My scientific focus is to understand how tissue development is stimulated by mechanical stimuli. Most tissues modulate their developmental programs to match the mechanical stresses they encounter in everyday life. These include gravitational forces, tensile strains, compressive forces, shear stresses, or dynamic mechanical stimulation resulting from muscular activity (movement/exercise). Notable examples of mechanosensitive tissues include all classes of muscle (skeletal, cardiac and smooth), bone, cartilage, tendons, ligaments and blood vessels. Indeed, tissues exhibiting mechanically-regulated development are rather the rule rather than exception and give rise to over 80% of our entire body mass.
Recent evidence now indicates that mechanical input is less effective in the old at stimulating the regeneration of mechanosensitive tissues, in particular muscle and bone, giving rise to clinical scenarios known as sarcopenia and osteopenia, respectively. The essential homeostatic roles that muscle and bone play in general human health and wellbeing bring to focus an imminent global economic crisis as the mean of the human race rapidly rises. In some western countries it is estimated that the number of individuals over retirement age will double in less than 25 years. The economic burden of maintaining the aging population ambulatory and self-sufficient will be particularly hard felt in Japan, Sweden and Switzerland, the countries with the oldest populations on earth. Thus, mechanosensitive tissues are ubiquitous and how to optimize their regeneration in later life is becoming of great global clinical importance.
I am particularly interested in those common mechanosensitive developmental processes that impinge on cellular calcium homeostasis for their fruition. Mechanically-gated calcium channels (TRPC1) are the molecular entities that are responsible for translating mechanical stimuli into a calcium signal that then regulates key enzymatic and genetic cascades involved in mechanosensitive tissue development. In particular, we have demonstrated that calcium influx via TRPC1 is responsible for instigating stem cell expansion during the initial stages of the regenerative response, agreeing with previous reports that cyclic mechanical stimuli promotes stem cell expansion. Understanding how the cell converts mechanical signals into a calcium-regulated developmental response will thus lead to more effective therapeutic strategies aimed at reversing trauma- and age-related muscle and bone degeneration. A major focus of my group is the development of methods to appropriately modulate TRPC1 activity for optimal mechanosensitive tissue regeneration.
- Mechanobiology of Muscle Development
- Flow Cytometry
- Cellular and Organismal Electromagnetics
Originally, the application is being submitted in combination with that of Dr. Pawel Pelczar of the UZH, Institute of Laboratory Animal Science. Dr. Pelczar and I have established a strong collaboration examining muscle development using transgenic reporter systems that monitor calcium-dependent mechanosensitive developmental responses.
I have also assisted in the development of a novel method to activate mechanosensitive tissue development in the absence of mechanical stimulation that will have important clinical implications for conditions characterized by mechanical dysfunction such as old age, injury or certain muscular diseases. This method uses Pulsed Electromagnetic Fields (PEMFs) in the very low frequency range (15 Hz) and low field strengths (100s of mTs) to initiate the expansion of the stem cell pool. We now have convincing evidence that PEMFs vicariously, yet specifically, activate mechanically-gated calcium channels (TRPC1) in all mechanosensitive tissues where we have examined.
A major obstacle in regenerative medicine is the selection of highly proliferative and pre-fated stem cells for subsequent tissue engineering applications or re-implantation into the host. We are currently developing a technology to specifically detect stem cells in the early stages of expansion that will ultimately have great utility in regenerative medicine and will be open for testing in the near future.