Decoding Human Hematopoietic Stem Cell Self-Renewal

Abstract

Abstract Purpose of Review Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by balancing quiescence, self-renewal, and differentiation. HSCs can be used in lifesaving transplantation treatments to create a healthy hematopoietic system in patients suffering from malignant or inherited blood diseases. However, lack of matching bone marrow donors, and the low quantity of HSCs in a single cord blood graft, are limitations for successful transplantation. The enormous regenerative potential of HSCs has raised the hope that HSC self-renewal could be recapitulated in culture to achieve robust expansion of HSCs for therapeutic use. Yet, when HSCs are cultured ex vivo their function becomes compromised, limiting successful expansion. Recent Findings After decades of efforts to expand human HSCs ex vivo that resulted in minimal increase in transplantable units, recent studies have helped define culture conditions that can increase functional HSCs. These studies have provided new insights into how HSC stemness can be controlled from the nucleus by transcriptional, posttranscriptional and epigenetic regulators, or by improving the HSC microenvironment using 3D scaffolds, niche cells, or signaling molecules that mimic specific aspects of human HSC niche. Recent studies have also highlighted the importance of mitigating culture induced cellular stress and balancing mitochondrial, endoplasmic reticulum, and lysosomal functions. These discoveries have provided better markers for functional human HSCs and new insights into how HSC self-renewal and engraftment ability may be controlled ex vivo. Summary Uncovering the mechanisms that control the human HSC self-renewal process may help improve the ex vivo expansion of HSCs for clinical purposes.