TY - JOUR

T1 - Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis

AU - Grigoryan, Ani

AU - Zacharaki, Dimitra

AU - Balhuizen, Alexander

AU - Côme, Christophe Rm

AU - Garcia, Alejandro Garcia

AU - Hidalgo Gil, David

AU - Frank, Anne Katrine

AU - Aaltonen, Kristina

AU - Mañas, Adriana

AU - Esfandyari, Javanshir

AU - Kjellman, Pontus

AU - Englund, Emelie

AU - Rodriguez, Carmen

AU - Sime, Wondossen

AU - Massoumi, Ramin

AU - Kalantari, Nasim

AU - Prithiviraj, Sujeethkumar

AU - Li, Yuan

AU - Dupard, Steven J.

AU - Isaksson, Hanna

AU - Madsen, Chris D.

AU - Porse, Bo T.

AU - Bexell, Daniel

AU - Bourgine, Paul E.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.abm6391

DO - 10.1126/scitranslmed.abm6391

M3 - Journal article

C2 - 36223446

AN - SCOPUS:85139793218

VL - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 666

M1 - eabm6391

ER -