Concise Review: In Vitro Formation of Bone-Like Nodules Sheds Light on the Application of Stem Cells for Bone Regeneration

Abstract

: Harnessing the differentiation of stem cells into bone-forming cells represents an intriguing avenue for the creation of functional skeletal tissues. Therefore, a profound understanding of bone development and morphogenesis sheds light on the regenerative application of stem cells in orthopedics and dentistry. In this concise review, we summarize the studies deciphering the mechanisms that govern osteoblast differentiation in the context of in vitro formation of bone-like nodules, including morphologic and molecular events as well as cellular contributions to mineral nucleation, occurring during osteogenic differentiation of stem cells. This article also highlights the limitations of current translational applications of stem cells and opportunities to use the bone-like nodule model for bone regenerative therapies.

Significance: Harnessing the differentiation of stem cells into bone-forming cells represents an intriguing avenue for the creation of functional skeletal tissues. Therefore, a profound understanding of bone development and morphogenesis sheds light on the regenerative application of stem cells in orthopedics and dentistry. In this concise review, studies deciphering the mechanisms that govern osteoblast commitment and differentiation are summarized. This article highlights the limitations of current translational applications of stem cells and the opportunities to use the bone-like nodule model for bone regenerative therapies.

Keywords: Bone-like nodule; Differentiation; Extracellular matrix mineralization; Osteoblast; Stem cells.

Figure 1.

Bone-like nodule formation. (A): Schematic overview of developmental sequences involving morphologic progressions and selective expression of genes that regulate cell proliferation and promote osteoprogenitor commitment and bone-like nodule formation. These processes were schematically illustrated by three major stages divided by two restrictive points. Downregulation of proliferation/ECM accumulation and ECM remodeling/mineral deposition corresponds, respectively, to the first and second restrictive points. Details about OB-mediated ECM mineralization (red square) are provided in (B). (B): The proposed OB-dependent mechanism of calcium phosphate nucleation includes both extracellular and intracellular matrix vesicles. Abbreviations: AM, amorphous mineral; CK, cytoskeleton; COL-I, type-1 collagen; ECM, extracellular matrix; eMV, extracellular matrix vesicle; GJ, gap junction; I, integrin; iMV, intracellular matrix vesicle; M, mitochondria; MC, mineral crystal; MSC, mesenchymal stem cell; N, nucleus; OB, osteoblast; OP, osteoprogenitor cell; RER, rough endoplasmic reticulum.