SMC2 and Condensin II Subunits Are Essential for the Development of Hematopoietic Stem and Progenitor Cells in Zebrafish

Abstract

Hematopoietic stem and progenitor cells (HSPCs) play a pivotal role in blood cell production, maintaining the health and homeostasis of individuals. Dysregulation of HSPC function can lead to blood-related diseases, including cancer. Despite its importance, our understanding of the genes and pathways underlying HSPC development and the associated pathological mechanisms remains limited. To elucidate these unknown mechanisms, we analyzed databases of patients with blood disorders and performed functional gene studies using zebrafish. We employed bioinformatics tools to explore three public databases focusing on patients with myelodysplastic syndrome (MDS) and related model studies. This analysis identified significant alterations in several genes, especially SMC2 and other condensin-related genes, in patients with MDS. To further investigate the role of Smc2 in hematopoiesis, we generated smc2 loss-of-function zebrafish mutants using CRISPR mutagenesis. Further analyses of the mutants revealed that smc2 depletion induced G2/M cell cycle arrest in HSPCs, leading to their maintenance and expansion failure. Notably, although the condensin II subunits (ncaph2, ncapg2, and ncapd3) were essential for HSPC maintenance, the condensin I subunits did not affect HSPC development. These findings emphasize the crucial role of condensin II in ensuring healthy hematopoiesis via promoting HSPC proliferation.