Lysosome Acidification Facilitates the Expansion of Circulating Hematopoietic Stem and Progenitor Cells

Despite present in steady-state peripheral blood (SSPB) with high readily accessibility, circulating hematopoietic stem and progenitor cells (cHSPCs) is significantly limited in clinic application and basic research for their rarity and unclear molecular mechanisms. Here, we developed a monocyte-incubation system for human cHSPC expansion, and achieved phenotypically and functional primitive CD34⁺ cHSPCs. The system produced a 100-fold increase in LIN^-CD45RA^-CD34⁺CD38^- HSPC frequency, and the expanded cells were capable of hematopoietic repopulation for at least 9 months in immunocompromised mice. Mapping landscape comparison of the incubated and non-incubated cHSPC culture was revealed at transcriptome and proteome level including single-cell sequencing and label-free quantitative mass spectrometry analysis respectively. An integrative analysis combined with factor-inhibitor/agonist tests demonstrated that the effects of monocyte-incubation on HSPC expansion might resulted from a lysosome acidification and HIF-1-siganl-dependent manner. Finally, we validated that monocyte-incubation also promoted the expansion of umbilical cord blood-derived HSPCs (UCB-HSPCs), and improved the repopulation capacity of UCB-HSPCs. Monocyte-incubated system on HSPCs will facilitate the clinical application of steady-state peripheral blood- or umbilical cord blood-based therapies.

No relevant conflicts of interest to declare.