Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration.
Aging and obesity induce ectopic adipocyte accumulation in bone marrow cavities. This process is thought to impair osteogenic and hematopoietic regeneration. Here we specify the cellular identities of the adipogenic and osteogenic lineages of the bone. While aging impairs the osteogenic lineage, high-fat diet feeding activates expansion of the adipogenic lineage, an effect that is significantly enhanced in aged animals. We further describe a mesenchymal sub-population with stem cell-like characteristics that gives rise to both lineages and, at the same time, acts as a principal component of the hematopoietic niche by promoting competitive repopulation following lethal irradiation. Conversely, bone-resident cells committed to the adipocytic lineage inhibit hematopoiesis and bone healing, potentially by producing excessive amounts of Dipeptidyl peptidase-4, a protease that is a target of diabetes therapies. These studies delineate the molecular identity of the bone-resident adipocytic lineage, and they establish its involvement in age-dependent dysfunction of bone and hematopoietic regeneration.
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Thomas H
TH
Ambrosi
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton-Cambridge CB10 1SA, UK; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Genome Campus, Hinxton-Cambridge CB10 1SD, UK.
Antonio
A
Scialdone
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Antonia
A
Graja
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Sabrina
S
Gohlke
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Anne-Marie
AM
Jank
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Carla
C
Bocian
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
Lena
L
Woelk
Charité Universitätsmedizin, Berlin 10117, Germany.
Hua
H
Fan
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton-Cambridge CB10 1SA, UK; Monell Chemical Senses Center, Philadelphia, PA 19104, USA.
Darren W
DW
Logan
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
Annette
A
Schürmann
Sidra Medical and Research Center, Qatar Foundation, P.O. Box 26999, Doha, Qatar.
Luis R
LR
Saraiva
German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany. Electronic address: tim.schulz@dife.de.
Tim J
TJ
Schulz
D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000201:enzymology* / Q000473:pathology; D001861:Bone Regeneration; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D018819:Dipeptidyl Peptidase 4
DPP4; adipogenesis; adipogenic progenitors; aging; bone healing; bone marrow adipose tissue; hematopoiesis; mesenchymal stem cells; obesity; regeneration