TY - JOUR
T1 - On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
AU - Chou, David B.
AU - Frismantas, Viktoras
AU - Milton, Yuka
AU - David, Rhiannon
AU - Pop-Damkov, Petar
AU - Ferguson, Douglas
AU - MacDonald, Alexander
AU - Vargel Bölükbaşı, Özge
AU - Joyce, Cailin E.
AU - Moreira Teixeira, Liliana S.
AU - Rech, Arianna
AU - Jiang, Amanda
AU - Calamari, Elizabeth
AU - Jalili-Firoozinezhad, Sasan
AU - Furlong, Brooke A.
AU - O’Sullivan, Lucy R.
AU - Ng, Carlos F.
AU - Choe, Youngjae
AU - Marquez, Susan
AU - Myers, Kasiani C.
AU - Weinberg, Olga K.
AU - Hasserjian, Robert P.
AU - Novak, Richard
AU - Levy, Oren
AU - Prantil-Baun, Rachelle
AU - Novina, Carl D.
AU - Shimamura, Akiko
AU - Ewart, Lorna
AU - Ingber, Donald E.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology.
AB - The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology.
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U2 - 10.1038/s41551-019-0495-z
DO - 10.1038/s41551-019-0495-z
M3 - Article
C2 - 31988457
AN - SCOPUS:85078444118
SN - 2157-846X
VL - 4
SP - 394
EP - 406
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 4
ER -