Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis
(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.
(Less)
- author
- organization
-
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Rheumatology
- Molecular Skeletal Biology (research group)
- WCMM-Wallenberg Centre for Molecular Medicine
- LUCC: Lund University Cancer Centre
- Molecular Pediatric Oncology (research group)
- Cancer and matrix remodelling (research group)
- Division of Translational Cancer Research
- Molecular Tumor Pathology (research group)
- Human Neural Developmental Biology (research group)
- Building Bone Killing Bugs (research group)
- LTH Profile Area: Engineering Health
- publishing date
- 2022-10-12
- 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
-
- scopus:85139793218
- pmid:36223446
- 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
- 2024-09-19 20:55:16
@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}}, }