P62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-κB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche

Kyung Hee Chang, Amitava Sengupta, Ramesh C. Nayak, Angeles Duran, Sang Jun Lee, Ronald G. Pratt, Ashley M. Wellendorf, Sarah E. Hill, Marcus Watkins, Daniel Gonzalez-Nieto, Bruce J. Aronow, Daniel T. Starczynowski, Roberto Civitelli, Maria T. Diaz-Meco, Jorge Moscat, Jose A. Cancelas

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MΦs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has beendemonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-κB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MΦ-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-κB signaling repression, osteogenesis, and BM progenitor retention.

Original languageEnglish
Pages (from-to)2084-2097
Number of pages14
JournalCell Reports
Volume9
Issue number6
DOIs
StatePublished - Dec 24 2014

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