Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration

Thomas H. Ambrosi, Antonio Scialdone, Antonia Graja, Sabrina Gohlke, Anne Marie Jank, Carla Bocian, Lena Woelk, Hua Fan, Darren W. Logan, Annette Schürmann, Luis Miguel Rodrigues Saraiva, Tim J. Schulz

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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. Ambrosi, Schulz, and colleagues define a stem cell-like population that gives rise to osteogenic progeny and promotes hematopoietic reconstitution. Aging and high-fat diet reprogram the mesenchymal lineage to preferentially give rise to adipogenic cells that impair reconstitution and bone fracture healing. Bone tissue repair is fully restored by DPP4 inhibition.

Original languageEnglish
JournalCell Stem Cell
DOIs
Publication statusAccepted/In press - 18 Apr 2016

Fingerprint

Bone Regeneration
Hematopoietic Stem Cells
Adipocytes
Obesity
Bone Marrow
Bone and Bones
High Fat Diet
Stem Cells
Dipeptidyl Peptidase 4
Fracture Healing
Bone Fractures
Hematopoiesis
Population
Regeneration
Peptide Hydrolases

Keywords

  • Adipogenesis
  • Adipogenic progenitors
  • Aging
  • Bone healing
  • Bone marrow adipose tissue
  • DPP4
  • Hematopoiesis
  • Mesenchymal stem cells
  • Obesity
  • Regeneration

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Ambrosi, T. H., Scialdone, A., Graja, A., Gohlke, S., Jank, A. M., Bocian, C., ... Schulz, T. J. (Accepted/In press). Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. Cell Stem Cell. https://doi.org/10.1016/j.stem.2017.02.009

Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. / Ambrosi, Thomas H.; Scialdone, Antonio; Graja, Antonia; Gohlke, Sabrina; Jank, Anne Marie; Bocian, Carla; Woelk, Lena; Fan, Hua; Logan, Darren W.; Schürmann, Annette; Rodrigues Saraiva, Luis Miguel; Schulz, Tim J.

In: Cell Stem Cell, 18.04.2016.

Research output: Contribution to journalArticle

Ambrosi, TH, Scialdone, A, Graja, A, Gohlke, S, Jank, AM, Bocian, C, Woelk, L, Fan, H, Logan, DW, Schürmann, A, Rodrigues Saraiva, LM & Schulz, TJ 2016, 'Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration', Cell Stem Cell. https://doi.org/10.1016/j.stem.2017.02.009
Ambrosi, Thomas H. ; Scialdone, Antonio ; Graja, Antonia ; Gohlke, Sabrina ; Jank, Anne Marie ; Bocian, Carla ; Woelk, Lena ; Fan, Hua ; Logan, Darren W. ; Schürmann, Annette ; Rodrigues Saraiva, Luis Miguel ; Schulz, Tim J. / Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. In: Cell Stem Cell. 2016.
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abstract = "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. Ambrosi, Schulz, and colleagues define a stem cell-like population that gives rise to osteogenic progeny and promotes hematopoietic reconstitution. Aging and high-fat diet reprogram the mesenchymal lineage to preferentially give rise to adipogenic cells that impair reconstitution and bone fracture healing. Bone tissue repair is fully restored by DPP4 inhibition.",
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