TY - JOUR
T1 - Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation
AU - Landspersky, Theresa
AU - Stein, Merle
AU - Saçma, Mehmet
AU - Geuder, Johanna
AU - Braitsch, Krischan
AU - Rivière, Jennifer
AU - Hettler, Franziska
AU - Marquez, Sandra Romero
AU - Vilne, Baiba
AU - Hameister, Erik
AU - Richter, Daniel
AU - Schönhals, Emely
AU - Tuckermann, Jan
AU - Verbeek, Mareike
AU - Herhaus, Peter
AU - Hecker, Judith S.
AU - Bassermann, Florian
AU - Götze, Katharina S.
AU - Enard, Wolfgang
AU - Geiger, Hartmut
AU - Oostendorp, Robert A.J.
AU - Schreck, Christina
N1 - Publisher Copyright:
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
PY - 2024/10/22
Y1 - 2024/10/22
N2 - 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), which include skeletal progenitors, from mice undergoing HSCT. Such MSPCs showed reduced fibroblastic colony-forming units frequency, increased DNA damage, and enhanced occurrence of cellular senescence, whereas there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small Rho guanosine triphosphate hydrolase 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.
AB - 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), which include skeletal progenitors, from mice undergoing HSCT. Such MSPCs showed reduced fibroblastic colony-forming units frequency, increased DNA damage, and enhanced occurrence of cellular senescence, whereas there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small Rho guanosine triphosphate hydrolase 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.
UR - http://www.scopus.com/inward/record.url?scp=85208258079&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2024012879
DO - 10.1182/bloodadvances.2024012879
M3 - Article
C2 - 39159429
AN - SCOPUS:85208258079
SN - 2473-9529
VL - 8
SP - 5400
EP - 5414
JO - Blood advances
JF - Blood advances
IS - 20
ER -