Sanchez-Danes, A. | bioRxiv Science

bioRxiv2026

A shared extracellular plasticity program drives brain repair and tumor progression

Injury induces complex multicellular repair responses that restore tissue integrity and replenish lost cells. In the brain, regeneration is limited and depends on the proliferation of neural and glial progenitors. But how these cells remodel the microenvironment to support repair remains poorly understood. Here, we profile dividing cells in the injured fruit fly brain revealing signatures of neural stem cell activation and ECM remodeling. We find that rapid activation of a Heparan Sulfate-binding factor (Hpsl) and changes in glypicans condition the extracellular space for proliferation. Hpsl promotes signalling of scarce Dpp/BMP ligands in brain cells with latent proliferative capacity and regulates organismal resilience to brain injury. We further show that malignant cells in fly and mouse brains promote similar HS-interactions to support tumor progression. Together, our findings identify extracellular proteoglycan remodeling as a key regulator of brain repair and uncover a common plasticity program engaged by brain damage and tumorigenesis.

cell biology↗

bioRxiv2024

Biomechanics of stem cell fate decisions in multilayered tissues

Tissue homeostasis relies on a precise balance of fate choices between renewal and differentiation, which is dysregulated during tumor initiation. Although much progress has been done over recent years to characterize the dynamics of cellular fate choices at the single cell level, their underlying mechanistic basis often remains unclear. In particular, although physical forces are increasingly characterized as regulators of cell behaviors, a unifying description of how global tissue mechanics interplays with local cellular fate choices is missing. Concentrating on skin epidermis as a paradigm for multilayered tissues with complex fate choices, we develop a 3D vertex-based model with proliferation restrained in the basal layer, showing that mechanics and competition for space naturally gives rise to homeostasis and neutral drift dynamics that are seen experimentally. We then explore the effect of introducing mechanical inhomogeneities, whereby subpopulations have differential tensions. We uncover that relatively small mechanical disparities can be sufficient to heavily tilt cellular towards symmetric renewal and exponential growth. Importantly, the simulations predict that such mechanical inhomogeneities are reflected by distinct morphological changes in single-cell shapes. This led us to derive a master relationship between two very different experimentally measurable parameters, cell shape and long-term clonal dynamics, which we validated using a model of basal cell carcinoma (BCC) consisting in clonal Smoothened overexpression in mouse tail epidermis. Altogether, we propose a theoretical framework to link mechanical forces, quantitative cellular morphologies and cellular fate outcomes in complex tissues.

biophysics↗