Attenuation of CDC42 activity aims to boost MSPC quality after HSCT
Landspersky T, Stein M, Sacma M, et al. Targeting CDC42 Reduces Skeletal Degeneration After Hematopoietic Stem Cell Transplantation. Blood Advances. 2024; (doi: 10.1182/bloodadvances.2024012879).
Researchers say pharmacological attenuation of CDC42, a protein coding gene, effectively addresses bone-related problems caused by cytotoxic conditioning required before hematopoietic stem cell transplantation (HSCT). In their observations of mice that underwent HSCT, investigators noted reduced bone volume in the animals. Additionally, examination of mesenchymal stem and progenitor cells (MSPCs) that included skeletal progenitors from mice undergoing HSCT revealed unusual levels of DNA harm and cellular senescence. MSPC dysfunction was linked to increased activation of CDC42, which regulates F-actin fiber alignment, mitochondrial function, and mitophagy in those cells. However, a pharmacological intervention introduced in vitro curbed CDC42 activation, reversing the effects of elevated activation: disorganized F-actin distribution, mitochondrial abnormalities, and impaired mitophagy. Restored MSPC quality following in vivo treatment in mice undergoing HSCT correlated with better bone volume and increased trabecular bone thickness. The patterns seen in mice were also observed in human HSCT patients.