“Osteo‐Organogenesis Niche” Hyaluronic Acid Engineered Materials Directing Re‐Osteo‐Organogenesis via Manipulating Macrophage CD44‐MAPK/ERK‐ETV1/5‐MRC1 Axis

Abstract The strategy of re‐organogenesis provides an optimal framework for restoring complex organ structures and functions in adult damage. While the focus has often been on restoring organogenesis stem cells, there is limited investigations of reverting the environmental niche to support this approach. The guiding principle of “Nature selects the fittest to survive” drives the intricate dynamic changes in cellular events within the niche environment, especially through immune surveillance. The extracellular matrix (ECM) serves as the “self‐associated molecular patterns” of the niche, containing extensive data on cell‐niche reaction data and acting as the active tuner of immune surveillance. In this study, hyaluronic acid (HA) is identified as a unique component of the ECM in cranial osteo‐organogenesis. Mechanistically, HA activates the Cluster of Differentiation 44 (CD44)‐Mitogen‐Activated Protein Kinase (MAPK)/Extracellular Signal‐Regulated Kinase (ERK)‐Ets Variant 1/5 (ETV1/5)‐ Mannose Receptor C‐Type 1 (MRC1) axis in macrophages, establishing a distinct immune surveillance during osteo‐organogenesis. Furthermore, HA is utilized as a novel engineered material for an “Osteo‐organogenesis niche”, restoring immune surveillance and synergistically regulating stem cells to achieve re‐osteo‐organogenesis in cranial defects of rats. Taken together, the study unveils a previously unknown strategy for leveraging re‐organogenesis by utilizing “organogenesis niche” ECM engineered materials to manipulate immune surveillance, thereby comprehensively regulating stem cells and other tissue cells effectively for re‐organogenesis.