Matrix Viscoelasticity Regulates the Stemness and Multilineage differentiation of Primary Neural Progenitor-Stem Cells in 3D

Neural progenitor-stem cells (NPSCs), found in dynamic brain environments, develop into various cell types including neurons, astrocytes, and oligodendrocytes. While previous research has shown matrix viscoelasticity impacts neural maturation and neurogenic differentiation, its role in primary NPSCs beyond neurogenesis remains unclear.

This study used tunable stiffness and stress relaxation hydrogels to examine how matrix stress relaxation affects primary subventricular zone (SVZ)-derived NPSCs in three-dimensional conditions. The findings indicate that matrices with quicker stress relaxation enhance NPSC stemness, induce radial glial-like marker expression, and promote differentiation towards neuronal, astrocytic, and oligodendrocytic lineages in appropriate biochemical settings.

When in mixed neuronal/astrocytic environments, fast-relaxing matrices favor neuronal differentiation. These NPSC responses to stress relaxation involve integrin-mediated adhesion, actomyosin contractility, actin polymerization, and Piezo1 activity, with varying contributions to each differentiation pathway. In conclusion, this research demonstrates how matrix stress relaxation governs primary NPSC stemness and multilineage differentiation via multiple mechanotransduction pathways in a three-dimensional context.