(Joint Appointment with the Department of Chemical & Biochemical Engineering, Faculty of Engineering)
Ph.D. University of Toronto
B.A.Sc. University of Toronto
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:
(1) The design of dynamic culture systems for human ASC expansion
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.
(2) 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, 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.
(3) 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 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.
Russo V, Yu C, Belliveau P, Hamilton GA, Flynn LE*. (2014) Comparison of human adipose-derived stem cells isolated from subcutaneous, omental and intrathoracic adipose tissue depots for regenerative applications. Stem Cells Translational Medicine 3(2), doi:10.5966/.
Cheung HK, Han T, Maracek, D, Watkins JF, Amsden BG, Flynn LE*. (2014) Composite photocrosslinkable hydrogel scaffolds incorporating decellularized adipose tissue for soft tissue engineering with adipose-derived stem cells. Biomaterials 35(6), 1914-23.
Yu C, Bianco J, Brown C, Fuetterer L, Watkins JF, Samani A, Flynn LE*. (2013) Porous decellularized adipose tissue foams for soft tissue regeneration. Biomaterials 34, 3290-302.
Sukarto A, Yu C, Flynn LE, Amsden BG*. (2012) Co-delivery of adipose-derived stem cells and growth-factor loaded microspheres in RGD-graft N-methacrylate glycol chitosan gels for focal chondral repair. Biomacromolecules 13 (8), 2490–2502.
Zhao Y, Waldman SD, Flynn LE*. (2012) Multilineage co-culture of adipose-derived stem cells for tissue engineering. Journal of Tissue Engineering and Regenerative Medicine, Published online Nov. 8, 2012 (doi:10.1002/).
Turner AEB, Yu C, Bianco J, Watkins JF, Flynn LE*. (2012) The performance of decellularized adipose tissue microcarriers as an inductive substrate for human adipose-derived stem cells. Biomaterials 33(18), 4490-9.
Turner AEB and Flynn LE*. (2012) Design and characterization of porous extracellular matrix-derived microcarriers. Tissue Engineering Part C Methods 18(3), 186-97.
Zhao Y, Waldman SD, Flynn LE*. (2012) The effect of serial passaging on the proliferation and differentiation of bovine adipose-derived stem cells. Cells Tissues Organs 195(5), 414-27.
Flynn LE*. (2010) The use of decellularized adipose tissue to provide an inductive microenvironment for the adipogenic differentiation of human adipose-derived stem cells. Biomaterials 31(17), 4715-4724.