On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
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Joyce, Cailin E.
Moreira Teixeira, Liliana S.
O’Sullivan, Lucy R.
Ng, Carlos F.
Myers, Kasiani C.
Weinberg, Olga K.
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CitationChou, David, Viktoras Frismantas, Yuka Milton, Rhiannon David, Petar Pop-Damkov, Douglas Ferguson, Alexander MacDonald et al. "On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology." Nature Biomedical Engineering 4, no. 4 (2020): 394-406. DOI: 10.1038/s41551-019-0495-z
AbstractThe inaccessibility of living bone marrow hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human bone-marrow-on-a-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 marrow injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation as well as marrow recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and bone-marrow-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 bone-marrow 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 bone-marrow-on-a-chip may serve as a human-specific alternative to animal testing for the study of bone-marrow pathophysiology.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37370981
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