We generated, on titanium surfaces, self-assembled layers of vertically oriented TiO2 nanotubes with defined diameters between 15 and 100 nm and show that adhesion, spreading, growth, and differentiation of mesenchymal stem cells are critically dependent on the tube diameter. A spacing less than 30 nm with a maximum at 15 nm provided an effective length scale for accelerated integrin clustering/focal contact formation and strongly enhances cellular activities compared to smooth TiO2 surfaces. Cell adhesion and spreading were severely impaired on nanotube layers with a tube diameter larger than 50 nm, resulting in dramatically reduced cellular activity and a high extent of programmed cell death. Thus, on a TiO2 nanotube surface, a lateral spacing geometry with openings of 30-50 nm represents a critical borderline for cell fate.
One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo.
Studies of biomimetic surfaces in medicine and biomaterial fields have explored extensively how the micrometer-scale topography of a surface controls cell behavior, but only recently has the nanoscale environment received attention as a critical factor for cell behavior. Several investigations of cell interactions have been performed using surface protrusion topographies at the nanoscale; such topographies are typically based on polymer demixing, ordered gold cluster arrays, or islands of adhesive ligands at distinct length scales. [1][2][3] Recent work has indicated that the fabrication of ordered TiO 2 nanotube layers with controlled diameters can be achieved by anodization of titanium in adequate electrolytes. [4][5][6] Such surfaces can almost ideally be used as nanoscale spacing models for size-dependent cellular response. This is particularly important as these studies are carried out on titanium surfaces-a material used for clinical titanium implantations for the purpose of bone, joint, or tooth replacements. Therefore, principles elucidated from this work can guide implant surface modifications toward an optimized surface geometry and profile to best fit and cell interactions for adequate bone growth. [7,8] Previously we showed that vitality, proliferation, and motility of mesenchymal stem cells (MSCs) and their differentiation to bone-forming cells is critically influenced by nanoscale TiO 2 surface topography with a specific response to nanotubes with diameters between 15 and 100 nm. [9,10] We demonstrated that adhesion, proliferation, migration, and differentiation of MSCs was maximally induced on 15-nm nanotubes, but prevented on 100-nm nanotubes, which induced cell death. It remained unclear, however, whether this high sensitivity of cell response-detecting minute differences of pore size from 15 nm up to 100 nm-is a specific phenomenon of stem cells or reflects a universal cell behavior. Therefore, in the present work, we explore the nanoscale response of two main bone cells: osteoblasts and osteoclasts.For maintaining bone homeostasis, the balance between the bone-forming activity of osteoblasts and the bone-resorbing activity of osteoclasts is finely regulated by a complex mechanism involving paracrine and autocrine signals as well as cellular interactions between these cells and their extracellular matrix. Osteoclasts are originally derived from hematopoietic stem cells (HSCs) capable of differentiating into monocytes/macrophages and activated monocytes/macrophages, while osteoblasts are derived from mesenchymal stem/progenitor cells. [11][12][13][14][15][16] Their differentiation can be induced by cytokines such as m-CSF (macrophage colony-stimulating factor) and by interaction with osteoblasts through the RANK/ RANKL (receptor activator of nuclear factor-kB ligand) system. Bone-resorbing cells play an important role not only for daily bone remodeling but also for bone regeneration as occurring in osseous integration of implant materials. [17,18] Therefore, we address here the interaction of ost...
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