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Extracellular Matrix Composition and Stiffness Differentially Regulate Hematopoietic Stem Cell and Myeloid Progenitor Fate

  • Author(s): Edwards, Nathan
  • Advisor(s): Passegue, Emmanuelle
  • Weaver, Valerie
  • et al.
Abstract

The hematopoietic stem cell (HSC) and the granulocyte/macrophage progenitor (GMP), a downstream myeloid progenitor, reside within distinct bone marrow (BM) niches. The biophysical properties of these BM niches and the effect of these biophysical properties on the regulation of HSCs and GMP cell function remain unknown. We determined the mechanical properties of the endosteum, the perivasculature and non-vascularized central marrow, three specific BM niches that HSCs or GMPs have been shown to reside. We then used ex vivo adhesion assays to determine the extracellular matrix (ECM) ligands to which HSCs and GMPs preferentially adhere. Ex vivo culture on polyacrylamide (PA) hydrogels mimicking distinct BM niche microenvironments were then used to assay the effect of ECM elasticity on cell expansion and lineage differentiation capacity. We also performed transplantation assays after HSC expansion on PA gels to determine the role of ECM elasticity on engraftment potential. We found that GMPs preferentially bound to fibrillar collagen, but also adhered to fibronectin, and showed greater expansion on soft, compliant environments. Conversely, HSCs adhered only to fibronectin, and after growth on stiff environments, had greater cell expansion and higher engraftment potential due to increased expression of homing receptors. Myeloid differentiation was found to be affected by ECM elasticity such that compliant ECM niches enhanced granulocyte production. Conversely, stiff environments enhanced macrophage lineage commitment. Mechanotransduction of ECM elasticity was determined to be dependent on actomyosin contraction and activation of focal adhesion kinase (FAK) likely through integrin engagement. Together, our data show that the biophysical properties of specific BM niches function in controlling the differential growth and differentiation of HSCs and progenitors during homeostasis, and may even have the potential to regulate hematopoietic regeneration following insult, injury or transplantation.

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