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Inflammation and Benign Prostatic Hyperplasia: Role of immune cells and their interactions in chronic inflammation and cellular hyperplasia

thesis
posted on 28.07.2021, 17:50 by Meaghan M BromanMeaghan M Broman

Benign prostatic hyperplasia (BPH) is a common urologic condition among older men, affecting approximately half of men by age 50 and nearly 80% by age 80. Lower urinary tract symptoms (LUTS) associated with BPH may significantly impact quality of life for many of these men. Inflammation has been associated with the development and progression of BPH however, the precise impact and role(s) of immune cells in these conditions remains unclear. Many previous studies over the decades have explored the roles of immune cells in prostate disease in animal models and prostate tissues from human patients, and, more recently, through transcriptomic analyses of bulk cell populations and of single cells. These and other emerging technologies continue to add to the body of knowledge related to this area.

The prostate is a complex organ composed of multiple epithelial and mesenchymal cell types and subtypes. The growth, morphology, and function of these cells is influenced by autocrine and paracrine cell-cell interactions in ways that are largely not yet understood. A better understanding of the composition, heterogeneity, morphology, interactions, and functional features of various prostate cell types, particularly involving immune cells in the context of inflammatory processes, is expected to improve our understanding of the impact of altered cellular composition and communication on prostate homeostasis and disease.

Inflammation has been shown to impact the growth, morphology, and function of various prostate cell types. It is hypothesized that inflammation promotes epithelial cell proliferation and differentiation in BPH despite androgen-targeted therapy. It is hypothesized that communications between and within various immune cell populations perpetuate the non-resolving inflammatory microenvironment that promotes prostate cell expansion. In this research, the POET-3 mouse model of inducible autoimmune inflammation is used to evaluate the impact of autoimmune-type inflammation on basal epithelial cell progenitor growth and differentiation in the absence of androgens mimicking the conditions of androgen deprivation therapy (ADT), and to demonstrate the enhanced growth and differentiation potential conferred on basal progenitors by inflammation.

Additionally, this research evaluates the morphology, gene expression, and cell-cell interaction predictions of BPH prostate immune cells to explore the role of immune cells and their interactions in driving BPH inflammation.

Overall, inflammation induced epithelial and stromal expansion and basal progenitor cell proliferation in vivo and promoted basal progenitor cell growth and differentiation in vitro under androgen-deficient conditions mimicking androgen-targeted therapy. Histologic evaluation of BPH specimens reveals the composition and distribution of immune cells, including organizing lymphoid structures resembling tertiary lymphoid structures (TLS). Also, analyses of single cell RNA sequencing data of gene expression patterns and signaling pathways reveal a mixed inflammatory microenvironment in BPH. Furthermore, predicted ligand-receptor interactions indicate mixed inflammatory signaling between and among immune cell populations, including T cells, macrophages, and mast cells, that likely to the unresolving nature of BPH inflammation.

In all, the results of these studies demonstrate inflammation-induced epithelial and stromal expansion in a mouse model of resolving prostatitis and indicate potential roles for multiple immune cell populations and their interactions in driving the ongoing inflammation of BPH, suggesting that this ongoing inflammation may impact the progressive stromal and epithelial expansion characteristic of BPH.

Funding

1P20DK116185

History

Degree Type

Doctor of Philosophy

Department

Comparative Pathobiology

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Timothy Ratliff

Additional Committee Member 2

Shihuan Kuang

Additional Committee Member 3

Suresh Mittal

Additional Committee Member 4

Changdeng Hu

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