Research in the Flynn lab is focused on the application of adipose-derived stem/stromal cells (ASCs) in new cell-based therapeutic strategies for soft tissue augmentation and wound healing, therapeutic angiogenesis, and musculoskeletal regeneration. As a regenerative cell source, adipose tissue (fat) is abundant, easily accessible, and uniquely expendable. ASCs can be stimulated to differentiate into mature fat, bone, cartilage, and muscle cells, and can contribute to regeneration by secreting a broad array of cytokines and growth factors that promote angiogenesis, limit apoptosis, enhance endogenous stem cell recruitment, and modulate the inflammatory response. However, key questions must be addressed before ASCs can be safely and effectively translated to the clinic, including how to best deliver the cells to ensure retention and survival, and how to more fully harness their pro-regenerative capacities to enhance healing and functional recovery. To address these challenges, the three central themes of ongoing research in the Flynn lab are:
The design of dynamic culture systems for human ASC expansion and lineage-specific differentiation
A bioreactor system that enables the large-scale expansion of ASCs isolated from small tissue biopsies, while maintaining the pro-regenerative cell phenotype, would represent a significant advance towards the translation of ASCs for a broad range of clinical therapies. As such, we are designing 3-D culture strategies for expanding ASCs, as well as for promoting their lineage-specific differentiation. Bioreactor systems can allow for better control over the culture conditions than static culturing, and we are tuning the dynamic culture conditions to modulate stem cell proliferation and/or differentiation, including incorporating tissue-specific extracellular matrix (ECM) as a cell-instructive substrate.
Decellularized bioscaffolds for soft tissue regeneration and wound healing
The extracellular microenvironment plays a critical role in mediating stem cell lineage commitment and differentiation. There is evidence to support that this regulation occurs through both biochemical and biomechanical signalling. The complexity of these cell-ECM interactions points to the need for tissue-specific strategies to re-engineering stem cell niches. Recent studies have highlighted the potential for bioscaffolds derived from the ECM of tissues to naturally direct stem cell proliferation and differentiation. Building on our expertise in decellularization technologies, our group is engineering a range of ECM-derived biomaterials, such as 3-D scaffolds, foams, films, microcarriers, and gels. Further, we are investigating ASCs within these bioscaffolds to probe the role of cell-ECM interactions in mediating ASC viability, proliferation and lineage-specific differentiation in the development of tissue-specific regenerative therapies, including for soft tissue reconstruction and wound healing applications.
The development of tissue-specific injectable ASC delivery strategies
Injected ASCs have been shown to home to sites of injury and ischemic tissues. Depending on the context, a fraction of the ASCs may contribute to regeneration through direct engraftment and differentiation. However, recent studies suggest that transplanted ASCs may primarily function to promote healing by establishing a more regenerative milieu within the host through the secretion of paracrine factors that modulate the rate and extent of healing. Although ASCs have shown great potential for a broad range of applications in cell therapy, scientific hurdles remain in terms of how to best deliver the cells and how to sustain the localized regenerative effects to enable complete healing with functional recovery. Working in close collaboration with an interdisciplinary team of scientists and engineers, our research team is designing new injectable ASC delivery strategies for applications in therapeutic angiogenesis and musculoskeletal regeneration.