MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes

David Ferland-McCollough, Davide Maselli, Gaia Spinetti, Maria Sambataro, Niall Sullivan, Ashley Blom, Paolo Madeddu

Research output: Contribution to journalArticle (Academic Journal)

14 Citations (Scopus)
162 Downloads (Pure)

Abstract

Fat accumulates in bone marrow (BM) of patients with diabetes. In this study, we investigated the mechanisms and consequences of this phenomenon. BM mesenchymal stromal cells (BM-MSCs) from patients with type 2 diabetes (T2D) constitutively express adipogenic markers and robustly differentiate into adipocytes (ADs) upon in vitro induction as compared with BM-MSCs from subjects without diabetes. Moreover, BM-ADs from subjects with T2D (T2D BM-ADs) paracrinally stimulate a transcriptional adipogenic program in BM-MSCs. Antagonism of MCP-1, a chemokine pivotally expressed in T2D BM-ADs, prevented the T2D BM-AD secretome from converting BM-MSCs into ADs. Mechanistic validation of human data was next performed in an obese T2D mouse model. Systemic antagonism of MCP-1 improved metabolic control, reduced BM fat, and increased osteocyte density. It also indirectly re-established the abundance of long-term versus short-term hematopoietic stem cells. We reveal a diabetic feedback loop in which 1) BM-MSCs are constitutively inclined to make ADs, and 2) mature BM-ADs, via secreted MCP-1, relentlessly fuel BM-MSC determination into new fat. Pharmacological inhibition of MCP-1 signaling can contrast this vicious cycle, restoring, at least in part, the balance between adipogenesis and hematopoiesis in BM from subjects with T2D.
Original languageEnglish
Pages (from-to)1380-1394
Number of pages15
JournalDiabetes
Volume67
Issue number7
Early online date22 Jun 2018
DOIs
Publication statusPublished - 1 Jul 2018

Structured keywords

  • Centre for Surgical Research

Keywords

  • bone marrow
  • adipocytes
  • stem cells
  • Hematopoietic Stem Cells
  • Mesenchymal stem cells
  • Diabetes
  • OBESITY
  • MCP-1

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