Biology subjects

Gallini, S.

Publications and source records attributed to Gallini, S..

3 recordsLinked to original sources

bioRxiv2025

Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages

Regenerative organs, like the skin, depend on niche-stem cell interactions that sustain continuous cellular turnover. In cell culture, skin fibroblasts promote epidermal stem cell proliferation and differentiation. Yet, it remains elusive how fibroblasts regulate epidermal stem cell behaviors and differentiation in skin in vivo. Here, we asked how fibroblast depletion may impact epidermal stem cell proliferation in the context of adult homeostasis. Surprisingly, we find that significant depletion of fibroblast density does not affect epidermal stem cell proliferative capacity during adult stages in vivo. We next probed earlier neonatal stages when skin is actively remodeling but found no change in epidermal stem cell proliferative capacity following fibroblast depletion. These results demonstrate that across different ages, epidermal stem cell proliferative capacity can persist in the face of a largely reduced fibroblast population. Interestingly, neonatal fibroblast depletion does not significantly reduce their secreted collagen I density but affects basement membrane mechanics and epidermal stem cell delamination. Despite these changes, the skin continues to maintain its protective barrier function. Thus, our work demonstrates the skin regenerative program employs robust compensatory mechanisms in the face of fibroblast depletion to maintain functional capacity.

cell biology↗

bioRxiv2022

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation

Tissue regeneration and maintenance rely on coordinated stem cell behaviors. This orchestration can be impaired by oncogenic mutations leading to tissue architecture disruption and ultimately cancer formation. However, it is still largely unclear how oncogenes perturb stem cells functions to break tissue architecture. Here, we used intravital imaging and a novel signaling reporter to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking the same hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner. This tissue architecture abnormality is linked with a spatial dysregulation of stem cell proliferation as well as abnormal migration during hair follicle growth. By using a reporter mouse that allows us to capture real-time ERK signal dynamics at the single cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts the pulsatile ERK signal fluctuation in the stem cells into sustained activation. Furthermore, by combining drug treatment with longitudinal imaging, we demonstrated that temporary inhibiting ERK signal reverts the KrasG12D-induced tissue deformation, suggesting that sustained ERK activation leads to tissue architecture disruption in Kras mutant hair follicles. Altogether, our work suggests that oncogenic mutations induce tissue abnormalities when spatiotemporally specific conditions are met, which allows mutant stem cells to disturb local cell coordination through altering dynamic signal communications.

cancer biology↗

bioRxiv2022

Injury suppresses Ras cell competitive advantage through enhanced wild-type cell proliferation

Healthy skin is a tapestry of wild-type and mutant clones. Although injury can cooperate with Ras mutations to promote tumorigenesis, the consequences in genetically mosaic skin are unknown. Here, we show that wild-type cells prevent oncogenic Ras-induced aberrant growth after injury. Although HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue, their competitive advantage is suppressed after injury due to a selective increase in wild-type cell proliferation. EGFR inhibition abolishes the competitive advantage of wild-type cells after injury of HrasG12V/+-mosaic skin. Global loss of the cell cycle inhibitor p21 increases wild-type cell proliferation even without injury, suppressing the competitive advantage of HrasG12V/+ cells. Thus, injury plays an unanticipated role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin. One sentence SummaryInjury-repair selectively induces wild-type cell proliferation to suppress oncogenic growth in Ras-mosaic skin epithelium.

cell biology↗