Stem Cells From Human Exfoliated Deciduous Teeth as a Potent Cell Therapy for Radiation‐Induced Osteonecrosis Model

ABSTRACT

Osteonecrosis is a serious disorder leading to subchondral bone collapse and joint dysfunction. Osteonecrosis has been increasingly diagnosed before bone collapse; however, effective treatments for regenerating necrotic bone remain unavailable. Mesenchymal stem cell (MSC)‐based therapies are promising; however, bone marrow‐derived MSCs (BMSCs) are limited by donor burden, low yield, and suboptimal regenerative efficacy. Stem cells from human exfoliated deciduous teeth (SHED) exhibit higher proliferative capacity, enhanced growth factor secretion, minimal senescence, and noninvasive harvesting, making them a strong alternative. We evaluated SHED and BMSCs in a refractory rat model of radiation‐induced tibial osteonecrosis. In vitro, SHED secreted similar or higher levels of proangiogenic and chemotactic factors—including vascular endothelial growth factor, angiopoietin‐2, stem cell factor, monocyte chemoattractant protein‐1, and C‐C motif chemokine ligand 5—than BMSCs and significantly enhanced macrophage migration. Hydroxyapatite/collagen scaffolds seeded with SHED or BMSCs were transplanted into irradiated tibial bone defects in vivo. Micro‐computed tomography revealed significantly accelerated bone regeneration with SHED, but not with BMSCs, compared with cell‐free scaffolds. Histology confirmed new bone and marrow formation at SHED‐treated sites, accompanied by increased periosteal proliferation and vascularity. Bulk RNA sequencing showed that SHED transplantation upregulated angiogenesis and immune cell recruitment–related pathways, whereas BMSCs upregulated genes associated with endochondral ossification without effective regeneration. Notably, SHED did not differentiate into osteoblasts or chondrocytes in vivo, indicating paracrine mediation of angiogenesis and macrophage recruitment. Given the limited regenerative capacity of necrotic bone, SHED's angiogenic and immunomodulatory activities position it as a promising candidate for cell‐based therapy in refractory osteonecrosis.