Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation
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.
Authors
- Peter Herhaus
- Jan Tuckermann (ORCID: https://orcid.org/0000-0003-3691-275X)
- Hartmut Geiger (ORCID: https://orcid.org/0000-0002-5794-5430)
- Wolfgang Enard (ORCID: https://orcid.org/0000-0002-4056-0550)
- Krischan Braitsch (ORCID: https://orcid.org/0000-0003-4028-5357)
- Robert A.J. Oostendorp (ORCID: https://orcid.org/0000-0002-4947-0412)
- Merle Stein (ORCID: https://orcid.org/0000-0003-2926-6219)
- Christina Schreck (ORCID: https://orcid.org/0000-0002-0377-1412)
- Sandra Romero Marquez
- Jennifer Rivière (ORCID: https://orcid.org/0000-0002-4680-2071)
- Franziska Hettler
- Emely Schönhals
- Daniel Richter (ORCID: https://orcid.org/0000-0003-1681-727X)
- Florian C. Bassermann (ORCID: https://orcid.org/0000-0003-4435-2609)
- Judith S. Hecker (ORCID: https://orcid.org/0000-0002-1531-0517)
- Katharina S. S. Götze (ORCID: https://orcid.org/0000-0002-6276-8002)
- Erik Hameister (ORCID: https://orcid.org/0000-0002-7985-4767)
- Mareike Verbeek
- Johanna Geuder (ORCID: https://orcid.org/0000-0002-5070-3404)
- Mehmet Saçma (ORCID: https://orcid.org/0000-0003-3450-674X)
- Baiba Vilne (ORCID: https://orcid.org/0000-0002-1084-7067)
- Theresa Landspersky (ORCID: https://orcid.org/0009-0001-7323-5113)
Institutions
- Universität Ulm (DE)
- TUM Klinikum (DE)
- Riga Stradiņš University (LV)
- Max Planck Institute of Neurobiology (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Blood Advances
- Published
- 2024-08-19
- DOI
- https://doi.org/10.1182/bloodadvances.2024012879
- Citations
- 3
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 1.36
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Technische Universität München