title: p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche.
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.
authors.affiliation: 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.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Amitava
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Nayak
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Pratt
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Wellendorf
authors.affiliation: Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, OH 45267, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hill
authors.affiliation: 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.
authors.forename: Marcus
authors.initials: M
authors.lastname: Watkins
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez-Nieto
authors.affiliation: Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: 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.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D054407:Chemokine CCL4 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D011506:Proteins / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054407:Chemokine CCL4; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C486326:Nbr1 protein, mouse; D011506:Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051550:I-kappa B Kinase