Integrating mechanical forces - a cellular mechanodampener
Lead Research Organisation:
University of Southampton
Department Name: Sch of Biological Sciences
Abstract
To develop healthy body tissues, cells define their type and behaviour by following a genetic instruction manual. This is fine-tuned by responses to both biological and physical signals. Comparatively, our understanding of how tissue biology is shaped by changing physical forces is limited. This limits our appreciation of both tissue formation, maturation and of the processes that safeguard life-long tissue health. All tissues require the successful mixing of biological signals such as secreted proteins and physical signals. One example is flow in blood vessels, another is the formation of our skeleton whilst we move.
Much of our skeleton is formed from cartilage, which transitions to bone in a highly coordinated process called endochondral ossification. The cartilage lining our joints must resist this pre-programmed transition but the cartilage that forms bone must control this change in cell identity and tissue environment. This shaping of our skeleton is both sensitive and resilient to physical forces.
Recent evidence from studies in adolescent mice, strongly implicates a tiny compartment of cell called primary cilia in protecting programmed adjustments to cell type, regulated mineralisation of the environment and the formation of bone from cartilage. We hypothesise they use it to level out responses to unequal forces as our skeleton matures.
We now wish to understand which cartilage cell subtypes use cilia to protect their behaviour in the context of force and what messaging they use to enable this. Secondly, we would like to use both mice and an engineered model of endochondral ossification to understand how cilia aid these processes and how we can use such models to understand the role of mechanics in shaping tissue development and health.
Much of our skeleton is formed from cartilage, which transitions to bone in a highly coordinated process called endochondral ossification. The cartilage lining our joints must resist this pre-programmed transition but the cartilage that forms bone must control this change in cell identity and tissue environment. This shaping of our skeleton is both sensitive and resilient to physical forces.
Recent evidence from studies in adolescent mice, strongly implicates a tiny compartment of cell called primary cilia in protecting programmed adjustments to cell type, regulated mineralisation of the environment and the formation of bone from cartilage. We hypothesise they use it to level out responses to unequal forces as our skeleton matures.
We now wish to understand which cartilage cell subtypes use cilia to protect their behaviour in the context of force and what messaging they use to enable this. Secondly, we would like to use both mice and an engineered model of endochondral ossification to understand how cilia aid these processes and how we can use such models to understand the role of mechanics in shaping tissue development and health.
Technical Summary
There is still much to understand about how cells incorporate extrinsic force into phenotypic plasticity and stability during morphogenesis and homeostasis respectively. This project will dissect an apparent tissue mechano-rheostat that protects coordinated biological programmes from anisotropic forces. This is relevant to most tissue types.
The hypothesis is that the primary cilium acts as a "mechano-dampener" to integrate unequal forces and growth factor signals.
The coordinated formation of bone, during endochondral ossification, shapes our skeleton to build a fit-for-purpose frame for locomotion. The transition of cartilage to bone, chondrocyte to osteoblast is critical to these morphogenetic events, regulation of this transition and resilience of chondrocyte phenotype is pertinent to long-life musculoskeletal health. We have identified that the gene IFT88, canonically associated with the primary cilium, safeguards articular cartilage health and protects cartilage transitions in the growth plate in the adolescent limb. Deletion of ciliary IFT88 in cartilage in the juvenile mouse results in a failure of ossification in the peripheral limb growth plate. This effect is mimicked by increasing loading through the limb in normal mice. The effect of IFT88 deletion is inhibited when the limb is immobilised, which implicates IFT88 in mechano-regulated morphogenesis in vivo. Deletion of IFT88 and increases in loading, uncouple phenotypic switching, which impairs chondro-osseous transdifferentiation.
Using a combination of in vivo experiments in the mouse and a developmental engineering approach in vitro this programme will explore the following.
1. The mechanoregulation of cartilage-bone phenotypic plasticity
2. The role of primary cilia integrating force and growth factor signalling
3. The exploitation of a developmental engineering model of chondro-osseous mechanobiology.
The hypothesis is that the primary cilium acts as a "mechano-dampener" to integrate unequal forces and growth factor signals.
The coordinated formation of bone, during endochondral ossification, shapes our skeleton to build a fit-for-purpose frame for locomotion. The transition of cartilage to bone, chondrocyte to osteoblast is critical to these morphogenetic events, regulation of this transition and resilience of chondrocyte phenotype is pertinent to long-life musculoskeletal health. We have identified that the gene IFT88, canonically associated with the primary cilium, safeguards articular cartilage health and protects cartilage transitions in the growth plate in the adolescent limb. Deletion of ciliary IFT88 in cartilage in the juvenile mouse results in a failure of ossification in the peripheral limb growth plate. This effect is mimicked by increasing loading through the limb in normal mice. The effect of IFT88 deletion is inhibited when the limb is immobilised, which implicates IFT88 in mechano-regulated morphogenesis in vivo. Deletion of IFT88 and increases in loading, uncouple phenotypic switching, which impairs chondro-osseous transdifferentiation.
Using a combination of in vivo experiments in the mouse and a developmental engineering approach in vitro this programme will explore the following.
1. The mechanoregulation of cartilage-bone phenotypic plasticity
2. The role of primary cilia integrating force and growth factor signalling
3. The exploitation of a developmental engineering model of chondro-osseous mechanobiology.
