Application of in vitro erythropoiesis from bone marrow derived progenitors to detect and study genotoxicity

Assays that predict toxicity are an essential part of drug development and there is a demand for efficient models to better predict human responses. The in vivo micronucleus (MN) assay is a robust toxicity test that assesses the genotoxic effect of drugs on adult bone marrow (BM) using the metric of genotoxic damage to the reticulocyte population in mice. An in vitro correlate to this assay might facilitate extension to human cells and thus provide a highly predictive genotoxicity assay. As first steps in developing a toxicity assay, this thesis work (a) adapted a fetal liver-based in vitro erythropoietic culture system to induce optimized erythropoietic growth from the lineage-marker-negative (Lin) population in adult BM, as adult hematopoietic tissue is ultimately a feasible source of cells; and (b) demonstrated that exposure to alkylating agents induces physiological MN-formation in erythroid populations derived in vitro. The potential for increased efficiency in this in vitro model depends on the ability to stimulate terminal erythroid differentiation at an optimal level from adult BM.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2007

Author dc:creator

• Shuga, Joseph F. (Joseph Francis)

Advisor dc:contributor.advisor

• Linda G. Griffith and Leona D. Sampson.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/38978

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/38978