Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages.

Regenerative organs, like the skin, depend on niche-stem cell interactions that sustain cellular turnover. In culture, skin fibroblasts promote epidermal stem cell proliferation and differentiation. Yet, it remains elusive how fibroblasts regulate epidermal stem cell behaviors and differentiation in vivo in skin. Here, we asked how fibroblast depletion may impact proliferation of the epidermal stem cell compartment. Surprisingly, we find that significant depletion of fibroblast density does not affect epidermal stem cell proliferation during adult or neonatal stages in vivo. These results demonstrate that across different ages, proliferation of epidermal stem cells can persist in the face of a depleted fibroblast population. Interestingly, neonatal fibroblast depletion does not significantly reduce 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 response to fibroblast depletion to maintain functional capacity.