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Cell Rep. 2014 Dec 24;9(6):2084-97. doi: 10.1016/j.celrep.2014.11.031. Epub 2014 Dec 18.

p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche.

Author information

1
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, OH 45267, USA.
2
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Stem Cell and Leukemia Lab, Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja SC Mullick Road, Kolkata 700032, West Bengal, India.
3
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
4
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
5
Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, OH 45267, USA.
7
Division of Bone and Mineral Diseases, Departments of Internal Medicine and Cell Biology and Physiology, Washington University School of Medicine, One Brookings Drive, St. Louis, MO 63110, USA.
8
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Bioengineering and Telemedicine Group, Center for Biomedical Technology, Universidad-Politécnica de Madrid, Pozuelo de Alarcon 28223, Spain.
9
Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
10
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, OH 45267, USA. Electronic address: jose.cancelas@uc.edu.

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 been demonstrated, 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.

PMID:
25533346
PMCID:
PMC4277497
DOI:
10.1016/j.celrep.2014.11.031
[Indexed for MEDLINE]
Free PMC Article

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