Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Elaine Fuchs
Abstract
Barrier tissues serve as our interface with the outside world. They protect us from harmful agents, while helping us assimilate what we need from the environment. Two prime examples of barrier tissues are the skin and intestinal epithelia, which constitute the largest surfaces of our body. They undergo continuous epithelial turnover to maintain barrier integrity and in doing so, rely on tissue- resident stem cells, which balance processes of self-renewal with differentiation. Epidermal (EpdSCs) and hair follicle stem cells (HFSCs) in the skin are opposite of intestinal stem cells (ISCs) in the gut, all of which are embedded in a rich and diverse network of neighboring cell types, the so-called niche. The multifarious composition of the niche and its underlying signaling axes are still unfolding. In the first part of this thesis, I paired single cell with spatial transcriptomics of the mouse intestine to map the communication network of ISCs and their microenvironment in the gut in unprecedented detail. Using newly developed deconvolution (BayesPrism) and dimensional reduction (SpaceFold) algorithms, I was able to computationally recapitulate the in vivo tissue landscape of the intestine on a cellular and transcriptional level. These approaches unearthed lymphatic capillaries as a hitherto unappreciated component of the ISC niche – mirroring what had been reported for the HFSC niche in the skin. Lymphatics intimately associated with ISCs throughout the intestinal tract and emerged as a potent signaling hub in ISC proximity – secreting a suite of canonical (WNTs, R-spondins) and non-canonical (REELIN, IL-33) stem cell factors. Combining conditional genetic knockout mouse and first-of-their-kind lymphatic:organoid co-culture models, I expose lymphatic-secreted REELIN as a novel factor in ISC maintenance. Paralleling lymphatics as a cellular component that was conserved, the second part of this thesis focuses on Il33 as a transcriptional candidate, whose expression was spatially tailored to stem cell niches across barrier sites. By employing cell type-specific conditional Il33 knockout mouse lines I reveal how compensatory mechanisms appear to be in place in high-turnover tissues like the intestine to sustain IL-33 levels and uphold ISC maintenance. In the skin, IL-33 at homeostasis was confined to epithelial cells in the basal epidermis. IL-33 transitioned from its nuclear location to its secreted form as an alarmin in response to calcium-dependent keratinocyte differentiation. Loss of epithelial IL-33 in the skin induced EpdSC proliferation, which resulted in stem cell exhaustion upon chronic challenge. Across barrier sites, Il33 was enriched in stem cell niches and seems to curb epithelial proliferation in an effort to maintain tissue fitness long-term. In summary, my thesis work dissects stem cell:niche crosstalk from a spatial angle. It highlights commonalities and differences between the EpdSC, HFSC and ISC niches of the skin and gut, pinpoints lymphatics as a preserved cellular and IL-33 as a preserved transcriptional candidate of stem cell regulation across barrier sites. Beyond that, my integrated transcriptomic approaches emphasize spatially tailored gene expression as a previously unappreciated way for cells to co- adapt and fine-tune functional output.
License and Reuse Information
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Recommended Citation
Schernthanner, Marina, "Spatial Landscaping of Stem Cell:Niche Crosstalk in Barrier Tissues" (2026). Student Theses and Dissertations. 865.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/865
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy