Date of Completion
4-12-2018
Embargo Period
4-9-2028
Keywords
Fibro-adipogenic progenitors, Heterotopic ossification, Fibrodysplasia ossificans progressiva, Muscular dystrophy, Skeletal muscle stem cell
Major Advisor
Dr. David Goldhamer
Associate Advisor
Dr. Craig Nelson
Associate Advisor
Dr. Charles Giardina
Associate Advisor
Dr. Akiko Nishiyama
Associate Advisor
Dr. Adam Zweifach
Field of Study
Genetics and Genomics
Degree
Doctor of Philosophy
Open Access
Open Access
Abstract
The goal of this project is to identify and characterize the cells-of-origin of non-myogenic aggregates that occupy the skeletal muscle domain in response to regenerative failure. Defective muscle tissue repair can occur as a result of disease, traumatic injuries or aging, and any disability caused by the loss of muscle mass and function is further compounded by the colonization of the muscle microenvironment by fibrotic, fatty or bony deposits. A comprehensive understanding of the cellular and signaling components that regulate muscle homeostasis and repair is absolutely critical for the development of therapies aimed at restoring muscle integrity and function. In particular, identifying the cellular source of the ectopic collagen, fat or bone could provide a target for inhibitory drugs. There is evidence that implicates satellite cells, which are muscle stem cells, in injury-associated adipogenesis and osteogenesis. Previous studies from our lab also suggest that cells of the Tie2-gene lineage exhibit multipotentiality, specifically fibrogenic, chondrogenic and osteogenic capacity, in response to triggers that induce skeletal muscle degeneration and ectopic ossification. However, given the promiscuity of Tie2 gene expression, further analyses are necessary to establish the precise identity of the responding cells. In this study, we present a novel multipotent skeletal muscle-resident progenitor (called fibro-adipogenic progenitor or FAP) that contributes robustly to heterotopic ossification and dystrophy-associated fibrosis. Our observations also provide irrefutable proof that satellite cells remain committed to a myogenic fate and do not undergo transdifferentiation during regenerative failure. Collectively, these findings provide a potential cellular target for therapeutic intervention in the treatment of muscle degenerative diseases.
Recommended Citation
Biswas, Arpita, "Dysregulation of a Skeletal Muscle-Resident Fibro-Adipogenic Progenitor (FAP) Population Causes Musculoskeletal Disease" (2018). Doctoral Dissertations. 1737.
https://digitalcommons.lib.uconn.edu/dissertations/1737