Date of Completion

Spring 5-1-2022

Thesis Advisor(s)

David J. Goldhamer; Geoffrey R. Tanner; Adam Zweifach

Honors Major

Molecular and Cell Biology

Disciplines

Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Disease Modeling | Genetics | Medicine and Health Sciences | Musculoskeletal Diseases

Abstract

While we often perceive disease as negative, there is potential to engineer seemingly negative biological phenomena into therapeutics to treat a variety of human illnesses. Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder involving uncontrolled, widespread, extraskeletal bone growth, or heterotopic ossification (HO). In FOP patients, stem cells called fibro/adipogenic progenitors (FAPs) follow an abnormal, osteogenic pathway. In the present study, we investigate whether we can adapt these Acvr1 mutant FAPs, which are exceptional at producing bone, to repair bone fractures in otherwise normal patients. The primary aims of this study are (1) to devise and optimize a novel method to simulate bone fractures less invasively in mice, and (2) to test whether mutant FAPs can form bone at fracture sites in a controlled and localized manner. Through micro-CT, we visualize and quantify ectopic bone volumes and observe that mutant FAPs form HO in both immunocompromised, SHO-PrkdcscidHrhr (SCID) hosts and Acvr1tnR206H/+;R26NG/+;Tie2-Cre mice. However, HO does not appear to be highly localized to bone fragments without the use of activin A monoclonal antibody. Promisingly, donor bone fragments remain stable until at least 28 days post-transplantation. Notably, one replicate exhibited a remarkable increase in bone volume and change in morphology by day 14 followed by a decrease in bone volume by day 21 post-transplantation. Future work should involve the use of activin A monoclonal antibody, a greater number of bone fragments to maximize available bone morphogenetic proteins (BMPs), histological analyses to visualize cell populations contributing to bone fragment changes (both stem cells and immune populations), and additional trials. Ultimately, this study is an innovative way to adapt an aberrant process to treat another ailment.

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