Generation and use of a humanized bone marrow ossicle niche for hematopoietic xenotransplantation into mice

Nat Protoc, 2017 · DOI: 10.1038/nprot.2017.088 · Published: October 1, 2017

Simple Explanation

This paper describes how to create a human-like bone marrow environment in mice. This is done by transplanting human bone marrow cells under the skin of mice, where they form a small bone-like structure called an ossicle. Researchers can then transplant human blood cells into this ossicle to study how these cells behave in a more natural environment. This model is useful for studying diseases like leukemia, where the bone marrow environment plays a critical role.

Study Duration

6 – 10 weeks to form ossicles, engraftment analysis 8 – 16 weeks after transplantation

Participants

NSG mice, human BM aspirates, UCB, primary leukemia samples

Evidence Level

Not specified

Key Findings

1
The ossicles allow for accelerated and superior engraftment of primary patient-derived acute myeloid leukemia (AML) and other hematologic malignancies such as myelofibrosis (MF) in mice.
2
A humanized engraftable BM microenvironment can be formed within 6 – 10 weeks.
3
Engraftment of human hematopoietic cells can be evaluated by flow cytometry 8 – 16 weeks after transplantation.

Research Summary

The study presents a detailed protocol for generating humanized bone marrow ossicles in mice to improve the study of human hematopoiesis and leukemia. This method involves in situ differentiation of bone marrow-derived mesenchymal stromal cells (MSCs) to create a functional bone marrow microenvironment. The resulting ossicles facilitate better engraftment of human hematopoietic cells, including AML and myelofibrosis cells, offering a more physiological model for studying human hematologic malignancies.

Practical Implications

Improved Disease Modeling

The humanized ossicle model allows for more accurate modeling of human hematopoietic diseases, such as AML and myelofibrosis, in mice.

Enhanced Engraftment Studies

This system improves the engraftment of human hematopoietic cells, enabling better study of normal and malignant hematopoiesis.

Therapeutic Development

The model can be used for development of novel therapeutic approaches for hematologic malignancies.

Study Limitations

1
Although bone, cartilage, and mesenchymal stromal cells within the ossicle BM microenvironment are of human origin, the vasculature and the developing BM sinusoidal structures are mouse-derived.
2
In our studies, all humanized ossicles are conditioned using sublethal irradiation to increase human normal and leukemic engraftment.
3
Alternative conditioning regimens, which are less toxic to the niche, such as antibody based approaches 58–60 or feeding mice amino-acid deficient diets 61 could be explored to deplete hematopoietic elements.

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