TY - JOUR
T1 - P62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-κB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche
AU - Chang, Kyung Hee
AU - Sengupta, Amitava
AU - Nayak, Ramesh C.
AU - Duran, Angeles
AU - Lee, Sang Jun
AU - Pratt, Ronald G.
AU - Wellendorf, Ashley M.
AU - Hill, Sarah E.
AU - Watkins, Marcus
AU - Gonzalez-Nieto, Daniel
AU - Aronow, Bruce J.
AU - Starczynowski, Daniel T.
AU - Civitelli, Roberto
AU - Diaz-Meco, Maria T.
AU - Moscat, Jorge
AU - Cancelas, Jose A.
N1 - Funding Information:
This study was supported by the Heimlich Institute of Cincinnati, the Department of Defense (10580355), the NIH (R01-HL087159 and HL087159S1), and funds from Hoxworth Blood Center and Cincinnati Children’s Hospital Medical Center (to J.A.C.): R01-CA132847 and R01-CA170225 (to J.M.); R01-CA134530 (to M.T.D.-M.); and R01-AR041255, R01-AR055913, and R01-AR056678 (to R.C.). K.H.C is a National Blood Foundation research funding awardee. A.S. was an awardee of The International Lady Tata Memorial Trust, London and acknowledges funding from CSIR, DST-SERB (SB/SO/HS-053/2013), and Ramalingaswami Fellowship (BT/RLF/RE-ENTRY/06/2010), Department of Biotechnology, India. We thank Cincinnati Children’s Research Foundation Mouse, Flow Cytometry, and Immunobiology Cores for services, supported by the Center of Excellence in Molecular Hematology (P30 DK090971). We also thank Yi Zheng and Hartmut Geiger for critical reading of the manuscript and Ms. Margaret O’Leary for editorial revision.
Publisher Copyright:
© 2014 The Authors.
PY - 2014/12/24
Y1 - 2014/12/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84919847558&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.11.031
DO - 10.1016/j.celrep.2014.11.031
M3 - Article
C2 - 25533346
AN - SCOPUS:84919847558
SN - 2211-1247
VL - 9
SP - 2084
EP - 2097
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -