This study investigates the role of cell mechanics on enforcement of cell shape and cell fate (cell lineage commitment) during de novo formation of tissues. Shape and fate are intrinsic manifestations of form and function at the cellular level. At the length scale of the tissue, mechanical stress influences structure and function during prenatal development and postnatal healing. At the length scale of the embryonic mesenchymal stem cell, recent data demonstrate a high degree of mechanosensitivity, which modulates their assembly to form tissues and organs. Furthermore, recent developmental biology and cell mechanics studies implicate cell shape as a powerful modulator of cell fate after homing of stem cells to target tissues in adult organisms. One aim of this research program is to study shape as a measure of a cell's adaptation to prevailing mechanical stimuli during de novo tissue formation. A further aim is to correlate the spatiotemporal enforcement of shape, via mechanical signals, to the specification of cell lineage (fate). Finally, a third goal is to test the feasibility of exploiting mechanical cues to engineer templates of bone and blood vessels for tissue replacements.
The research program will help to decipher how mechanical signals, intrinsic to life on Earth, modulate the adaptation and specialization of cells to their environment during prenatal development as well as engineering and manufacture of tissues. Through elucidation of Nature's mechanobiological engineering paradigms, mechanical cues can be exploited to prevent defects during development as well as to generate tissues in the laboratory and in the surgical operating room. The impact of the research program on education will be amplified through tight integration of the research approach and insights with a newly developed college level course Cell and Tissue Engineering: Learning from Nature's Mechanobiological Paradigms? and a Science, Technology, Engineering and Math (STEM) high school class which will be taught to student groups from Cleveland Municipal School District and inner ring schools.
National Science Foundation - funded researchers at Case Western Reserve University have recently shown that the stem cell's cytoskeleton adapts to its local mechanical environment, revealing a more organized and directed response to mechanical stimuli than previously known. Like the tennis player's dominant arm, the skeleton of the cell adapts in response to mechanical forces. Interestingly, these forces appear to shape not only the cell's form but also its biological function and ultimately its fate. Namely, exposure to short term, controlled mechanical stresses results in significant changes to gene activity, signaling commitment of stem cells to specific lineages such as bone and cartilage. Development of new experimental mechanics and imaging methods allow the "MechBio" Team to deliver controlled mechanical stresses to live stem cells while imaging their immediate deformation and as well as their adaptation over time. Not only do stem cells exhibit an innate capacity to sense their immediate environment and strengthen their structural systems to protect themselves, but they also change their own environment by producing and secreting structural proteins as well as by aggregating with other cells and changing their higher order architecture. Based on these studies, the MechBio Team has begun to "map the mechanome", plotting stress - strain -fate curves that may serve in the future as reference libraries to direct cell fate using mechanical cues, like "physical therapy protocols for stem cells". As a whole, these studies bring to light the common mechanisms behind stem cell fate commitment, both during prenatal development, wound healing and regeneration, as well as de novo engineering of tissues. Insights from this research program are likely to have broader impacts on society. For example, through newfound understanding of how cells build living materials such as tissues "from scratch", mechanical cues could potentially be harnessed to prevent defects during development as well as to generate tissues in the laboratory and in the body. The impact of this research program on education is being amplified through tight integration of the research approach and insights with the Principal Investigator's courses, "Cell and Tissue Engineering: Learning from Nature's Mechanobiological Paradigms" and "Cell Mechanics", which she taught at her home university as well as, in part, at Harvard University and University of Paris Est Créteil. The graduate students who carry out the research serve as teaching assistants in each of these courses; these graduate students mentor not only undergraduates during their educational experience in the classroom but also in the laboratory when the undergraduates carry out proposal related work as part of summer research experiences or senior capstone projects. The "chain of mentoring" continues through the high school and middle school levels, as the principal investigator and her graduate students participate in STEM outreach programs describing the role of solid and fluid mechanics in natural bioengineering systems, with themes including "Secret Lives of Trees" and "Life in our Mechanical World". This outreach has debuted in the greater Cleveland area, reaching as far North as the Inuit youth of Pangnirtung, near the Arctic Circle in Nunavut, Canada.
