19 October 2022

Mice with humanized bones

Human mini-bones obtained in mice

Yulia Panchenko, PCR.news

The microenvironment of the bone marrow supports blood production throughout life. This niche and associated populations of mesenchymal cells are involved in the development of leukemia and solid tumors. The mechanisms of these processes are poorly understood, including due to the shortcomings of model systems. Human blood cancers and solid tumors are often studied on mouse xenographs. However, mouse bones, for example, do not correlate with the human bone marrow microenvironment.

A possible solution is to create ectopic human niches in mice, for example, miniature humanized bones (humanized ossicles, hOss). With their help, it is possible to recreate human blood cancers, cancer and bone metastases. However, existing approaches to creating hOss suffer from low reproducibility. In the new work, researchers from Sweden and Denmark used a human mesenchymal cell line to produce standardized hOss systems. Earlier, the same team obtained an immortalized mesenchymal cell line (Mesenchymal Sword of Damocles, MSOD) from primary human mesenchymal stromal cells. The authors constitutively expressed BMP-2 in these cells, resulting in the MSOD-B line.

The scientists seeded MSOD-B cells onto a collagen substrate, and then gave them signals to differentiate. Under the action of the chondrogenic signal, the cells produced more SOX9, COL2 and COLX, and under the action of the osteogenic signal, only SOX9. After some time, mature cartilage and osteoid tissues were formed. Their implantation in mice led to the formation of hOss.

These hOss supported human hematopoiesis. Mice were irradiated after tissue implantation, after which hematopoietic progenitor cells were transplanted into them. Peripheral blood analysis confirmed successful cell engraftment in both types of hOss.

RNA analysis of single cells showed that MSOD-B, after receiving a chondrogenic signal and forming hOss, forms four cell populations. These populations form a niche that supports human hematopoiesis.

Next, the authors obtained mice with hOss, irradiated them and implanted them with CD45+CD19−CD3−CD34+ or CD45+CD19−CD3−cells selected from patients with acute myeloid leukemia. Bones with bone marrow were formed from all hOss. Hematopoietic cell transplantation was successful. hOss can also be used to form metastases from breast cancer cells and neuroblastoma.

Thus, the authors obtained the MSOD-B cell line, from which miniature bones can be formed with high efficiency. The authors obtained more than 1000 hOss from the same clonal population. These hOss had an architecture comparable to real bones. The authors also validated the analysis of single cells of the niche of the human oblique brain. MSOD-B hOss can also be used in the context of pathology.

Article by Grigoryan et al. Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis is published in the journal Science Translational Medicine.

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