Johnna Temenoff, PhD (Georgia Institute of Technology)
Robert Guldberg, PhD (University of Oregon)
Nick Willett, PhD (Georgia Institute of Technology)
Levi Wood, PhD (Georgia Institute of Technology)
Christopher Evans, PhD (Mayo Clinic)
Modulation of Mesenchymal Stromal Cell Proliferation and Secretion for the Treatment of Osteoarthritis
Mesenchymal stromal cells (MSCs) are highly-secretory cells that are of great clinical interest due to their immunomodulatory and pro-regenerative properties when transplanted in vivo. Their secretory potential has been utilized to treat multiple orthopedic conditions, including osteoarthritis (OA), a degenerative condition that affects a significant portion of the adult population and has no disease-modifying treatments. Despite their promise, MSCs and other cell therapies that rely on secretory activity are limited by large doses, requiring cell culture strategies that both enable large-scale expansion of MSCs without comprising their paracrine activity. Although standard culture methods promote large-scale MSC expansion, none are designed to improve secretory potential following therapeutic administration. Thus, the overall objectives of this work are to (1) identify culture conditions that promote MSC proliferative and secretory activity, (2) utilize these conditions to develop novel substrates for MSC expansion and delivery, and (3) evaluate their improvements to MSC therapies for treating OA. MSC proliferation and paracrine activity have been shown to be sensitive to several physical conditioning methods, including forced aggregation and the material properties of their adhesive culture substrate. Therefore, screening these conditions could identify the parameters that critically modulate their expansion potential and immunomodulatory factor secretion. These critical parameters will be used to develop novel adhesive substrates that both promote MSC proliferation in vitro and enhance the secretion in vivo. Subsequent improvements to their ability to reduce the progression of OA will be assessed by intra-articular delivery of unmodified as well as genetically-modified MSCs into a small animal model for post-traumatic OA, where resulting degeneration of the knee joint will be quantified primarily using contrast-enhanced microcomputed tomography (uCT)-based methods. Overall, this work aims to improve the production of highly-secretory MSCs in a manner that that aids their development as therapies for treating degenerative diseases such as OA.