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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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1380-1394
Number of pages15
JournalDiabetes
Volume67
Issue number7
Early online date22 Jun 2018
DOIs
DateAccepted/In press - 19 Apr 2018
DateE-pub ahead of print - 22 Jun 2018
DatePublished (current) - 1 Jul 2018

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.

    Structured keywords

  • Centre for Surgical Research

    Research areas

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

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    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via the American Diabetes Association at https://doi.org/10.2337/db18-0044 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 270 KB, PDF document

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