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

Theresa Landspersky, Mehmet Saçma, Jennifer Rivière, Judith S. Hecker, Franziska Hettler, Erik Hameister, Katharina Brandstetter, Rouzanna Istvánffy, Sandra Romero Marquez, Romina Ludwig, Marilena Götz, Michèle Buck, Martin Wolf, Matthias Schiemann, Jürgen Ruland, Dirk Strunk, Akiko Shimamura, Kasiani Myers, Terry P. Yamaguchi, Matthias KieslingerHeinrich Leonhardt, Florian Bassermann, Katharina S. Götze, Hartmut Geiger, Christina Schreck, Robert A.J. Oostendorp

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)690-703
Number of pages14
JournalBlood
Volume139
Issue number5
DOIs
StatePublished - 3 Feb 2022
Externally publishedYes

Fingerprint

Dive into the research topics of 'Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress'. Together they form a unique fingerprint.

Cite this