Three dimensional and microphysiological bone marrow models detect in vivo positive compounds

Abstract Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather,...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rhiannon David, Sarah Gee, Kainat Khan, Amy Wilson, Ann Doherty
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0d2a586f0fc4f4e9d2b85c530eb68b8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a0d2a586f0fc4f4e9d2b85c530eb68b8
record_format	dspace
spelling	oai:doaj.org-article:a0d2a586f0fc4f4e9d2b85c530eb68b82021-11-14T12:17:38ZThree dimensional and microphysiological bone marrow models detect in vivo positive compounds10.1038/s41598-021-01400-52045-2322https://doaj.org/article/a0d2a586f0fc4f4e9d2b85c530eb68b82021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01400-5https://doaj.org/toc/2045-2322Abstract Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0–0.070 µM) and PARPi (0–150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0–1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies.Rhiannon DavidSarah GeeKainat KhanAmy WilsonAnn DohertyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rhiannon David Sarah Gee Kainat Khan Amy Wilson Ann Doherty Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
description	Abstract Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0–0.070 µM) and PARPi (0–150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0–1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies.
format	article
author	Rhiannon David Sarah Gee Kainat Khan Amy Wilson Ann Doherty
author_facet	Rhiannon David Sarah Gee Kainat Khan Amy Wilson Ann Doherty
author_sort	Rhiannon David
title	Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
title_short	Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
title_full	Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
title_fullStr	Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
title_full_unstemmed	Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
title_sort	three dimensional and microphysiological bone marrow models detect in vivo positive compounds
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a0d2a586f0fc4f4e9d2b85c530eb68b8
work_keys_str_mv	AT rhiannondavid threedimensionalandmicrophysiologicalbonemarrowmodelsdetectinvivopositivecompounds AT sarahgee threedimensionalandmicrophysiologicalbonemarrowmodelsdetectinvivopositivecompounds AT kainatkhan threedimensionalandmicrophysiologicalbonemarrowmodelsdetectinvivopositivecompounds AT amywilson threedimensionalandmicrophysiologicalbonemarrowmodelsdetectinvivopositivecompounds AT anndoherty threedimensionalandmicrophysiologicalbonemarrowmodelsdetectinvivopositivecompounds
_version_	1718429304881152000

Three dimensional and microphysiological bone marrow models detect in vivo positive compounds

Ejemplares similares