Multiscale Modeling of Idiopathic Pulmonary Fibrosis

Cells are constantly communicating with each other and with their microenvironment through organized, but complex pathways that ultimately dictate cell fate decisions such as proliferation, apoptosis, and quiescence. The internalization of these external signals initiates a myriad of different signaling pathways that in summation influence the cell’s response. Within a tissue the aggregate of many individual cell decisions leads to an emergent tissue phenotype that represents tissue homeostasis or signs of disease, such as fibrosis. The study of these inherently multiscale systems requires the use of a multiscale approach, both experimentally and computationally, to fully appreciate the system’s dynamics. In this thesis I develop multiscale frameworks for studying two crucial tissue remodeling mechanisms, microvascular remodeling and fibrotic scar formation, that integrate computational and experimental techniques to advance our understanding of these processes. I apply these frameworks to understand intracellular, cellular, and tissue level contributions to the disease idiopathic pulmonary fibrosis (IPF). A progressive fibrotic disease of the lung that’s origins are still not fully understood, IPF is grim prognosis for patients with limited treatment options and no cure. Multiscale computational models can advance our understanding of potential disease progression and treatment opportunities by integrating experimental techniques from the bench with clinical reports from patient data. First, I will explore how the disruption of coupling between the cells that make up the microvasculature, endothelial cells and pericytes, leads to abnormal remodeling responses that contribute to mixed reports of excess, leaky vasculature and areas devoid of vasculature in the IPF lung. I will then shift my focus to the cells that are primarily responsible for the production of fibrotic scar, fibroblasts, and the integration of sub-populations identified via single-cell RNAseq with multiscale computational modeling to understand the impact of these sub-populations on collagen content and characteristics of fibrotic foci. In summary, the development of multiscale computational models that can incorporate experimental and clinical findings have large potential for accelerating biomedical research through advancing the understanding of disease progression and identification of therapeutic targets.