Advances in Umbilical Cord Blood Stem Cell Expansion and Clinical Translation.

Abstract

Umbilical cord blood (CB) is a rich source of hematopoietic stem cells (HSCs) with important applications in allogeneic stem cell transplantation. However, low numbers of hematopoietic stem and progenitor cells (HSPC) in banked units remains a major limitation. Protocols developed for HSPC expansion ex vivo or to improve HSPC homing to the marrow represent solutions to overcome this shortcoming. Over the last decades, wide arrays of functionally divergent approaches were developed for the amplification of HSPCs. These include optimization of cytokine cocktails, coculture systems, delivery systems for HSPC-expansion genes and more recently on small molecules. Herein, we review past and current strategies, focusing on studies that characterized the contribution of expanded CB HSPCs to short- and long-term engraftment in transplantation models or in clinical trials. Also discussed are homing effectors used to promote engraftment. In summary, these studies underscore that early acting cytokines alone can expand HSPC with short-term engraftment activity but that robust expansion of HSPC with long-term engraftment necessitates the synergistic action of multiple HSC-expansion agonists. In support of this, early clinical trials based on cytokine-driven HSPC expansion protocols delivered disappointing results, whereas recent trials based on the synergistic action of cytokines and HSPC-expansion agonists reported significant improvements in engraftment and therapeutic outcomes. Conversely, molecules that enhance homing of HSPCs may represent a complementary approach to improve and perhaps accelerate engraftment. Optimization of the next generation HSPC-expansion and priming strategies should support a paradigm shift in CB transplantation in which smaller, better matched units may preferentially be used.