Culturing patient-derived malignant hematopoietic stem cells in engineered and fully humanized 3D niches
García-García, Andrés ; Klein, Thibaut ; Born, Gordian ; Hilpert, Morgane ; Scherberich, Arnaud ; Lengerke, Claudia ; Skoda, Radek C. ; Bourgine, Paul E. LU
and Martin, Ivan
(2021)
In Proceedings of the National Academy of Sciences of the United States of America
118(40).
- Abstract
Human malignant hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches, which remain challenging to explore due to limited in vivo accessibility and constraints with humanized animal models. Several in vitro systems have been established to culture patient-derived HSPCs in specific microenvironments, but they do not fully recapitulate the complex features of native bone marrow. Our group previously reported that human osteoblastic BM niches (O-N), engineered by culturing mesenchymal stromal cells within three-dimensional (3D) porous scaffolds under perfusion flow in a bioreactor system, are capable of maintaining, expanding, and functionally regulating healthy human cord blood-derived HSPCs. Here, we first... (More)
Human malignant hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches, which remain challenging to explore due to limited in vivo accessibility and constraints with humanized animal models. Several in vitro systems have been established to culture patient-derived HSPCs in specific microenvironments, but they do not fully recapitulate the complex features of native bone marrow. Our group previously reported that human osteoblastic BM niches (O-N), engineered by culturing mesenchymal stromal cells within three-dimensional (3D) porous scaffolds under perfusion flow in a bioreactor system, are capable of maintaining, expanding, and functionally regulating healthy human cord blood-derived HSPCs. Here, we first demonstrate that this 3D O-N can sustain malignant CD34+ cells from acute myeloid leukemia (AML) and myeloproliferative neoplasm patients for up to 3 wk. Human malignant cells distributed in the bioreactor system mimicking the spatial distribution found in native BM tissue, where most HSPCs remain linked to the niches and mature cells are released to the circulation. Using human adipose tissue-derived stromal vascular fraction cells, we then generated a stromal-vascular niche and demonstrated that O-N and stromal-vascular niche differentially regulate leukemic UCSD-AML1 cell expansion, immunophenotype, and response to chemotherapy. The developed system offers a unique platform to investigate human leukemogenesis and response to drugs in customized environments, mimicking defined features of native hematopoietic niches and compatible with the establishment of personalized settings.
(Less)
- author
- García-García, Andrés
; Klein, Thibaut
; Born, Gordian
; Hilpert, Morgane
; Scherberich, Arnaud
; Lengerke, Claudia
; Skoda, Radek C.
; Bourgine, Paul E.
LU
and Martin, Ivan
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 3D perfusion bioreactors, AML/MPN, Engineering stem cell niches, Osteoblastic niche, Stromal-vascular niche
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 118
- issue
- 40
- article number
- e2114227118
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:34580200
- scopus:85115986764
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.2114227118
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.
- id
- dc0571ef-cde6-4666-8e52-11b242e34aba
- date added to LUP
- 2021-10-19 11:48:16
- date last changed
- 2025-03-10 23:47:44
@article{dc0571ef-cde6-4666-8e52-11b242e34aba,
abstract = {{<p>Human malignant hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches, which remain challenging to explore due to limited in vivo accessibility and constraints with humanized animal models. Several in vitro systems have been established to culture patient-derived HSPCs in specific microenvironments, but they do not fully recapitulate the complex features of native bone marrow. Our group previously reported that human osteoblastic BM niches (O-N), engineered by culturing mesenchymal stromal cells within three-dimensional (3D) porous scaffolds under perfusion flow in a bioreactor system, are capable of maintaining, expanding, and functionally regulating healthy human cord blood-derived HSPCs. Here, we first demonstrate that this 3D O-N can sustain malignant CD34<sup>+</sup> cells from acute myeloid leukemia (AML) and myeloproliferative neoplasm patients for up to 3 wk. Human malignant cells distributed in the bioreactor system mimicking the spatial distribution found in native BM tissue, where most HSPCs remain linked to the niches and mature cells are released to the circulation. Using human adipose tissue-derived stromal vascular fraction cells, we then generated a stromal-vascular niche and demonstrated that O-N and stromal-vascular niche differentially regulate leukemic UCSD-AML1 cell expansion, immunophenotype, and response to chemotherapy. The developed system offers a unique platform to investigate human leukemogenesis and response to drugs in customized environments, mimicking defined features of native hematopoietic niches and compatible with the establishment of personalized settings.</p>}},
author = {{García-García, Andrés and Klein, Thibaut and Born, Gordian and Hilpert, Morgane and Scherberich, Arnaud and Lengerke, Claudia and Skoda, Radek C. and Bourgine, Paul E. and Martin, Ivan}},
issn = {{0027-8424}},
keywords = {{3D perfusion bioreactors; AML/MPN; Engineering stem cell niches; Osteoblastic niche; Stromal-vascular niche}},
language = {{eng}},
number = {{40}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Culturing patient-derived malignant hematopoietic stem cells in engineered and fully humanized 3D niches}},
url = {{http://dx.doi.org/10.1073/pnas.2114227118}},
doi = {{10.1073/pnas.2114227118}},
volume = {{118}},
year = {{2021}},
}