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

Area of Science:

• Toxicology
• Drug Safety
• In Vitro Models

Background:

• Micronucleus (MN) assessment is crucial for drug safety evaluation.
• In vivo bone marrow (BM) MN assays show positives for non-genotoxic compounds due to uncharacterized BM complexity, halting drug progression.
• There is a need for physiologically relevant BM models to bridge in vitro and in vivo testing gaps.

Purpose of the Study:

• To evaluate two human 3D BM models (fluidic and static) for MN assessment.
• To determine if these models can detect MN induction from compounds exhibiting pharmacological effects in vivo but not in vitro.
• To assess the potential of these models to reduce reliance on animal studies.

Main Methods:

• Micronucleus induction was assessed in 2D L5178Y and human BM cells, alongside two novel 3D human BM models (fluidic and static).
• Cells were treated with etoposide (genotoxic), Poly-ADP Ribose Polymerase inhibitor (PARPi), and prednisolone (pharmacological in vivo positive).
• MN induction was quantified following treatment with varying concentrations of each compound.

Main Results:

• Both 3D BM models successfully detected MN induction by etoposide and PARPi, confirming their utility in genotoxicity testing.
• PARPi treatment showed a trend of MN induction in the 3D models that more closely resembled in vivo results.
• Crucially, prednisolone induced MN in both 3D BM models, indicating these models recapitulate the in vivo microenvironment and its pharmacological effects.

Conclusions:

• The developed 3D human BM models are effective for MN assessment, capable of detecting both genotoxic and pharmacologically induced micronuclei.
• These models offer a more physiologically relevant platform to understand drug effects on the bone marrow, potentially predicting in vivo outcomes.
• Implementing these advanced 3D models can aid in mechanistic understanding, reduce false positives in drug development, and decrease the need for animal testing.