Abstract
AbstractThe 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.
Highlights
Declining niche homeostasis is an underlying defect contributing to aging and the development of aging-related malignant hematopoietic diseases.[1]
In O5AD/D mice, Wnt5a is deleted in mesenchymal stem and progenitor cells (MSPCs) and osteoblastic cells (OBCs), but is still expressed by CD311 endothelial cells (ECs), and is even elevated in LT-hematopoietic stem cells (HSCs)
Our present study shows that autophagy controlled by CDC42 is a critical factor for maintaining hematopoietic support by bone marrow (BM) niche cells during stress
Summary
Declining niche homeostasis is an underlying defect contributing to aging and the development of aging-related malignant hematopoietic diseases.[1]. It is important to understand the mechanisms governing cellular health of niche cells. Efforts studying HSC dysfunction have shown that interconnected cellular maintenance mechanisms, such as mitochondrial quality control,[4] macroautophagy (autophagy),[5] and lysosomal lysis[6,7] are critical for safeguarding HSC division and function. Dysfunctional HSCs further show altered noncanonical WNT5A-CDC42 signaling with a loss of polarized cytoskeletal components,[8,9,10] associated with activation of the small GTPase CDC42 in both stem cells[8,9] and mature cells.[10] Since the cytoskeleton guides autophagosome formation and lysosomal fusion,[11] as well as mitochondrial fission,[12] correct assembly and orientation of the cytoskeleton is pivotal for cellular maintenance
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