Dissertation
Controlling inflammation to promote tissue renegeration
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2024
DOI:
https://doi.org/10.17918/00010677
Abstract
Dysfunctional tissue repair manifests in a number of conditions, including aging, diabetes, and catastrophic injuries. As key directors of the immune response, macrophages are responsible for sustaining a pro-regenerative environment within injuries, partly via modulation of other immune cells and progenitor cells. Normally, pro-inflammatory (M1) macrophages dominate the site of injury early on, and are subsequently replaced by reparative (M2) macrophages. M2 macrophages, typically activated with IL-4, may derive from circulating monocytes or M1 macrophages that have switched phenotypes. However, it is unknown whether these populations are different in terms of reparative function. Furthermore, in injuries where regeneration is stalled, M1 macrophages are dysfunctional and fail to switch to the M2 phenotype, resulting in chronic inflammation. This thesis sought to first understand the mechanisms underlying the "M1-to-M2" switch, then leverage it in a macrophage cell therapy to promote tissue regeneration. First, the responses of unactivated (M0) and M1 macrophages to IL-4 were compared in terms of gene, protein, and functional expression. Next, the crosstalk between macrophages and T helper cells was investigated using direct co-culture of human cells in vitro and a cutaneous wound model in mice. Finally, these findings informed the design of a macrophage cell therapy in which mRNA-loaded lipid nanoparticles intracellularly maintained a reparative macrophage phenotype in a murine model of volumetric muscle loss. Altogether, this thesis demonstrates the need to control the macrophage M1-to-M2 switch to promote healing, and offers a potential strategy to do so.
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Details
- Title
- Controlling inflammation to promote tissue renegeration
- Creators
- Erin Michelle O'Brien
- Contributors
- Kara L. Spiller (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 122 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991021906709804721