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

Grigoryan, Ani LU ; Zacharaki, Dimitra LU ; Balhuizen, Alexander LU ; Côme, Christophe Rm ; Garcia, Alejandro Garcia LU ; Hidalgo Gil, David LU ; Frank, Anne-Katrine ; Aaltonen, Kristina LU ; Mañas, Adriana LU and Esfandyari, Javanshir LU , et al. (2022) In Science Translational Medicine 14(666). p.1-15
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Bone and Bones, Disease Models, Animal, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, Mice, Reproducibility of Results, Stem Cell Niche, Tumor Microenvironment
in
Science Translational Medicine
volume
14
issue
666
article number
eabm6391
pages
1 - 15
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:36223446
  • scopus:85139793218
ISSN
1946-6242
DOI
10.1126/scitranslmed.abm6391
language
English
LU publication?
yes
id
ad852d3b-1559-44c6-b855-157dffd4d019
date added to LUP
2022-10-31 17:03:22
date last changed
2024-02-17 21:38:02
@article{ad852d3b-1559-44c6-b855-157dffd4d019,
  abstract     = {{<p>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.</p>}},
  author       = {{Grigoryan, Ani and Zacharaki, Dimitra and Balhuizen, Alexander and Côme, Christophe Rm and Garcia, Alejandro Garcia and Hidalgo Gil, David and Frank, Anne-Katrine and Aaltonen, Kristina and Mañas, Adriana and Esfandyari, Javanshir and Kjellman, Pontus and Englund, Emelie and Rodriguez, Carmen and Sime, Wondossen and Massoumi, Ramin and Kalantari, Nasim and Prithiviraj, Sujeethkumar and Li, Yuan and Dupard, Steven J and Isaksson, Hanna and Madsen, Chris D and Porse, Bo T and Bexell, Daniel and Bourgine, Paul E}},
  issn         = {{1946-6242}},
  keywords     = {{Animals; Bone and Bones; Disease Models, Animal; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Mice; Reproducibility of Results; Stem Cell Niche; Tumor Microenvironment}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{666}},
  pages        = {{1--15}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.abm6391}},
  doi          = {{10.1126/scitranslmed.abm6391}},
  volume       = {{14}},
  year         = {{2022}},
}