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
Affiliations
Kyung Hee Chang
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Amitava Sengupta
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Ramesh C. Nayak
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Angeles Duran
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Sang Jun Lee
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Ronald G. Pratt
Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Ashley M. Wellendorf
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Sarah E. Hill
Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, OH 45267, USA
Marcus Watkins
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
Daniel Gonzalez-Nieto
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Bruce J. Aronow
Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Daniel T. Starczynowski
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Roberto Civitelli
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
Maria T. Diaz-Meco
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Jorge Moscat
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Jose A. Cancelas
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
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.
