OSCILLATORY FLUID FLOW AFFECTS THE OSTEOGENIC DIFFERENTIATION OF HUMAN BONE MARROW STROMAL CELLS IN A PRIMARY CILSUM DEPENDENT MANNER

摘要

Osteoporosis is a debilitating bone disease which occurs in part when bone marrow stromal cells (BMSCs) fail to produce sufficient numbers of osteoblasts to counteract bone resorption by osteoclasts. The majority of research to date has described chemically induced differentiation of BMSCs but a key regulator of stromal cell differentiation is physical loading. BMSCs experience both hydrostatic pressure and fluid flow within the marrow cavity and such modes of loading have been shown to significantly alter gene expression in vitro [1,2]. In particular, the effect of oscillatory fluid flow (OFF) induced shear stress results in the upregulation of osteogenic genes in pre-osteoblastic cells; however the effect of this mode of loading is not well characterized in human MSCs (hMSCs) [3]. Understanding how MSCs translate a mechanical stimulus into a chemical response is an active area of research. Primary cilia are immotile, solitary cellular extensions that protrude from the apical surface of nearly every cell in the human body. Recent studies have revealed the primary cilium to be a multifunctional antenna, sensing both mechanical (fluid flow, pressure, touch, vibration) and chemical (light, odor, growth factor) changes in the extracellular environment [4]. In particular, primary cilia have been shown to act as fluid flow sensors in tissues such as kidney, liver and bone where fluid flow deflects the cilium, triggering signaling cascades within the cell [4,5]. Furthermore, primary cilia have recently been shown to act as a pivotal switch guiding biochemically induced lineage commitment in hMSCs [6]. However, to date their role in stem cell mechanotransduction is unknown. In this study we aimed to investigate the effect of OFF on the osteogenic gene expression of hMSCs and determine whether primary cilia act to translate this mechanical stimulus into a biochemical response.