Abstract
Non-motile primary cilia are dynamic cellular sensory structures and are expressed in adipose-derived stem cells (ASCs). We have previously shown that primary cilia are involved in chemically-induced osteogenic differentiation of human ASC (hASCs) in vitro. Further, we have reported that 10% cyclic tensile strain (1 Hz, 4 hours/day) enhances hASC osteogenesis. We hypothesize that primary cilia respond to cyclic tensile strain in a lineage dependent manner and that their mechanosensitivity may regulate the dynamics of signaling pathways localized to the cilium. We found that hASC morphology, cilia length and cilia conformation varied in response to culture in complete growth, osteogenic differentiation, or adipogenic differentiation medium, with the longest cilia expressed in adipogenically differentiating cells. Further, we show that cyclic tensile strain both enhances osteogenic differentiation of hASCs while it suppresses adipogenic differentiation as evidenced by upregulation of RUNX2 gene expression and downregulation of PPARG and IGF-1, respectively. This study demonstrates that hASC primary cilia exhibit mechanosensitivity to cyclic tensile strain and lineage-dependent expression, which may in part regulate signaling pathways localized to the primary cilium during the differentiation process. We highlight the importance of the primary cilium structure in mechanosensing and lineage specification and surmise that this structure may be a novel target in manipulating hASC for in tissue engineering applications.
Highlights
Www.nature.com/scientificreports this mechanically controlled phenotypic development has been observed in Human adipose-derived stem cells (hASC)-derived chondrogenic[14] and myogenic lineages[4]
Within mesenchymal and adipose-derived stem cell types, adipogenesis is generally thought to be at odds with osteogenesis with each lineage resulting in cell types of very different physiological function
This theoretical paradigm of stem cell differentiation (Fig. 6d) is in part supported by the signaling pathways involved in phenotypic differentiation, suggesting that adipogenic cell types are mutually exclusive with osteogenic cell types when undergoing these lineage commitment processes[33]
Summary
Www.nature.com/scientificreports this mechanically controlled phenotypic development has been observed in hASC-derived chondrogenic[14] and myogenic lineages[4]. The primary cilium emanates from the basal body, formed by the mother centriole, and it is composed of nine microtubule doublets arranged in a 9 + 0 configuration, with nine concentric tubulin doublets forming the axoneme of the cilium They are structurally distinct from motile cilia (9 + 2), which are present in the mucosal epithelial layers of tissues such as the lung and intestinal tract and have a 9 + 2 microtubule configuration with an additional central pair of microtubules. The primary cilium is somewhat contiguous with the microtubule cytoskeleton via the docking of the centrosome at the apical surface of the cell[31] It follows that the cilium structure itself may be sensitive to morphological changes effected by cytoskeletal reorganization in response to mechanical cues[32]. We postulate that the cilium structure is intimately involved in lineage specification processes and that it dynamically modulates and/or is modulated by chemically- and mechanically- induced hASC differentiation
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