Epitenon-derived progenitor cells in tendon healing and adaptation

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Project Summary This K99/R00 NIH Pathway to Independence Award application outlines the research training and career development plan that will prepare Dr. Anne Nichols for a career as an independent investigator in the field of tendon cell mechanobiology. The research project is designed to train Dr. Nichols in the use of cutting-edge transcriptomic analyses and in-depth mechanical testing techniques to answer fundamental questions about the role of the epitenon, a poorly characterized structure surrounding all tendons. Though thought to serve many important functions, the true identity and function of the epitenon has remained elusive due to a lack of genetic markers that specifically target epitenon cells. In preliminary studies, Dr. Nichols identified a novel, heterogenous, population of GLAST-lineage (GLASTLin) cells in the epitenon that contribute to both tendon healing following acute injury and tendon adaptation in response to mechanical overload by differentiating into scleraxis (Scx)- expressing tenocytes. Identification of a genetic marker for epitenon cells as well as demonstration of their capacity for tenogenic differentiation has opened an exciting new avenue of tendon research that will form the basis of Dr. Nichols’ independent research program. The aims outlined in this proposal will build on these preliminary studies and make use of the numerous sophisticated genetic mouse models developed by Dr. Nichols to test the central hypothesis that GLASTLin epitenon cells are an indispensable source of tenogenic progenitor cells for both tendon healing and adaptation. During the K99 phase of this award, she will define the various GLASTLin epitenon subpopulations and identify the specific subset that serves as a tenogenic progenitor pool (Aim 1) and demonstrate that GLASTLin epitenon cells are required for proper tendon healing (Aim 2). During the R00 phase, Dr. Nichols will establish coordination between GLASTLin epitenon cells and tenocytes as a key effector of adaptive tendon growth (Aim 3). Collectively, these data will provide the first comprehensive characterization of epitenon cells and their function in tendon biology. In addition to a rigorous scientific training plan, career development activities at URMC, such as grant-writing workshops, lab mentorship, and teaching experience during the K99 phase will prepare Dr. Nichols to transition to a faculty position in the R00 phase. Dr. Nichols also will benefit greatly from the collective scientific expertise and career advice of her assembled Scientific Mentoring and Career Development Advisory Committee (SMCDAC). In addition to the genetic mouse model and spatial RNA-sequencing expertise of her primary mentor, Dr. Alayna Loiselle, interaction with her SMCDAC will allow Dr. Nichols to acquire additional expertise in single-cell transcriptomic analyses (Dr. Chia- Lung Wu), mechanical testing techniques (Dr. Mark Buckley), and models of tendon adaptation (Dr. Lou Soslowsky). With the help and critical feedback of her SMCDAC career advisors (Drs. Soslowsky, Laura Calvi, and Robert Dirksen), Dr. Nichols will be well-prepared to successfully compete for faculty positions and lead her own independent research program.