Hematopoietic cells can provide benefit in a variety of clinical settings. These include cells for support of patients undergoing high-dose chemotherapy, as a target for replacement gene therapy, and as a source of cells for immunotherapy. The limitation to many of these applications has been the insufficient number of donor cells. An efficient and practical ex vivo expansion of hematopoietic progenitors (HPC) and hematopoietic stem cells (HSC) is critical in realizing the tremendous potential of HPC/HSC transplantation. The overall objective of this project is to develop a clinically relevant approach, through biomaterials engineering, to efficiently expand human hematopoietic cells. Signals emanating from the HSC niche play a crucial role in regulating the fate decision of HSC on whether to self-renew or differentiate. Extracellular matrix (ECM) components are important elements of the HSC niche. They provide the adhesive interactions between HSCs and cell adhesion molecules in the regulation of hematopoiesis in bone marrow. In hypothesizing that a favorable hematopoietic, bone marrow-like topographical microenvironment can be created by immobilizing adhesion molecules on the surface of a three-dimensional scaffold, we propose to optimize the expansion of CD34-selected as well as unselected umbilical cord blood cells (CB) in these biofunctional scaffolds. We will first establish a robust synthetic scheme of conjugating fibronectin (FN), CS1 peptide, and heparin to the surface of poly(ethylene terephthalate) (PET) scaffolds with different topographical features. After evaluating the expansion of hematopoietic cells in these scaffolds with respect to their self-renewal, differentiation, and in vivo engraftment potential, we will test the most promising scaffolds in a scaled-up culture. We propose a novel bioreactor design that will take advantage of these optimized biofunctional scaffolds by maximizing the contact area of the hematopoietic cells with the scaffolds. There has not been a systematic effort to optimize the expansion of hematopoietic cells from cord blood through a combination of biomaterials and bioreactor design. With this systematic and focused approach we aspire to develop a clinically practical strategy of efficiently expanding hematopoietic cells. ? ? ?
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