Author ORCID Identifier
https://orcid.org/0009-0004-4035-1136
Date of Award
7-2026
Document Type
Thesis (Ph.D.)
Department or Program
Molecular and Systems Biology
First Advisor
Dr. Michael L. Whitfield
Abstract
Systemic sclerosis (Scleroderma, SSc) is a rare, yet fatal autoimmune disease characterized by fibrosis of skin and organs. Disease pathogenesis is poorly understood and there are no curative therapies. To understand SSc and help patients, we need models that resemble disease on a phenotypic and genetic level. Since SSc is an extremely heterogeneous disease, multiple models are needed to capture the subtypes of patients and disease states. This dissertation focuses on two such models, one a 3D skin-like tissue, the other a mouse model of fibrosis.
In the second chapter of this dissertation, I collaborated with tissue engineering experts and established a human skin equivalent (HSE) 3D tissue model containing T cells, fibroblasts, and monocytes from healthy control (HC) individuals. T cells in HSE tissues survived and were functional. Using single cell RNA sequencing (scRNA-seq), I showed that the fibroblasts and T cells in HSE tissues differentiated into subpopulations, and that they communicated by ligand-receptor pairs TNFSF12–TNFRSF12A and ANXA1–FPR1.
In chapter three, I again worked with tissue engineers to incorporate SSc patient derived cells into HSE tissues, and analyzed them by scRNA-seq. I found fibroblast and T cell populations resembling publicly available scRNA-seq data on a gene expression level, as well as PI3K and ERBB signaling that aligned with previously documented findings. Monocytes were able to differentiate into macrophages, and non-autologous keratinocytes form distinct layers. Finally, I identified a CXCL12-CXCR4 signaling pathway between fibroblasts and T cells that is relevant for human disease.
Finally in chapter four, I generated tools to investigate the tight skin 2 (Tsk2/+) mouse, which has been documented to resemble the fibroproliferative intrinsic molecular subset of SSc. I generated primary fibroblasts from the Tsk2/+ mouse and validated that they retained their genotype and phenotype in culture. Bulk RNA-sequencing, split by mouse sex, showed differential expression of hair cycle genes. Gene set enrichment analysis (GSEA) showed enrichment of unfolded protein response (UPR) and extracellular matrix (ECM) assembly gene sets within female mice.
Within this work, I used transcriptomic and molecular approaches to characterize models of SSc, supporting them as tools for better understanding this disease.
Recommended Citation
Morrisson, Madeline J., "Molecular Characterization of Human and Mouse Models of Systemic Sclerosis to Identify Fibroblast-Immune Cell Mediators That Drive Fibrosis" (2026). Dartmouth College Ph.D Dissertations. 529.
https://digitalcommons.dartmouth.edu/dissertations/529
