cells resulting from the specific Sirpa polymorphism in NOD background mice [3]. We previously established NOG-based second-generation humanized mice that systemically express myeloid cell–accelerated cytokines and successfully induce the differentiation of multiple human myeloid lineage cells, such as monocytes/macrophages, basophils, mast cells [4], eosinophils [5], and neutrophils [6]. To achieve sufficient human hematopoietic cell engraftment in humanized mice, standard methods require a large number of enriched CD34+ HSCs along with total body irradiation before transplantation. Human hematopoietic cells can be engrafted into immunodeficient NSG or NOD/B6-scid IL-2rgnull mice with a point mutation in the c-kit tyrosine kinase domain without X-ray irradiation [7, 8]. Compared to conventional humanized mice,
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Ryoji Ito, Yusuke Ohno, Yunmei Mu, Yuyo Ka, Shuko Ito, Maiko Emi-Sugie, Misa Mochizuki, Kenji Kawai, Motohito Goto, Tomoyuki Ogura, Riichi Takahashi, Akira Niwa, Tatsutoshi Nakahata, Mamoru Ito (2026). Improvement of multilineage hematopoiesis in hematopoietic stem cell-transferred c-kit mutant NOG-EXL humanized mice. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03799-w
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Frequently Asked Questions
What are NOGW mice?
NOGW mice are a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant), which allows efficient engraftment of human hematopoietic stem cells with reduced cell numbers and without irradiation.
How do NOGW-EXL mice improve humanized mouse models?
NOGW-EXL mice express human cytokines IL-3 and GM-CSF, leading to enhanced multilineage reconstitution, particularly of granulocytes and platelets/megakaryocytes, even in non-irradiated recipients.
What is the significance of the c-kit mutation in NOGW mice?
The c-kit mutation impairs the mouse stem cell factor signaling, creating a competitive advantage for human HSCs, thereby improving engraftment without the need for high-dose irradiation.
Can NOGW mice be used without irradiation?
Yes, NOGW mice support efficient human CD45+ cell engraftment without irradiation when transplanted with 20,000–40,000 CD34+ HSCs, reducing the need for total-body irradiation.
What are the potential applications of NOGW-EXL humanized mice?
These mice provide a versatile platform for studying human hematopoiesis, immunology, and preclinical drug testing, with improved multilineage differentiation and long-term HSC maintenance.
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