Hematopoiesis is the physiological process where hematopoietic stem cells (HSCs) continuously generate the body’s complement of blood and immune cells within unique regions of the bone marrow termed niches. Although previous investigations have revealed gradients in cellular and extracellular matrix (ECM) content across the marrow, and matrix elasticity and ligand type are believed to be strong regulators of stem cell fate, the impact of biophysical signals on HSC response is poorly understood. Using marrow-inspired ECM ligand–coated polyacrylamide substrates that present defined stiffness and matrix ligand cues, we demonstrate that the interplay between integrin engagement and myosin II activation processes affects the morphology, proliferation, and myeloid lineage specification of primary murine HSCs within 24 hours ex vivo. Notably, the impact of discrete biophysical signals on HSC fate decisions appears to be correlated to known microenvironmental transitions across the marrow. The combination of fibronectin and marrow matrix-associated stiffness was sufficient to maintain hematopoietic progenitor populations, whereas collagen and laminin enhanced proliferation and myeloid differentiation, respectively. Inhibiting myosin II–mediated contraction or adhesion to fibronectin via specific integrins (a5b1 and anb3) selectively abrogated the impact of the matrix environment on HSC fate decisions. Together, these findings indicate that adhesive interactions and matrix biophysical properties are critical design considerations in the development of biomaterials to direct HSC behavior in vitro.
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