Abstract
Nuclear morphology, which modulates chromatin architecture, plays a critical role in regulating gene expression and cell functions. While most research has focused on the direct effects of nuclear morphology on cell fate, its impact on the cell secretome and surrounding cells remains largely unexplored, yet is especially crucial for cell-based therapies. In this study, we fabricated implants with a micropillar topography using methacrylated poly(octamethylene citrate)/hydroxyapatite (mPOC/HA) composites to investigate how micropillar-induced nuclear deformation influences cell paracrine signaling for osteogenesis and cranial bone regeneration. In vitro, cells with deformed nuclei showed enhanced secretion of proteins that support extracellular matrix (ECM) organization, which promoted osteogenic differentiation in neighboring human mesenchymal stromal cells (hMSCs). In a mouse model with critical-size cranial defects, nuclear-deformed hMSCs on micropillar mPOC/HA implants elevated Col1a2 expression, contributing to bone matrix formation, and drove cell differentiation toward osteogenic progenitor cells. These findings indicate that micropillars not only enhance the osteogenic differentiation of human mesenchymal stromal cells (hMSCs) but also modulate the secretome, thereby influencing the fate of surrounding cells through paracrine effects.