New developments with umbilical cord blood

Abstract

In this issue of Cytotherapy, three papers present, between them, the derivation of mesenchymal stromal cells (MSC) and colony-forming unit megakaryocytes (CFU-Meg) from human umbilical cord blood (UCB) cells and their immuno-equivalence to adult bone marrow (BM)-derived MSC. Briefly, Choi et al. [1] describe the derivation of viable MSC from human UCB and use both phenotypic/ enzymatic expression and reverse transcriptase-polymerase chain reaction (RT-PCR) to demonstrate their adipoand osteogenic lineages. They use atelocollagen matrix and type II collagen synthesis to demonstrate the chondrogenic potential of these UCB-derived MSC. In another paper, Shirvaikar et al. [2] describe the generation of CFU-Meg from UCB in the presence of thrombopoietin (TPO) and interleukin-3 (IL-3) and demonstrate synthesis of both matrix metalloproteinase-9 (MMP) and the membrane-type (MT) variety, MT1-MMP. They also demonstrate expression of CXCR4, the unique receptor for the chemokine stromal cell-derived factor-1 (SDF-1), a chemokine important for both progenitor cell homing and up-regulation of MMP-9 and MT1-MMP. Lastly, Ennis et al. [3] explore the immunogenicity of human UCB perivascular cells (HUCPVC) and demonstrate immuno-equivalence to BM-derived MSC using standard lymphoproliferative assays and T-cell CD25 and CD45 cell-surface receptor expression. What is novel about marrow vs. UCB-derived MSC and SDF-1? MSC found in human BM are multipotent progenitors of mesenchymal tissues and have novel regenerative and immune properties [4]. SDF-1 exerts its effect via its unique receptor, CXCR4. SDF-1 is a potent chemoattractant for all cells expressing CXCR4, including T cells and hematopoietic stem cells. Although low levels of CXCR4 expression are found in minor subpopulations of cultured MSC, the majority of marrow and UCBderived MSC lack CXCR4 and, hence, do not migrate toward an SDF-1 gradient. In addition, SDF-1 stimulates pre-B-lymphocyte cell growth, is important in hematopoetic stem cell survival, and increases survival of human CD34 cells [5]. SDF-1 is important in stem cell migration and CXCR4 mediates its effects. SDF-1-induced migration appears to be dependent on CXCR4 expression. SDF-1 activates adhesion molecules on progenitor cells, and monoclonal antibodies (MAb) against SDF-1 inhibit transendothelial migration of hematopoetic progenitor cells [6]. SDF-1 activates CXCR4 CD34 cells and leads to their adhesion and transendothelial migration. In rhabdomyosarcoma cells that are CXCR4 , SDF-1 increases MMP-2 and decreases tissue inhibitors of MMP (TIMP) secretion [7]. Hence, SDF-1 may facilitate, through its actions on CXCR4, stem cell migration to injured tissue and, through its actions on MMP-2 and TIMP, stem cell-mediated repair of injured tissues. Taken together, observations by Shirvaikar et al. on this issue of up-regulation of metalloproteinases by SDF-1 emphasizes the critical role SDF-1 plays in UCB-derived regenerative cellular medicine. We have demonstrated previously that transduction of human MSC with a retroviral vector expressing CXCR4 improved in vitro migration to SDF-1 [8]. However, given safety and ethical concerns over retroviral transduction of human progenitor cells to be administered clinically, identification of a UCB source of progenitor cells with naturally sufficient CXCR4 expression to facilitate SDF-1mediated homing remains an important discovery and has strong potential in cell therapy strategies, both from a safety as well as a feasibility standpoint.