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Dynamic human erythropoiesis in a three-dimensional perfusion bone marrow biomimicry
- Allenby, Mark C., Panoskaltsis, Nicki, Tahlawi, Asma, Dos Santos, Susana Brito, Mantalaris, Athanasios
- Biomaterials 2019 v.188 pp. 24-37
- biomimetics, bioreactors, bone marrow, drug evaluation, erythrocytes, erythropoiesis, erythropoietin, extracellular matrix proteins, humans, image analysis, niches, stem cell factor, umbilical cord
- Traditional culture systems for human erythropoiesis lack microenvironmental niches, spatial marrow gradients and dense cellularity rendering them incapable of effectively translating marrow physiology ex vivo. Herein, a bio-inspired three-dimensional (3D) perfusion bioreactor was engineered and inoculated with unselected single donor umbilical cord blood mononuclear cells (CBMNCs). Functional stromal and hematopoietic environments supporting long-term erythropoiesis were generated using defined medium supplemented only with stem cell factor (SCF) and erythropoietin (EPO) at near physiological concentrations. Quantitative 3D image analyses spatiotemporally mapped 21 multi-lineal cell distributions and interactions within multiple microenvironments that secreted extracellular matrix proteins and at least 16 endogenous hematopoietic and stromal growth factors. Tissue-like culture densities (≥2∙10⁹ cells/mL), 1000-fold above flask cultures, were attained with continuous erythropoiesis and erythrocyte harvest. We propose this physiologically-relevant system for understanding normal and abnormal erythropoiesis, as well as for drug testing and/or discovery aimed at clinical translation.