Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress.

The cellular mechanisms required to ensure homeostasis of the hematopoietic niche and the ability of this niche to support hematopoiesis upon stress remain elusive. We here identify Wnt5a in Osterix+ mesenchymal progenitor and stem cells (MSPCs) as a critical factor for niche-dependent hematopoiesis. Mice lacking Wnt5a in MSPCs suffer from stress-related bone marrow (BM) failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small GTPase CDC42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. In MSPCs from patients from BM failure states which share features of peripheral cytopenia and hypocellular BM, we find similar defects in actin stress fiber orientation, reduced and incorrect colocalization of autophagosomes and lysosomes, and CDC42 activation. Strikingly, a short pharmacological intervention to attenuate elevated CDC42 activation in vivo in mice prevents defective actin-anchored autophagy in MSPCs, salvages hematopoiesis and protects against lethal cytopenia upon stress. In summary, our study identifies Wnt5a as a restriction factor for niche homeostasis by affecting CDC42-regulated actin stress-fiber orientation and autophagy upon stress. Our data further imply a critical role for autophagy in MSPCs for adequate support of hematopoiesis by the niche upon stress and in human diseases characterized by peripheral cytopenias and hypocellular BM.

Treatment of Scaphoid Nonunion: Radiologic Outcome of 286 Patients in 10 Years.

Background: We analyzed the radiologic outcome of different treatment options for scaphoid nonunion. The results were compared with literature, and a treatment algorithm was proposed. Methods: On the basis of a retrospective case-control study, 286 patients suffering from scaphoid nonunion were treated over a 10-year period. Patients were grouped depending on the location of the nonunion: proximal (n = 126), middle (n = 130), or distal (n = 30) third. In the presence of an avascular proximal fragment or after prior unsuccessful operation, interposition of a vascularized pedicled bone graft from the distal radius was performed (n = 82). Scaphoid healing was detected by conventional radiography and computed tomography. Results: Excellent healing rates of 96.3% were obtained for middle and distal third scaphoid nonunions by conventional iliac crest bone grafting (n = 137). Furthermore, we achieved healing rates of 91.3% for persistent nonunions using a palmar vascularized bone graft from the distal radius after prior unsuccessful operation (n = 23). When using a dorsal vascularized bone graft from the distal radius, scaphoid consolidation was reached in 81.1% for avascular proximal fragments (n = 59). Conclusions: Applying a sophisticated treatment algorithm, the prognosis of scaphoid nonunion is very good.