title: Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells.
abstract: 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 (α5β1and ανβ3) 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.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Ji Sun
authors.identifier: 0000-0001-9302-7840
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Brendan A C
authors.identifier: 0000-0001-5458-154X
authors.initials: BA
authors.lastname: Harley
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D000818:Animals; D049109:Cell Proliferation; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D055153:Stem Cell Niche; D054457:Tissue Scaffolds / Q000737:chemistry*; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D000099166:Polyacrylamides
keywords: biophysical cues; extracellular matrix; hematopoietic stem cell; stem cell niche