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

Ani Grigoryan, Dimitra Zacharaki, Alexander Balhuizen, Christophe Rm Côme, Alejandro Garcia Garcia, David Hidalgo Gil, Anne-Katrine Frank, Kristina Aaltonen, Adriana Mañas, Javanshir Esfandyari, Pontus Kjellman, Emelie Englund, Carmen Rodriguez, Wondossen Sime, Ramin Massoumi, Nasim Kalantari, Sujeethkumar Prithiviraj, Yuan Li, Steven J Dupard, Hanna IsakssonChris D Madsen, Bo T Porse, Daniel Bexell, Paul E Bourgine*

*Corresponding author for this work

Abstract

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.

Original languageEnglish
Article numbereabm6391
JournalScience translational medicine
Volume14
Issue number666
Pages (from-to)eabm6391
ISSN1946-6234
DOIs
Publication statusPublished - 12 Oct 2022

Keywords

  • Animals
  • Bone and Bones
  • Disease Models, Animal
  • Hematopoiesis
  • Humans
  • Leukemia, Myeloid, Acute
  • Mice
  • Reproducibility of Results
  • Stem Cell Niche
  • Tumor Microenvironment

Fingerprint

Dive into the research topics of 'Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis'. Together they form a unique fingerprint.

Cite this