Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.
Theresa LandsperskyMerle SteinMehmet SaçmaJohanna GeuderKrischan BraitschJennifer RivièreFranziska HettlerSandra Romero MarquezBaiba VilneErik HameisterDaniel RichterEmely SchönhalsJan P TuckermannMareike VerbeekPeter HerhausJudith S HeckerFlorian BassermannKatharina S GötzeWolfgang EnardHartmut GeigerRobert A J OostendorpChristina SchreckPublished in: Blood advances (2024)
Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs) that include skeletal progenitors from mice undergoing HSCT. Such MSPCs showed reduced CFU-F frequency, increased DNA damage and enhanced occurrence of cellular senescence, while there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small RhoGTPAse Cdc42, disorganized F-actin distribution, mitochondrial abnormalities and impaired mitophagy in MSPCs. Changes and defects similar to those in mice were also observed in MSPCs from humans undergoing HSCT. A pharmacological treatment that attenuated the elevated activation of CDC42 restored F-actin fiber alignment, mitochondrial function, and mitophagy in MSPCs in vitro. Finally, targeting CDC42 activity in vivo in animals undergoing transplants improved MSPC quality to increase both bone volume and trabecular bone thickness. Our study shows that attenuation of CDC42 activity is sufficient to attenuate reduced function of MSPCs in a BM transplant setting.
Keyphrases
- bone mineral density
- dna damage
- cell cycle
- hematopoietic stem cell
- postmenopausal women
- soft tissue
- bone loss
- stem cells
- high fat diet induced
- cancer therapy
- bone marrow
- bone regeneration
- endothelial cells
- risk factors
- metabolic syndrome
- optical coherence tomography
- cell proliferation
- type diabetes
- drug delivery
- insulin resistance
- skeletal muscle