p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-kappa B/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche

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

来源：Cell Reports, 2014, 9(6): 2084-2097.

DOI：10.1016/j.celrep.2014.11.031

In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (M Phi s), 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-kappa B 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 %26quot;M Phi-Ob niche%26quot; is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-kappa B signaling repression, osteogenesis, and BM progenitor retention.

• 出版日期2014-12-24