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Mechanical regulation of tissue growth and signalling

Periodic Reporting for period 1 - MRTGS (Mechanical regulation of tissue growth and signalling)

Reporting period: 2016-01-01 to 2017-12-31

The control of tissue size and morphology is a fundamental problem that is remarkably ill understood. Although extensive research has focused on the genetic and biochemical control of tissue growth, significantly less attention has been paid to the mechanical aspect of growth regulation, even though any deformation or shape change is a result of a force acting on a mass. Unravelling the basis of the mechanical-biochemical co-regulation in tissue growth is instrumental in our understanding of organismal development and also presents novel therapeutic targets in growth-related diseases such as cancer and tissue repair. With this in mind the fellowship addressed two main objectives: 1) How do mechanical stresses impact signaling networks to support tissue shape? 2) What is the function of in situ mechanical force on normal tissue growth and 3D architecture?

The results from this fellowship have expanded our understanding of how forces drive precision of tissue development. Several signaling pathways activated downstream of mechanical stretch have been identified and their function in growth and tissue shape maintenance defined.
Objective 1: Mechanical signalling in tissue shape maintenance and growth

By screening fluorescently tagged fly reporters with a novel stretching and compression device we have established that Myosin 2 (MyoII) becomes polarized with mechanical stretch (Fig. 1). We have identified the upstream mediators of MyoII polarity through targeted RNAi approach and defined their physiological relevance in regulation of wing disc shape. By combining stretching assays and genetic mosaic techniques in Drosophila wing disc we have shown that upon loss of polarized MyoII tissue loses its stiffness and elasticity and acquires an aberrant shape. Finally we have demonstrated that polarity of MyoII changes material properties of the tissue to protect any occurrent injury from propagating and compromising tissue shape and integrity. In its entirety we have discovered a completely new molecular pathway that is essential for tissues to rapidly respond to mechanical stress to maintain a functional tissue shape. These findings are currently under review for publication.

Objective 2: Coupling of growth and mechanics in 3D tissue sculpting and fold formation

The work from this fellowship has unravelled the nature of mechanochemical coupling in the context of a developing tissue, specifically in the formation of tissue 3D folds. Based on tissue size and shape quantification, we have determined that Drosophila wing disc’s folds always formed at stereotypical position during development and thus their formation appeared to be tightly regulated. By experimentally deriving the spatial and temporal patterns of wing disc growth and coupling it into finite element simulations we have found that precise fold position is driven by mechanical stresses resultant from heterogeneous proliferation rates of the wing disc. Further in silico and experimental growth perturbation will identify key regions of growth driving tissue folding. A manuscript summarizing this work is currently being prepared.
We have used a novel biomechanical tool that has revealed a fundamental way in which developing tissues actively change their material properties in response to deformations in order to protect the tissue from mechanical damage. This we believe will interest a wide audience: from developmental biologists to applied scientists. We also expect this phenomenon to inspire engineers and clinicians in the design of bioactive materials for therapies related to wound healing, cancer, scarring, tissue engineering and bio-architecture. This fellowship has also uncovered how mechanical forces are directing the precision of morphogenesis and development. Our findings show that simple patterns of mechanical tension rather than complicated biochemical circuits can be at the basis of specialized and precise organismal patterning such as 3D tissue folding. This changes fundamentally the way we understand organismal growth.

At the Institute level and beyond this fellowship has brought multiple collaborations and new ongoing projects as well as wide range of novel mechanobiological (tissue stretching, compression, tissue force relaxation assays, tissue micropipetting) and computational (3D finite element model of the tissue) assays and techniques that will establish a unique tissue and cell mechanobiology recognition to the Host Institute. New members of Institute staff have also been hired to follow up on the findings stemming from this fellowship. Finally, given the resultant data, the fellowship will likely help the Project Lead as well as the Beneficiary to establish themselves as the to-go experts in the field of tissue mechanobiology.
Myosin 2 polarizes with mechanical stretch