Multigradient hydrogels to decode extrinsic regulation of hematopoietic stem cell fate

Hematopoiesis is a physiological process responsible for the generation of all the blood and immune cells of the body. The cells responsible for this process are the hematopoietic stem cells (HSCs), primarily located within the bone marrow. They are housed in specific microenvironments (niches) that provide stochastically and temporally mutable signals that influence stem cell fate of differentiation, quiescence, self-renewal and apoptosis. The niche signals may also contribute to HSC disregulation and hematopoietic pathologies, notably leukemia stem cell (LSC) mediated leukemogenesis. The niche consists of several components such as the extracellular matrix (ECM), surrounding niche cells and several soluble or ECM-bound factors that influence the HSC fate. Critical as the function of the niche seems, surprisingly little is known about these regulatory processes and the mechanisms governing them. This thesis attempts to provide an engineering solution to understanding the complex biological mechanism of HSC-niche cell interaction and its influence on HSC fate. We believe that combinatorial biomaterials can be used to systematically expose discrete populations of HSCs and niche cells to defined 3D microenvironments; such tools can generate critical information to help decode the interrelationship between extrinsic cues, intracellular signaling networks, and HSC fate