Influential role of cell - ECM interactions in leukemogenesis
Vu Thi Thu Thao
Date of Issue2012
School of Chemical and Biomedical Engineering
Cellular interaction with the extracellular matrix (ECM) inside the bone marrow is an important component in the regulation and progression of leukemia. In this inaugural work, we were able to entrap whole ECM proteins in an intricate microporous matrix that enabled us to study the effects of three-dimensional (3D) cell-ECM interactions in a controlled in vitro system. The Ca-alginate hydrogel was first examined for its physical properties, with respect to matrix topography, stiffness and constitutive components of the alginate. It was then investigated for its ability to support myeloleukemia cell proliferation and differentiation both in the presence and absence of supporting ECM proteins such as fibronectin, laminin and collagen-I. We used the erythroleukemic cell line K562 as a model for chronic myeloid leukemia. Our results show that 3D Ca-alginate hydrogel provided superior support in proliferation and was able to induce spontaneous multi-lineage differentiation of K562 cells in vitro. In the presence of fibronectin and laminin, enhanced cell proliferation was achieved in 3D hydrogels but not observed in 2D cultures. In addition, we discovered that protein-incorporated hydrogels were able to create hematopoietic inductive microenvironments for lineage-specific cell differentiation, not achieved in 2D cultures. The manipulation of biophysical and biochemical properties in the Ca-alginate hydrogel system provides a tool for recreating aspects of the bone marrow and allows us to move away from conventional models performed on 2D tissue culture systems that are deemed inadequate, as they often misrepresent molecular cues present in the intricate 3D bone marrow environment. In conclusion, the Ca-alginate hydrogel provides a robust engineering platform for studying hematopoiesis and leukemia in vitro.