Ex vivo reprogramming of human hematopoietic stem cells is accompanied by increased transcripts of genes regulating metabolic integrity

The regenerative potential of human hematopoietic stem cells (HSCs) is functionally defined by their ability to provide life-long blood cell production and to repopulate myeloablated allogeneic transplant recipients. The expansion of HSC numbers is dependent not only on HSC divisions but also on a coordinated adaptation of HSCs to metabolic stress. These variables are especially critical during the ex vivo culture of HSCs with cytokine combinations, which frequently results in HSC exhaustion. We have previously reported that human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be efficiently reprogrammed ex vivo and that the number of phenotypic HSCs with long-term repopulation capacity is expanded in the presence of a combination of cytokines and an epigenetic modifier. Here, we present evidence that ex vivo HSC reprogramming and maintenance is accompanied by increased transcripts of genes regulating metabolic integrity, including SIRT1 and SIRT3. & COPY; 2023 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/)

Automated summary

The regenerative potential of human hematopoietic stem cells (HSCs) relies on their ability to provide life-long blood cell production and repopulate myeloablated allogeneic transplant recipients. The expansion of HSC numbers during ex vivo culture is influenced by both HSC divisions and their adaptation to metabolic stress. Reprogramming of human CD34+ hematopoietic stem and progenitor cells (HSPCs), combined with cytokines and an epigenetic modifier, leads to an increased number of phenotypic HSCs with long-term repopulation capacity. This process is accompanied by an upregulation of genes involved in metabolic integrity, including SIRT1 and SIRT3.