3D NICHE ENGINEERING FOR REGULATION OF STEM CELL FATE DECISIONS

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Bone marrow houses hematopoietic stem cells (HSC) that are responsible for continuously regenerating blood tissue throughout one's lifetime. Bone marrow transplants, also called HSC transplants (HSCT), are life-saving procedures used to treat leukemia patients and more recently, autoimmune diseases like multiple sclerosis, which can lead to durable disease-free remission. However, HSCT are plagued by limited supply, tissue mismatching complications and high mortality rates (up to 10% of patients do not survive the transplant). Many more patients could benefit from safer HSCT if the number of HSC in each donor sample could be augmented. For this advancement to be engineered a more detailed understanding of the interplay between HSC and their native 3D bone marrow environment, or niche, is required. When removed from their native bone marrow niche and placed in culture, HSC and progenitor (HSPC) cells very quickly lose their stem cell function  (24-72h). Mounting evidence suggests that the bone marrow extracellular matrix (ECM) is a critical, yet underappreciated, component of the niche that may be instructive to stem cell regulation. In order for HSPCs to be expanded ex vivo, culture conditions that recapitulate the native ECM environment need to be developed. This program aims to develop technology that discovers ex vivo stem cell niche conditions and apply this knowledge to elucidate stem cell-ECM interactions. Combinatorial chemistry methods that systematically assemble and test individual, and combinations of ECM components will be employed with the intent of elucidating the contribution of each component to HSPC function. These findings will further be implemented in a novel 3D screening assay using "off-patent" drugs able to identify molecular targets that regulate stem cell function. Finally, 3D Printing technology will be developed to create a vascular system with the ECM and support HSPC survival in thick 3D constructs. This program leads to the development of tissue-matched engineered bone marrow tissue for personalized HSCT medicine. Canadian leukemia and autoimmune disease patients stand to benefit the most with shorter waiting times and safer procedures. Canadian healthcare savings can also be realized by accelerating patient treatment and recovery, thereby reducing healthcare costs of managing sick and deteriorating patients. Furthermore, this research can be applied to test new drugs that unintentionally cause myelosuppression toxicity, a potentially lethal side-effect, before approving investigational new drugs. This additional test for regulatory approval can reduce animal testing and promote safer news drugs. Within the program's first 5 years, a total of 3 PhDs, 3 MASc and 10 undergraduate research assistants will be will be trained in stem cells and tissue engineering and position them for academic or industry employment opportunities in high-impact areas such as regenerative medicine and biotechnology.