Research in the Flynn lab is focused on the application of adipose-derived stem 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, fat is abundant, easily accessible, and uniquely expendable. In culture, ASCs proliferate rapidly and can be stimulated to differentiate into mature bone, cartilage, adipose, and muscle cells, amongst other lineages. In terms of regeneration, ASCs can synthesize extracellular matrix (ECM) components, and can remodel tissue-engineered constructs to facilitate new tissue development. ASCs also indirectly modulate regeneration by secreting an array of paracrine factors that promote angiogenesis, limit apoptosis, enhance endogenous stem cell recruitment, and mediate the inflammatory response. While there is great promise, many questions remain in terms of how to safely and effectively apply ASCs in tissue-specific cell-based therapies before these methods can be advantageously translated to the clinical setting. A better understanding of the cell response within 3-D microenvironments is needed in order to achieve predictable regeneration and long-term functional recovery. To address these key challenges, the three central themes of ongoing research in the Flynn lab are:
A bioreactor system that enables the large-scale expansion of the ASC population from small tissue biopsies, while maintaining the stem cell phenotype, would represent a significant advance towards the translation of ASCs for a broad range of clinical therapies. We are designing 3-D culture strategies for expanding human ASCs under serum-free conditions. Bioreactor systems can allow for better control over the culture conditions than static culturing and the shear forces applied under dynamic culture can influence cell shape, which has the potential to mediate stem cell proliferation and differentiation.
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, including 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.
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 Dr. Brian Amsden at Queen's University, our research team is designing new injectable ASC delivery strategies for applications in therapeutic angiogenesis and musculoskeletal regeneration.