Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis

Studying the interaction of cells with the bone marrow microenvironment is important for understanding cancer metastasis, but human-mouse mismatch in xenograft mouse models makes this difficult. Here, Grigoryan et al. generated mini-bones (ossicles, hOss) in mice by culturing a human mesenchymal cell line engineered to express bone morphogenetic protein 2 under Cho or Ost conditions and then implanting the cells subcutaneously. Transplanted human cord blood hematopoietic stem/progenitor cells engrafted in the hOss, and acute myeloid leukemia cells also engrafted in hOss. The authors further demonstrated that human breast and neuroblastoma cancer cells metastasized to the hOss and formed osteolytic lesions, respectively. This engineered bone model could be useful for investigating cell interactions in the bone marrow niche.

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Preclinical research relies on xenograft mouse models, but these models preclude the human-specific functional interactions of stem cells with their bone marrow microenvironment. Instead, human mesenchymal cells can be exploited for the in vivo engineering of humanized niches, which confer robust engraftment of human healthy and malignant blood samples. However, mesenchymal cells are associated with major reproducibility issues in tissue formation. Here, we report the fast and standardized generation of human mini-bones by a custom-designed human mesenchymal cell line. These resulting humanized ossicles (hOss) consist of fully mature bone and bone marrow structures hosting a human mesenchymal niche with retained stem cell properties. As compared to mouse bones, we demonstrate superior engraftment of human cord blood hematopoietic cells and primary acute myeloid leukemia samples and also validate hOss as a metastatic site for breast cancer cells. We further report the engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically described osteolytic lesions. Collectively, our human mini-bones constitute a powerful preclinical platform to model bone-developing tumors using patient-derived materials.

Fonte: Science.org