Role of The Immune System In The Modulation of The Mmr-Deficient Intestinal Stem Cell Niche

<p>Mismatch Repair (MMR) is a crucial DNA repair system to maintain genomic integrity in cells that is integrated by specific genes including <em>MLH1</em>, <em>MSH2</em>, <em>MSH6</em>, and <em>PMS2. </em>These genes play a critical role in repairing errors that occur in base pairing by stabilizing the genetic material. When the MMR system fails to correct those errors, MMR deficiency occurs where monoallelic mutations in the MMR genes result in a condition known as Lynch Syndrome (LS). LS makes up approximately 3% of all colorectal cancer (CRC) and is regarded as a hereditary form of CRC, which progresses from MMR-deficient (MMRd) intestinal stem cells (ISCs). Many studies have shown that the immune system plays a critical role in influencing the genetic expression of stem cells. Our lab has also shown that naproxen, a non-steroidal anti-inflammatory drug (NSAID), has been effective at activating different subtypes of immune cells including macrophages. The purpose of this study was to understand how the immune cell compartment interacts with MMRd cells within the ISC niche. In this study, biopsied normal colorectal mucosa from MMRd patients after 6 months of exposure to naproxen was stained with stem cell and differentiation biomarkers using an <em>in situ</em> hybridization assay to quantify the marker density. Colon samples from MMRd mice were also collected and grown as organoids. The interactions between ISCs and the immune system were observed via changes in gene expression by culturing organoids with macrophage secretome. Mass Spectrometry was also used to identify factors in the macrophage secretome that may have contributed to the observed changes. Overall, results indicate that there is a significant increase in the quantification of stem cell biomarkers in MMRd normal mucosa after daily exposure to naproxen. There are also secreted factors present in the macrophage secretome, which are involved in the regulation of cellular proliferation and apoptosis thus validating our findings that the immune system modulates the MMRd ISC niche.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2023

Authors dc:creator

• Conner, Shepard
• <p>0000-0002-4367-4529</p>

Contributors dc:contributor

• Eduardo Vilar-Sanchez
• Subrata Sen
• Jared K. Burks

• MMR
• Lynch Syndrome
• Colorectal Cancer
• colon
• immune system
• macrophage
• intestinal stem cell
• MMRd
• LGR5
• Cancer Biology
• Cell and Developmental Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1313

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2370