Contributions
Abstract: EP761
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Life is stressful. Stressors like chronic infections or inflammation can alter both the composition and the function of hematopoietic niche cells, which affects blood cell formation.
Aims
We aim to identify cellular maintenance processes which ensure hematopoietic niche health upon stress.
Methods
For this purpose, we use mice in which the hematopoiesis maintenance factor Wnt5a is specifically deleted in Osterix+ mesenchymal progenitor and stem cells (MPSCs). These mice show normal steady state hematopoiesis, but progressive damage of hematopoietic stem cells upon stress.
Results
Mice lacking Wnt5a in MPSCs suffer from stress-related bone marrow failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small Rho GTPase Cdc42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. Strikingly, a short pharmacological intervention to attenuate elevated Cdc42 activation in vivo restored actin-anchored autophagy in MPSCs salvages hematopoiesis and as a consequence improves survival upon stress.
Conclusion
In summary, our study identifies Wnt5a, by affecting Cdc42 regulated actin stress fiber orientation and autophagy in niche cells, as a restriction factor for niche health upon stress. Our data further imply a critical role for autophagy in MPSCs for adequate support of hematopoiesis by the niche upon stress.
Keyword(s): Hematopoietic stem cell, Microenvironment, Survival, Wnt
Abstract: EP761
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Life is stressful. Stressors like chronic infections or inflammation can alter both the composition and the function of hematopoietic niche cells, which affects blood cell formation.
Aims
We aim to identify cellular maintenance processes which ensure hematopoietic niche health upon stress.
Methods
For this purpose, we use mice in which the hematopoiesis maintenance factor Wnt5a is specifically deleted in Osterix+ mesenchymal progenitor and stem cells (MPSCs). These mice show normal steady state hematopoiesis, but progressive damage of hematopoietic stem cells upon stress.
Results
Mice lacking Wnt5a in MPSCs suffer from stress-related bone marrow failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small Rho GTPase Cdc42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. Strikingly, a short pharmacological intervention to attenuate elevated Cdc42 activation in vivo restored actin-anchored autophagy in MPSCs salvages hematopoiesis and as a consequence improves survival upon stress.
Conclusion
In summary, our study identifies Wnt5a, by affecting Cdc42 regulated actin stress fiber orientation and autophagy in niche cells, as a restriction factor for niche health upon stress. Our data further imply a critical role for autophagy in MPSCs for adequate support of hematopoiesis by the niche upon stress.
Keyword(s): Hematopoietic stem cell, Microenvironment, Survival, Wnt