Date of Award
Spring 2026
Language
English
Embargo Period
4-21-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Nanoscale Science and Engineering
Program
Nanobioscience
First Advisor
Janet Paluh
Committee Members
Yubing Xie, Juan Andres Melendez, Scott Tenenbaum, Annalisa Scimemi, Randall Rasmusson
Keywords
gastruloid, cardiac, hiPSCs, senescence, miRNA
Subject Categories
Bioinformatics | Developmental Biology
Abstract
Human development as well as congenital and adult diseases emerge from coordinated interactions among multiple cell types, regulatory programs, and tissue compartments that remain largely unresolved. Conventional simple lineage-restricted in vitro systems poorly capture this complexity. My dissertation uses human stem cell-derived developmental models to study human cardiac morphogenesis and heart diseases and application of a networked neuron platform to explore senescence-associated neurodegeneration impact on Alzheimer’s neurons.
Elongating multi-lineage organized cardiac (EMLOC) gastruloids are a synthetic embryology model that co-generates contractile cardiomyocyte populations alongside mesenchymal, endothelial, epicardial-like, neural crest-associated, and neuronal cells within a shared in vitro developmental environment. Single-cell comparative transcriptomic profiling confirms alignment of EMLOC-cell populations with human embryonic cardiac lineages. Longitudinal miRNA profiling across an 18-day time course in EMLOCs reveals that canonical cardiac miRNA families are temporally co-organized into stage-specific regulatory modules. Their activation parallels shifts in cardiac lineage composition and maturation state, and overlaps with programs implicated in heart diseases of hypertrophy, arrhythmia, and compound heart failure. Directional comparison of the EMLOC model with human embryonic and fetal heart miRNA data confirms that temporal trajectories for muscle-enriched families are also conserved. My studies establish the utility of EMLOCs for studying regulatory programs at the interface of heart development and cardiac disease.
Networked neurons are a versatile 3D alginate-embedded model referred to as neuronal ribbons. Stem cell derived brain pyramidal neurons were generated to examine how senescence-associated exposure remodels the neuronal transcriptional and electrophysiological states. Neurons generated from a healthy human pluripotent stem cell control line and a familial Alzheimer's disease line with heterozygous PSEN2 N141I mutation were studied in 2D and 3D in the presence and absence of senescent fibroblasts and SASP factors. Single-cell RNA sequencing revealed that paracrine SASP treatment and direct co-culture with senescent IMR-90 fibroblasts each induced distinct stress programs. In control healthy neurons, SASP preferentially engaged mitochondrial and oxidative stress responses, while direct co-culture shifted cells toward ER and metabolic stress adaptation. In the Alzheimer’s PSEN2 N141I background, both exposures additionally activated calcium-mediated stress signaling, Wnt-associated remodeling, and redox pathways, linking senescence-associated cues to neurodegenerative vulnerability. A sxRNA sensor responsive to senescence-enriched miR-146a was tested for condition-dependent expression in mixed cultures, demonstrating single-cell resolution for this senescence-linked microRNA activity in this system. This research extends the use of neural ribbons for mechanism-directed investigation of factors impacting neurodegeneration.
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Paredes-Espinosa, Maria B., "Stem Cell-Derived Developmental Models for Translational Evaluation of Disease and Therapy" (2026). Electronic Theses & Dissertations (2024 - present). 400.
https://scholarsarchive.library.albany.edu/etd/400